Non-small cell lung cancer

Page editor		Section editor
	Amit Kulkarni, MBBS University of Minnesota Minneapolis, MN AmitKulkarniMD		Travis Osterman, DO, MS Vanderbilt University Nashville, TN TravisOsterman LinkedIn

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There are several related dedicated pages:

• CNS carcinoma
• NSCLC, ALK-positive
• NSCLC, BRAF-mutated
• NSCLC, EGFR-mutated
• NSCLC, KRAS-mutated
• NSCLC, MET-mutated
• NSCLC, RET-positive
• NSCLC, ROS1-positive

115 regimens on this page 229 variants on this page

Guidelines

ASCO

• 2020: Schneider et al. Lung Cancer Surveillance After Definitive Curative-Intent Therapy: ASCO Guideline
• 2017: Hanna et al. Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update PubMed

Older

• 2015: Masters et al. Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update

ASCO/CCO

Current

• 2017: Kris et al. Adjuvant systemic therapy and adjuvant radiation therapy for stage I to IIIA completely resected non–small-cell lung cancers: American Society of Clinical Oncology/Cancer Care Ontario clinical practice guideline update PubMed

Older

• 2007: Pisters et al. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline PubMed

ESMO

• 2018: Planchard et al. Metastatic Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
• 2016: Novello et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed
• 2015: Eberhardt et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. PubMed

Older

• 2014: Vansteenkiste et al. 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up. PubMed
• 2014: Besse et al. 2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease. PubMed
• 2014: Kerr et al. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. PubMed

NCCN

• NCCN Guidelines - Non-Small Cell Lung Cancer

Neoadjuvant therapy

Cisplatin & Docetaxel

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Pless et al. 2015 (SAKK 16/00)	Phase III (C)	Cisplatin & Docetaxel, then RT	Did not meet primary endpoint of EFS

This trial included patients with Stage IIIA or N2 NSCLC.

Chemotherapy

• Cisplatin (Platinol)
• Docetaxel (Taxotere)

Subsequent treatment

• Complete resection

References

1. SAKK 16/00: Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, Gerard MA, Xyrafas A, Früh M, Cathomas R, Zippelius A, Roth A, Bijelovic M, Ochsenbein A, Meier UR, Mamot C, Rauch D, Gautschi O, Betticher DC, Mirimanoff RO, Peters S; SAKK Lung Cancer Project Group. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015 Sep 12;386(9998):1049-56. Epub 2015 Aug 11. Erratum in: Lancet. 2015 Sep 12;386(9998):1040. link to original article PubMed

Cisplatin & Gemcitabine

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Scagliotti et al. 2011 (CHEST)	Phase III (E-esc)	Surgery alone	Seems to have superior OS

This trial included patients with Stage IB to IIIA NSCLC.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1, given at least 4 hours after gemcitabine
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection, 2 to 6 weeks after last dose of chemotherapy

References

1. CHEST: Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L, Facciolo F, Orlowski TM, Maiorino L, Hetzel M, Leschinger M, Visseren-Grul C, Torri V. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol. 2012 Jan 10;30(2):172-8. Epub 2011 Nov 28. link to original article contains verified protocol PubMed

Adjuvant therapy

Carboplatin & Paclitaxel

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Strauss et al. 2008 (CALGB 9633)	Phase III (E-esc)	Observation	Did not meet primary endpoint of OS

Preceding treatment

• Lobectomy or pneumonectomy, within 4 to 8 weeks

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 45 to 60 minutes once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

21-day cycle for 4 cycles

References

1. CALGB 9633: Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51. Epub 2008 Sep 22. link to original article contains protocol link to PMC article PubMed

Cisplatin & Docetaxel

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DC: Docetaxel & Cisplatin

Regimen

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Barlesi et al. 2015	Phase III (E-switch-ic)	Cisplatin & Gemcitabine		Did not meet primary endpoint of QoL
Wakelee et al. 2017 (ECOG-ACRIN E1505)	Phase III (C)	1. Cisplatin, Docetaxel, Bevacizumab 2. Cisplatin, Gemcitabine, Bevacizumab 3. Cisplatin, Pemetrexed, Bevacizumab 4. Cisplatin, Vinorelbine, Bevacizumab	Did not meet primary endpoint of OS

Preceding treatment

• Barlesi et al. 2015: Complete R0 resection, within 8 weeks
• ECOG-ACRIN E1505: Complete surgical resection, within 6 to 12 weeks

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for 3 cycles (Barlesi et al. 2015) or 4 cycles (ECOG-ACRIN E1505)

References

1. Barlesi F, Chouaid C, Crequit J, Le Caer H, Pujol JL, Legodec J, Vergnenegre A, Le Treut J, Fabre-Guillevin E, Loundou A, Auquier P, Simeoni MC, Thomas PA. A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective. Interact Cardiovasc Thorac Surg. 2015 Jun;20(6):783-90. Epub 2015 Mar 11. link to original article contains verified protocol PubMed
2. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains protocol PubMed

Cisplatin & Etoposide

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Arriagada et al. 2004 (IALT)	Phase III (E-esc)	Observation	Seems to have superior OS

Preceding treatment

• Complete surgical resection, within 60 days

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

28-day cycle for 4 cycles

References

1. IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed
   1. Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed

Cisplatin & Gemcitabine

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GC: Gemcitabine & Cisplatin

Regimen variant #1, 75/1200 x 4

Study	Evidence	Comparator	Comparative Efficacy
Wakelee et al. 2017 (ECOG-ACRIN E1505)	Phase III (C)	1. Cisplatin, Docetaxel, Bevacizumab 2. Cisplatin, Gemcitabine, Bevacizumab 3. Cisplatin, Pemetrexed, Bevacizumab 4. Cisplatin, Vinorelbine, Bevacizumab	Did not meet primary endpoint of OS

Preceding treatment

• Complete surgical resection, within 6 to 12 weeks

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Regimen variant #2, 75/1250 x 3

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Barlesi et al. 2015	Phase III (E-switch-ic)	Cisplatin & Docetaxel		Did not meet primary endpoint of QoL

This trial included patients with Stage IB–III NSCLC.

Preceding treatment

• Complete R0 resection, within 8 weeks

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 3 cycles

Regimen variant #3, 75/1250 x 4

Study	Evidence	Comparator	Comparative Efficacy
Groen et al. 2019 (NVALT-8)	Phase III (C)	GC & Nadroparin	Did not meet primary endpoint of RFS

This regimen was intended for patients with squamous histology.

Preceding treatment

• Complete R0 resection, within 6 weeks

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

References

1. Barlesi F, Chouaid C, Crequit J, Le Caer H, Pujol JL, Legodec J, Vergnenegre A, Le Treut J, Fabre-Guillevin E, Loundou A, Auquier P, Simeoni MC, Thomas PA. A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective. Interact Cardiovasc Thorac Surg. 2015 Jun;20(6):783-90. Epub 2015 Mar 11. link to original article contains verified protocol PubMed
2. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains protocol PubMed
3. NVALT-8: Groen HJM, van der Heijden EHFM, Klinkenberg TJ, Biesma B, Aerts J, Verhagen A, Kloosterziel C, Pieterman R, van den Borne B, Smit HJM, Hoekstra O, Schramel FMNH, van der Noort V, van Tinteren H, Smit EF, Dingemans AC; NVALT Study Group. Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study. Br J Cancer. 2019 Aug;121(5):372-377. Epub 2019 Jul 24. link to original article contains verified protocol PubMed

Cisplatin & Pemetrexed

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CPx: Cisplatin & Pemetrexed

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Kreuter et al. 2013 (TREAT)	2006-2009	Randomized Phase II (E-switch-ic)	Cisplatin & Vinorelbine	Did not meet secondary endpoint of OS (*)	Superior clinical feasibility rate
Wakelee et al. 2017 (ECOG-ACRIN E1505)		Phase III (C)	1. Cisplatin, Docetaxel, Bevacizumab 2. Cisplatin, Gemcitabine, Bevacizumab 3. Cisplatin, Pemetrexed, Bevacizumab 4. Cisplatin, Vinorelbine, Bevacizumab	Did not meet primary endpoint of OS
Groen et al. 2019 (NVALT-8)		Phase III (C)	CPx & Nadroparin	Did not meet primary endpoint of RFS

In TREAT, this treatment was intended for pathologically confirmed NSCLC stages (according to the TNM staging system version 6) IB, IIA, IIB or T3N1. Efficacy reported for TREAT is based on the 2016 update.

Preceding treatment

• TREAT & NVALT-8: Complete surgical resection, within 4 to 6 weeks
• ECOG-ACRIN E1505: Complete surgical resection, within 6 to 12 weeks

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

21-day cycle for 4 cycles

References

1. TREAT: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Zuna I, Griesinger F, Thomas M; TREAT investigators; AIO Lung Cancer Study Group; LLCG Leuven Lung Cancer Group. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol. 2013 Apr;24(4):986-92. Epub 2012 Nov 15. link to original article contains verified protocol PubMed NCT00349089
   1. Update: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt WE, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Griesinger F, Thomas M; TREAT investigators. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol. 2016 Jan;11(1):85-93. link to original article PubMed
2. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains protocol PubMed
3. NVALT-8: Groen HJM, van der Heijden EHFM, Klinkenberg TJ, Biesma B, Aerts J, Verhagen A, Kloosterziel C, Pieterman R, van den Borne B, Smit HJM, Hoekstra O, Schramel FMNH, van der Noort V, van Tinteren H, Smit EF, Dingemans AC; NVALT Study Group. Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study. Br J Cancer. 2019 Aug;121(5):372-377. Epub 2019 Jul 24. link to original article contains verified protocol PubMed

Cisplatin & Vinblastine

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Arriagada et al. 2004 (IALT)	Phase III (E-esc)	Observation	Seems to have superior OS

Note: Exact days for parts of the regimen were not specified by Arriagada et al. 2004. This vinblastine schedule is extrapolated from regimen information in Table 1 in which vinblastine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.

Preceding treatment

• Complete surgical resection, within 60 days

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once per day on days 1, 22, 43, 64
• Vinblastine (Velban) 4 mg/m² IV once per day on days 1, 8, 15, 22, 29, 43, 57

12-week course

References

1. IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed
   1. Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed

Cisplatin & Vindesine

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Arriagada et al. 2004 (IALT)	Phase III (E-esc)	Observation	Seems to have superior OS

Note: Exact days for parts of the regimen were not specified by Arriagada et al. 2004. This vindesine schedule is extrapolated from regimen information in Table 1 in which vindesine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.

Preceding treatment

• Complete surgical resection, within 60 days

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once per day on days 1, 22, 43, 64
• Vindesine (Eldisine) 3 mg/m² IV once per day on days 1, 8, 15, 22, 29, 43, 57

12-week course

References

1. IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed
   1. Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed

Cisplatin & Vinorelbine

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CVb: Cisplatin & Vinorelbine

Regimen variant #1, cisplatin 50 mg/m², 2 weeks out of 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Winton et al. 2005 (JBR.10)		Phase III (E-esc)	Observation	Seems to have superior OS
Kreuter et al. 2013 (TREAT)	2006-2009	Randomized Phase II (C)	Cisplatin & Pemetrexed	Did not meet secondary endpoint of OS (*)	Superior clinical feasibility rate

Note: Reported efficacy for TREAT is based on the 2016 update.

Preceding treatment

• JBR.10: Complete surgical resection, within 6 weeks
• TREAT: Complete surgical resection, within 4 to 6 weeks

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for 4 cycles

Regimen variant #2, cisplatin 75 mg/m², q3wk

Study	Evidence	Comparator	Comparative Efficacy
Wakelee et al. 2017 (ECOG-ACRIN E1505)	Phase III (C)	1. Cisplatin, Docetaxel, Bevacizumab 2. Cisplatin, Gemcitabine, Bevacizumab 3. Cisplatin, Pemetrexed, Bevacizumab 4. Cisplatin, Vinorelbine, Bevacizumab	Did not meet primary endpoint of OS

Preceding treatment

• Complete surgical resection, within 6 to 12 weeks

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Regimen variant #3, cisplatin 100 mg/m², q4wk

Study	Evidence	Comparator	Comparative Efficacy
Arriagada et al. 2004 (IALT)	Phase III (E-esc)	Observation	Seems to have superior OS
Douillard et al. 2006 (ANITA)	Phase III (E-esc)	Observation	Seems to have superior OS

Preceding treatment

• IALT: Complete surgical resection, within 60 days
• ANITA: Complete surgical resection

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for 4 cycles

References

1. IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed
   1. Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed
2. JBR.10: Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med. 2005 Jun 23;352(25):2589-97. link to original article PubMed
   1. Update: Butts CA, Ding K, Seymour L, Twumasi-Ankrah P, Graham B, Gandara D, Johnson DH, Kesler KA, Green M, Vincent M, Cormier Y, Goss G, Findlay B, Johnston M, Tsao MS, Shepherd FA. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol. 2010 Jan 1;28(1):29-34. Epub 2009 Nov 23. link to original article link to PMC article PubMed
3. ANITA: Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Rodrigues Pereira J, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006 Sep;7(9):719-27. link to original article PubMed
4. TREAT: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Zuna I, Griesinger F, Thomas M; TREAT investigators; AIO Lung Cancer Study Group; LLCG. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol. 2013 Apr;24(4):986-92. Epub 2012 Nov 15. link to original article contains verified protocol PubMed NCT00349089
   1. Update: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt WE, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Griesinger F, Thomas M; TREAT investigators. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol. 2016 Jan;11(1):85-93. link to original article PubMed
5. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains protocol PubMed

Tegafur & Uracil

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Kato et al. 2004	Phase III (E-esc)	Observation	Seems to have superior OS

Preceding treatment

• Surgery

Chemotherapy

• Tegafur and uracil (UFT) 250 mg PO once per day

2-year course

References

1. Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M; Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med. 2004 Apr 22;350(17):1713-21. link to original article contains protocol PubMed

Induction chemotherapy for locally advanced disease

Carboplatin & Paclitaxel

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PC: Paclitaxel & Carboplatin

Regimen variant #1, 6/200

Study	Evidence	Comparator	Comparative Efficacy
Belani et al. 2005 (LAMP)	Phase II
Huber et al. 2006 (CTRT99/97)	Non-randomized portion of RCT
Vokes et al. 2007 (CALGB 39801)	Phase III (E-esc)	No induction	Did not meet primary endpoint of OS50%

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for 2 cycles

Subsequent treatment

• LAMP: RT x 63 Gy
• CTRT99/97: Paclitaxel & RT versus RT
• CALGB 39801: Carboplatin, Paclitaxel, RT

Regimen variant #2, 6/225

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hoang et al. 2012 (ECOG 3598)	2000-2006	Phase III (C)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 225 mg/m² IV once on day 1

21-day cycle for 2 cycles

Subsequent treatment

• Carboplatin, Paclitaxel, RT

References

1. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. link to original article contains protocol PubMed
2. CTRT99/97: Huber RM, Flentje M, Schmidt M, Pöllinger B, Gosse H, Willner J, Ulm K; Bronchial Carcinoma Therapy Group. Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group. J Clin Oncol. 2006 Sep 20;24(27):4397-404. link to original article contains protocol PubMed
3. CALGB 39801: Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson DM, Akerley W, Green MR; CALGB. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007 Apr 2. link to original article contains protocol PubMed
4. ECOG 3598: Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. link to original article link to PMC article contains verified protocol PubMed

Cisplatin & Vinblastine

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Dillman et al. 1990 (CALGB 8433)	Phase III (E-esc)	No induction	Seems to have superior OS (*)
Sause et al. 1995 (RTOG 88-08)	Phase III (E-esc)	No induction	Seems to have superior OS
Curran et al. 2011 (RTOG 9410)	Phase III (C)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Reported efficacy for CALGB 8433 is based on the 1996 update.

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once per day on days 1 & 29
• Vinblastine (Velban) 5 mg/m² IV once per day on days 1, 8, 15, 22, 29

5-week course

Subsequent treatment

• RT x 60 to 63 Gy

References

1. CALGB 8433: Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, Carey RW, Frei EF 3rd, Green MR. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med. 1990 Oct 4;323(14):940-5. link to original article contains protocol PubMed
   1. Update: Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst. 1996 Sep 4;88(17):1210-5. link to original article PubMed
2. RTOG 88-08: Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, Emami B, Curran WJ, Byhardt RW, Turrisi AT, Dar AR, Cox JD. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst. 1995 Feb 1;87(3):198-205. link to original article contains protocol PubMed
   1. Update: Sause W, Kolesar P, Taylor S IV, Johnson D, Livingston R, Komaki R, Emami B, Curran W Jr, Byhardt R, Dar AR, Turrisi A 3rd. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest. 2000 Feb;117(2):358-64. link to original article PubMed
3. RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed

Definitive therapy for locally advanced disease

Carboplatin, Paclitaxel, RT

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PC & RT: Paclitaxel, Carboplatin, Radiation Therapy

Regimen variant #1, 2/40/60

Study	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2010 (WJTOG0105)	Phase III (E-switch-ic)	1. MVP & RT 2. Carboplatin, Irinotecan, RT	Inconclusive whether non-inferior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15, 22, 29, 36
• Paclitaxel (Taxol) 40 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

Radiotherapy

• Concurrent radiation therapy, 60 Gy

6-week course

Regimen variant #2, 2/45/60

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Lu et al. 2010 (ID99-303)		Phase III (C)	PC, AE-941, RT	Did not meet primary endpoint of OS
Hoang et al. 2012 (ECOG 3598)	2000-2006	Phase III (C)	See link	See link
Bradley et al. 2015 (RTOG 0617)	2007-2011	Phase III (C)	1. Carboplatin, Paclitaxel, Cetuximab, concurrent RT	Did not meet primary endpoint of OS
			2. Carboplatin, Paclitaxel, high-dose RT 3. Carboplatin, Paclitaxel, Cetuximab, high-dose RT	Superior OS
Liang et al. 2017		Phase III (C)	EP & RT	Might have inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Preceding treatment

• ECOG 3598: PC induction x 2

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, given second
• Paclitaxel (Taxol) 45 mg/m² IV over 1 to 3 hours once per day on days 1, 8, 15, given first

21-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy: 2 Gy fractions x 30 fractions (total of 60 Gy)

6-week course

Subsequent treatment

• RTOG 0617: PC consolidation x 2

Regimen variant #3, 2/45/63

Study	Evidence
Belani et al. 2005 (LAMP)	Phase II

Preceding treatment

• PC induction

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, given second
• Paclitaxel (Taxol) 45 mg/m² IV over 1 to 3 hours once per day on days 1, 8, 15, given first

21-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy: 1.8 Gy fractions x 25 fractions, then 2 Gy fractions x 9 fractions

7-week course

Subsequent treatment

• PC consolidation x 2

Regimen variant #4, 2/50/66

Study	Evidence
Vokes et al. 2007 (CALGB 39801)	Non-randomized portion of RCT

Preceding treatment

• PC x 2 versus no induction

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43, given second
• Paclitaxel (Taxol) 50 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, 43, given first

Radiotherapy

• Concurrent radiation therapy, 66 Gy

7-week course

References

1. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. link to original article contains protocol PubMed
2. CALGB 39801: Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson DM, Akerley W, Green MR; CALGB. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007 Apr 2. link to original article contains verified protocol PubMed
3. ID99-303: Lu C, Lee JJ, Komaki R, Herbst RS, Feng L, Evans WK, Choy H, Desjardins P, Esparaz BT, Truong MT, Saxman S, Kelaghan J, Bleyer A, Fisch MJ. Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial. J Natl Cancer Inst. 2010 Jun 16;102(12):859-65. Epub 2010 May 26. link to original article link to PMC article contains protocol PubMed
4. WJTOG0105: Yamamoto N, Nakagawa K, Nishimura Y, Tsujino K, Satouchi M, Kudo S, Hida T, Kawahara M, Takeda K, Katakami N, Sawa T, Yokota S, Seto T, Imamura F, Saka H, Iwamoto Y, Semba H, Chiba Y, Uejima H, Fukuoka M. Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: West Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol. 2010 Aug 10;28(23):3739-45. Epub 2010 Jul 12. link to original article contains protocol PubMed
5. ECOG 3598: Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. link to original article link to PMC article contains verified protocol PubMed
6. RTOG 0617: Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. Epub 2015 Jan 16. link to original article contains verified protocol link to PMC article PubMed NCT00533949
   1. Update: Bradley JD, Hu C, Komaki RR, Masters GA, Blumenschein GR, Schild SE, Bogart JA, Forster KM, Magliocco AM, Kavadi VS, Narayan S, Iyengar P, Robinson CG, Wynn RB, Koprowski CD, Olson MR, Meng J, Paulus R, Curran WJ Jr, Choy H. Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Mar 1;38(7):706-714. Epub 2019 Dec 16. link to original article link to PMC article PubMed
   2. Dataset: Project Data Sphere
7. Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. link to original article contains verified protocol PubMed NCT01494558

Carboplatin, Vinorelbine, RT

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Strøm et al. 2013	Phase III (E-esc)	Carboplatin & Vinorelbine	Superior OS

Chemotherapy

• Carboplatin (Paraplatin)
• Vinorelbine (Navelbine)

Radiotherapy

• Concurrent radiation therapy

References

1. Strøm HH, Bremnes RM, Sundstrøm SH, Helbekkmo N, Fløtten O, Aasebø U; Norwegian Lung Cancer Study Group. Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2013 Sep 17;109(6):1467-75. Epub 2013 Aug 20. link to original article link to PMC article PubMed

Carboplatin & RT

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Carboplatin & RT: Carboplatin & Radiation Therapy

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Atagi et al. 2012 (JCOG0301)	Phase III (E-esc)	RT	Seems to have superior OS

Chemotherapy

• Carboplatin (Paraplatin) 30 mg/m² IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26

Radiotherapy

• Concurrent radiation therapy: 60 Gy, details not available in abstract

References

1. JCOG0301: Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, Sawa T, Ishikura S, Shibata T, Fukuda H, Saijo N, Tamura T; JCOG Lung Cancer Study Group. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012 Jul;13(7):671-8. Epub 2012 May 22. link to original article contains protocol PubMed

Cisplatin & RT

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Cisplatin & RT: Cisplatin & Radiation Therapy

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Schaake-Koning et al. 1992	Phase III (E-esc)	1. Cisplatin & RT (weekly dosing)	Did not meet primary endpoint of OS
		2. RT	Superior OS

Chemotherapy

• Cisplatin (Platinol) 6 mg/m² IV once per day on days of radiation

Radiotherapy

• Concurrent radiation therapy as follows:
  • Weeks 1 & 2: 3 Gy fractions, five fractions per week
  • Weeks 3 to 5: no radiation
  • Weeks 6 & 7: 2.5 Gy fractions, five fractions per week

7-week course

References

1. Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, Kirkpatrick A, Koolen M, Maat B, Nijs A, Renaud A, Rodrigus P, Schuster-Uitterhoeve L, Sculier JP, van Zandwijk N, Bartelink H. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med. 1992 Feb 20;326(8):524-30. link to original article contains protocol PubMed

Cisplatin, Docetaxel, RT

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DC & RT: Docetaxel, Cisplatin, Radiation Therapy
DP & RT: Docetaxel, Platinol (Cisplatin), Radiation Therapy

Regimen variant #1, 20/20

Study	Evidence	Comparator	Comparative Efficacy
Oh et al. 2013 (KASLC 0401)	Phase III (C)	1. TP & RT 2. GP & RT	Did not meet primary endpoint of ORR
Ahn et al. 2015 (KCSG-LU05-04)	Non-randomized portion of RCT

In KCSG-LU05-04, no benefit was observed to giving post-definitive consolidation.

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36
• Docetaxel (Taxotere) 20 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

Radiotherapy

• Concurrent radiation therapy, 2.00 Gy fractions x 33 fractions (total dose: 66 Gy)

6-week course

Subsequent treatment

• KCSG-LU05-04: Cisplatin & Docetaxel consolidation versus no further treatment

Regimen variant #2, 40/40

Study	Evidence	Comparator	Comparative Efficacy
Segawa et al. 2010 (OLCSG 0007)	Phase III (E-switch-ic)	MVP & RT	Might have superior OS

Chemotherapy

• Cisplatin (Platinol) 40 mg/m² IV once per day on days 1 & 8
• Docetaxel (Taxotere) 40 mg/m² IV once per day on days 1 & 8

28-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy

References

1. OLCSG 0007: Segawa Y, Kiura K, Takigawa N, Kamei H, Harita S, Hiraki S, Watanabe Y, Sugimoto K, Shibayama T, Yonei T, Ueoka H, Takemoto M, Kanazawa S, Takata I, Nogami N, Hotta K, Hiraki A, Tabata M, Matsuo K, Tanimoto M. Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007. J Clin Oncol. 2010 Jul 10;28(20):3299-306. Epub 2010 Jun 7. link to original article contains protocol PubMed
2. KASLC 0401: Oh IJ, Kim KS, Kim YC, Ban HJ, Kwon YS, Kim YI, Lim SC, Chung WK, Nam TK, Song JY, Yoon MS, Ahn SJ. A phase III concurrent chemoradiotherapy trial with cisplatin and paclitaxel or docetaxel or gemcitabine in unresectable non-small cell lung cancer: KASLC 0401. Cancer Chemother Pharmacol. 2013 Dec;72(6):1247-54. Epub 2013 Oct 5. link to original article contains protocol PubMed
3. KCSG-LU05-04: Ahn JS, Ahn YC, Kim JH, Lee CG, Cho EK, Lee KC, Chen M, Kim DW, Kim HK, Min YJ, Kang JH, Choi JH, Kim SW, Zhu G, Wu YL, Kim SR, Lee KH, Song HS, Choi YL, Sun JM, Jung SH, Ahn MJ, Park K. Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol. 2015 Aug 20;33(24):2660-6. Epub 2015 Jul 6. link to original article contains verified protocol PubMed

Cisplatin, Etoposide, RT

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EP & RT: Etoposide, Platinol (Cisplatin), Radiation Therapy

Regimen variant #1, 45 Gy with response-adapted treatment

Study	Evidence
Albain et al. 2002 (SWOG 9019)	Phase II
Albain et al. 2009 (RTOG 93-09)	Non-randomized portion of RCT

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 1 & 8
• Etoposide (Vepesid) 50 mg/m² IV once per day on days 1 to 5

28-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy, 1.80 Gy fractions x 25 fractions (total dose: 45 Gy), to start within 24 hours of cycle 1 day 1

5-week course

Subsequent treatment

• SWOG 9019: Patients were re-imaged with CT scan (bone scan and head imaging were only done if patients had new symptoms), and those without progression or new metastatic disease received an additional 2.00 Gy per day x 8 fractions for a total of 61 Gy administered overall
• RTOG 93-09: Additional radiation to 61 Gy, then cisplatin & etoposide consolidation versus surgery, then cisplatin & etoposide consolidation

Regimen variant #2, 60 to 66 Gy

Study	Evidence	Comparator	Comparative Efficacy
Kelly et al. 2008 (SWOG S0023)	Non-randomized portion of RCT
Hanna et al. 2008 (HOG Lun 01-24)	Non-randomized portion of RCT
Senan et al. 2016 (PROCLAIM)	Phase III (C)	Cisplatin, Pemetrexed, RT, then Pemetrexed consolidation	Did not meet primary endpoint of OS
Liang et al. 2017	Phase III (C)	PC & RT	Might have superior OS

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 1 & 8
• Etoposide (Vepesid) 50 mg/m² IV once per day on days 1 to 5

28-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy, 1.80 to 2.00 Gy fractions x 30 to 33 fractions (total dose: 60 to 66 Gy)

6- to 6.5-week course

Subsequent treatment

• SWOG S0023: Docetaxel x 3, then gefitinib versus placebo
• HOG Lun 01-24: Docetexal consolidation versus observation
• PROCLAIM: Investigator's choice of: Carboplatin & Paclitaxel or Cisplatin & Etoposide or Cisplatin & Vinorelbine consolidation
• Liang et al. 2017: Optional consolidation chemotherapy

Regimen variant #3, 66 Gy, split cisplatin

Study	Evidence	Comparator	Comparative Efficacy
Fournel et al. 2005 (NPC 95-01)	Phase III (E-switch-ic)	Cisplatin & Vinorelbine, then RT	Did not meet primary endpoint of OS

Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 5
• Etoposide (Vepesid) 50 mg/m² IV once per day on days 1 to 5

28-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy, 2.00 Gy fractions x 33 fractions (total dose: 66 Gy)

6.5-week course

Subsequent treatment

• Cisplatin & Vinorelbine consolidation

Regimen variant #4, 69.6 Gy (hyperfractionated)

Study	Evidence	Comparator	Comparative Efficacy
Curran et al. 2011 (RTOG 9410)	Phase III (E-switch-ic)	1. Cisplatin, Vinblastine, RT	Did not meet primary endpoint of OS
		2. Cisplatin & Vinblastine, then RT	Might have superior OS

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 1 & 8
• Etoposide (Vepesid) 50 mg PO twice per day on days 1 to 5, 8 to 12

28-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy, 1.20 Gy fractions (total dose: 69.6 Gy), given twice per day for 5 days per week, starting on cycle 1 day 1

References

1. SWOG 9019: Albain KS, Crowley JJ, Turrisi AT 3rd, Gandara DR, Farrar WB, Clark JI, Beasley KR, Livingston RB. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol. 2002 Aug 15;20(16):3454-60. link to original article contains protocol PubMed
2. NPC 95-01: Fournel P, Robinet G, Thomas P, Souquet PJ, Léna H, Vergnenégre A, Delhoume JY, Le Treut J, Silvani JA, Dansin E, Bozonnat MC, Daurés JP, Mornex F, Pérol M; Groupe Lyon-Saint-Etienne d'Oncologie Thoracique; Groupe Français de Pneumo-Cancérologie. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol. 2005 Sep 1;23(25):5910-7. Epub 2005 Aug 8. link to original article contains protocol PubMed
3. SWOG S0023: Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, Ung YC, Lau DH, Crowley JJ, Gandara DR. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008 May 20;26(15):2450-6. Epub 2008 Mar 31. link to original article contains verified protocol PubMed
4. HOG Lun 01-24: Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, Reynolds C, Govindan R, Melnyk A, Fisher W, Richards D, Bruetman D, Anderson T, Chowhan N, Nattam S, Mantravadi P, Johnson C, Breen T, White A, Einhorn L; Hoosier Oncology Group; US Oncology. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol. 2008 Dec 10;26(35):5755-60. Epub 2008 Nov 10. link to original article contains protocol PubMed
5. RTOG 93-09: Albain KS, Swann RS, Rusch VW, Turrisi AT 3rd, Shepherd FA, Smith C, Chen Y, Livingston RB, Feins RH, Gandara DR, Fry WA, Darling G, Johnson DH, Green MR, Miller RC, Ley J, Sause WT, Cox JD. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009 Aug 1;374(9687):379-86. Epub 2009 Jul 24. link to original article contains verified protocol link to PMC article PubMed
6. RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed
7. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed
   1. Dataset: Project Data Sphere
8. Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. link to original article contains verified protocol PubMed NCT01494558

Cisplatin, Vinblastine, RT

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Curran et al. 2011 (RTOG 9410)	Phase III (E-switch-ic)	1. Cisplatin, Etoposide, RT	Did not meet primary endpoint of OS
		2. Cisplatin & Vinblastine, then RT	Seems to have superior OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once per day on days 1 & 29
• Vinblastine (Velban) 5 mg/m² IV once per day on days 1, 8, 15, 22, 29

Radiotherapy

• Concurrent radiation therapy

5-week course

References

1. RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed

Cisplatin, Vinorelbine, RT

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Eberhardt et al. 2015 (ESPATUE)	2004-2013	Phase III (E-switch-ooc)	Surgery	Did not meet primary endpoint of OS

Preceding treatment

• Cisplatin & Paclitaxel

Chemotherapy

• Cisplatin (Platinol)
• Vinorelbine (Navelbine)

Radiotherapy

• Concurrent radiation therapy

References

1. ESPATUE: Eberhardt WE, Pöttgen C, Gauler TC, Friedel G, Veit S, Heinrich V, Welter S, Budach W, Spengler W, Kimmich M, Fischer B, Schmidberger H, De Ruysscher D, Belka C, Cordes S, Hepp R, Lütke-Brintrup D, Lehmann N, Schuler M, Jöckel KH, Stamatis G, Stuschke M. Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). J Clin Oncol. 2015 Dec 10;33(35):4194-201. Epub 2015 Nov 2. link to original article PubMed

Radiation therapy

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RT: Radiation Therapy

Regimen variant #1, 20 Gy

Study	Evidence	Comparator	Comparative Efficacy
Ball et al. 1997	Phase III (C)	5-FU & RT	Seems to have inferior OS

Radiotherapy

• External beam radiotherapy 4 Gy in 5 fractions (20 Gy total)

5-day course

Regimen variant #2, 45 Gy + 18 Gy boost (63 Gy total)

Study	Evidence	Comparator	Comparative Efficacy
Belani et al. 2005 (LAMP)	Phase II
Curran et al. 2011 (RTOG 9410)	Phase III (C)	See link	See link

Preceding treatment

• LAMP: Carboplatin & Paclitaxel x 2
• RTOG 9410: Cisplatin & Vinblastine x 5 wk

Radiotherapy

• External beam radiotherapy 45 Gy in 1.80 Gy fractions x 25 fractions, then 18 Gy boost in 2.00 Gy fractions x 9 fractions

7-week course

Regimen variant #3, 60 Gy

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Morton et al. 1991		Phase III (C)	MACC & RT	Did not meet primary endpoint of OS
Clamon et al. 1999		Phase III (C)	Carboplatin & RT	Did not meet primary endpoint of OS
Bradley et al. 2002 (RTOG 93-04)		Phase III (C)	Beta-interferon & RT	Did not meet primary endpoint of OS
Groen et al. 2004	1995-1998	Phase III (C)	Carboplatin & RT	Did not meet primary endpoint of OS24
Atagi et al. 2012 (JCOG0301)		Phase III (C)	Carboplatin & RT	Seems to have inferior OS

Preceding treatment

• Clamon et al. 1999: Cisplatin & Vinblastine x 5 wk

Radiotherapy

• External beam radiotherapy 60 Gy

One course

References

1. Morton RF, Jett JR, McGinnis WL, Earle JD, Therneau TM, Krook JE, Elliott TE, Mailliard JA, Nelimark RA, Maksymiuk AW, Drummond RG, Laurie JA, Kugler JW, Anderson RT. Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer: a randomized, phase III trial. Ann Intern Med. 1991 Nov 1;115(9):681-6. link to original article PubMed
2. Ball D, Smith J, Bishop J, Olver I, Davis S, O'Brien P, Bernshaw D, Ryan G, Millward M. A phase III study of radiotherapy with and without continuous-infusion fluorouracil as palliation for non-small-cell lung cancer. Br J Cancer. 1997;75(5):690-7. link to PMC article PubMed
3. Clamon G, Herndon J, Cooper R, Chang AY, Rosenman J, Green MR; CALGB; ECOG. Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol. 1999 Jan;17(1):4-11. link to original article PubMed
4. RTOG 93-04: Bradley JD, Scott CB, Paris KJ, Demas WF, Machtay M, Komaki R, Movsas B, Rubin P, Sause WT. A phase III comparison of radiation therapy with or without recombinant beta-interferon for poor-risk patients with locally advanced non-small-cell lung cancer (RTOG 93-04). Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1173-9. link to original article contains protocol PubMed
5. Groen HJ, van der Leest AH, Fokkema E, Timmer PR, Nossent GD, Smit WJ, Nabers J, Hoekstra HJ, Hermans J, Otter R, van Putten JW, de Vries EG, Mulder NH. Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study. Ann Oncol. 2004 Mar;15(3):427-32. link to original article PubMed
6. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. link to original article contains protocol PubMed
7. RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed
8. JCOG0301: Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, Sawa T, Ishikura S, Shibata T, Fukuda H, Saijo N, Tamura T; JCOG Lung Cancer Study Group. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012 Jul;13(7):671-8. Epub 2012 May 22. link to original article contains protocol PubMed

Consolidation or maintenance after definitive therapy for inoperable disease

Carboplatin & Paclitaxel

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Regimen

Study	Years of enrollment	Evidence
Belani et al. 2005 (LAMP)		Phase II
Bradley et al. 2015 (RTOG 0617)	2007-2011	Non-randomized portion of RCT
Senan et al. 2016 (PROCLAIM)		Non-randomized portion of RCT

Preceding treatment

• LAMP and RTOG 0617: Carboplatin, Paclitaxel, RT
• PROCLAIM: Cisplatin, Etoposide, RT

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for 2 cycles

References

1. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. link to original article contains protocol PubMed
2. RTOG 0617: Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. Epub 2015 Jan 16. link to original article contains verified protocol link to PMC article PubMed NCT00533949
   1. Update: Bradley JD, Hu C, Komaki RR, Masters GA, Blumenschein GR, Schild SE, Bogart JA, Forster KM, Magliocco AM, Kavadi VS, Narayan S, Iyengar P, Robinson CG, Wynn RB, Koprowski CD, Olson MR, Meng J, Paulus R, Curran WJ Jr, Choy H. Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Mar 1;38(7):706-714. Epub 2019 Dec 16. link to original article link to PMC article PubMed
   2. Dataset: Project Data Sphere
3. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed
   1. Dataset: Project Data Sphere

Cisplatin & Etoposide

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Regimen

Study	Evidence
Senan et al. 2016 (PROCLAIM)	Non-randomized portion of RCT

Preceding treatment

• Cisplatin, Etoposide, RT

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 1 & 8
• Etoposide (Vepesid) 50 mg/m² IV once per day on days 1 to 5

28-day cycle for 2 cycles

References

1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed
   1. Dataset: Project Data Sphere

Cisplatin & Vinorelbine

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Regimen

Study	Evidence
Senan et al. 2016 (PROCLAIM)	Non-randomized portion of RCT

Preceding treatment

• Cisplatin, Etoposide, RT

Chemotherapy

• Cisplatin (Platinol) (dose not specified) mg/m² IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycle for 2 cycles

References

1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed
   1. Dataset: Project Data Sphere

Durvalumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Antonia et al. 2017 (PACIFIC)	2014-2016	Phase III (E-RT-esc)	Placebo	Superior OS (*)

Note: reported efficacy is based on the 2018 update.

Preceding treatment

• "Two or more cycles (defined according to local practice) of platinum-based chemotherapy (containing etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concurrently with definitive radiation therapy (54 to 66 Gy), in which the mean dose to the lung was less than 20 Gy, the V20 (the volume of lung parenchyma that received 20 Gy or more) was less than 35%, or both."

Immunotherapy

• Durvalumab (Imfinzi) 10 mg/kg IV once on day 1

14-day cycle for up to 26 cycles (1 year)

References

1. PACIFIC: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. Epub 2017 Sep 8. link to original article contains verified protocol PubMed
   1. Update: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350. Epub 2018 Sep 25. link to original article PubMed

Advanced or metastatic disease, first-line

Atezolizumab monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Spigel et al. 2019 (IMpower110)	Phase III	Cisplatin or Carboplatin & Pemetrexed Cisplatin or Carboplatin & Gemcitabine	Superior OS (TC3/IC3 only i.e PD-L1 TC>50%)

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycles

References

1. IMpower110: D. Spigel, F. de Marinis, G. Giaccone, N. Reinmuth, A. Vergnenegre, C.H. Barrios, M. Morise, E. Felip, Z.G. Andric, S. Geater, M. Özgüroğlu, S. Mocci, M. McCleland, I. Enquist, K.M. Komatsubara, Y. Deng, H. Kuriki, X. Wen, J. Jassem, R.S. Herbst, LBA78 - IMpower110: Interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC. Ann Oncology, 2019.Oct: 30(5):915. link to abstract NCT02409342

Carboplatin & Docetaxel

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DCb: Docetaxel & Carboplatin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fossella et al. 2003 (TAX 326)	1998-2000	Phase III (E-RT-switch-ic)	1. Cisplatin & Docetaxel	Not reported
			2. Cisplatin & Vinorelbine	Did not meet primary endpoint of OS
Booton et al. 2006 (BTOG1)	2001-2002	Phase III (E-switch-ic)	1. MIC 2. MVP	Did not meet primary endpoint of OS
Groen et al. 2011 (NVALT-4)	2003-2007	Phase III (C)	Carboplatin, Docetaxel, Celecoxib	Did not meet primary endpoint of OS
Lynch et al. 2010 (BMS099)	2005-2006	Phase III (C)	Carboplatin, Docetaxel, Cetuximab	Did not meet primary endpoint of PFS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for up to 5 cycles (NVALT-4), 6 cycles (BMS099), or indefinitely

References

1. TAX 326: Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed
2. BTOG1: Booton R, Lorigan P, Anderson H, Baka S, Ashcroft L, Nicolson M, O'Brien M, Dunlop D, O'Byrne K, Laurence V, Snee M, Dark G, Thatcher N. A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1). Ann Oncol. 2006 Jul;17(7):1111-9. Epub 2006 Apr 7. link to original article PubMed
3. BMS099: Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010 Feb 20;28(6):911-7. Epub 2010 Jan 25. link to original article contains protocol PubMed
4. NVALT-4: Groen HJ, Sietsma H, Vincent A, Hochstenbag MM, van Putten JW, van den Berg A, Dalesio O, Biesma B, Smit HJ, Termeer A, Hiltermann TJ, van den Borne BE, Schramel FM. Randomized, placebo-controlled phase III study of docetaxel plus carboplatin with celecoxib and cyclooxygenase-2 expression as a biomarker for patients with advanced non-small-cell lung cancer: the NVALT-4 study. J Clin Oncol. 2011 Nov 10;29(32):4320-6. Epub 2011 Oct 11. link to original article PubMed

Carboplatin & Etoposide

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Klastersky et al. 1990 (EORTC 07861)	Phase III (E-switch-ic)	Cisplatin & Etoposide	Might have inferior ORR

Chemotherapy

• Carboplatin (Paraplatin) 325 mg/m² IV over 60 minutes once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

3- to 4-week cycles

References

1. EORTC 07861: Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J, Cordier R, Finet C, Berchier MC, Sergysels R, Mommen P, Paesmans M. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organisation for Research and Treatment of Cancer Protocol 07861. J Clin Oncol. 1990 Sep;8(9):1556-62. link to original article contains verified protocol PubMed

Carboplatin & Gemcitabine

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GC: Gemcitabine & Carboplatin
GCa: Gemcitabine & Carboplatin
GCb: Gemcitabine & Carboplatin

Regimen variant #1, 4/1000

Study	Evidence	Comparator	Comparative Efficacy
Helbekkmo et al. 2007	Phase III (E-switch-ic)	VC	Did not meet primary endpoint of OS

Note: AUC was calculated using the Chatelut formula.

Chemotherapy

• Carboplatin (Paraplatin) AUC 4 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 8

21-day cycle for 3 cycles

Regimen variant #2, 5/1000 q3wk

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Grønberg et al. 2009	Phase III (C)	Carboplatin & Pemetrexed		Did not meet primary endpoint of HRQoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 4 cycles

Regimen variant #3, 5/1000 q4wk

Study	Evidence	Comparator	Comparative Efficacy
Danson et al. 2003	Phase III (E-switch-ic)	1. MIC 2. MVP	Did not meet primary endpoint of OS

Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycle for 4 cycles

Regimen variant #4, 5/1200

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Zatloukal et al. 2003	Phase III (E-switch-ic)	Cisplatin & Gemcitabine		Did not meet primary endpoint of grade 3/4 toxicity
Rudd et al. 2005	Phase III (E-switch-ic)	MIC	Superior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #5, 5/1250 q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Sederholm et al. 2005		Phase III (C)	Gemcitabine	Seems to have superior OS
Bepler et al. 2013 (MCC-15005)		Phase III (C)	ERCC1 and RRM1 expression-based chemotherapy	Did not meet primary endpoint of PFS6
Reck et al. 2016 (KEYNOTE-024)	2014-2015	Phase III (C)	Pembrolizumab	Inferior OS	Inferior HRQoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 to 6 cycles

Regimen variant #6, 5/1250 q4wk

Study	Evidence	Comparator	Comparative Efficacy
Wu et al. 2013 (FASTACT-2)	Phase III (C)	Carboplatin & Gemcitabine/Erlotinib	Seems to have inferior OS

Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

28-day cycle for 4 cycles

Regimen variant #7, 6/1000

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kosmidis et al. 2007	2000-2004	Phase III (C)	Gemcitabine & Paclitaxel	Did not meet primary endpoint of OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycles

Regimen variant #8, 6/1250 ("GCb6")

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Reck et al. 2016 (KEYNOTE-024)	2014-2015	Phase III (C)	Pembrolizumab	Inferior OS	Inferior HRQoL
Ferry et al. 2017 (BTOG2)		Phase III (E-switch-ic)	1. GC50	Seems to have superior OS
			2. GC80	Non-inferior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 to 6 cycles

Regimen variant #9, 300/1000

Study	Evidence	Comparator	Comparative Efficacy
Grigorescu et al. 2002	Phase III (E-switch-ic)	Cisplatin & Vinblastine	Superior OS

Chemotherapy

• Carboplatin (Paraplatin) 300 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. Grigorescu AC, Draghici IN, Nitipir C, Gutulescu N, Corlan E. Gemcitabine (GEM) and carboplatin (CBDCA) versus cisplatin (CDDP) and vinblastine (VLB) in advanced non-small-cell lung cancer (NSCLC) stages III and IV: a phase III randomised trial. Lung Cancer. 2002 Jul;37(1):9-14. link to original article contains protocol PubMed
2. Danson S, Middleton MR, O'Byrne KJ, Clemons M, Ranson M, Hassan J, Anderson H, Burt PA, Fairve-Finn C, Stout R, Dowd I, Ashcroft L, Beresford C, Thatcher N. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer. 2003 Aug 1;98(3):542-53. link to original article contains protocol PubMed
3. Zatloukal P, Petruzelka L, Zemanová M, Kolek V, Skricková J, Pesek M, Fojtů H, Grygárková I, Sixtová D, Roubec J, Horenková E, Havel L, Průsa P, Nováková L, Skácel T, Kůta M. Gemcitabine plus cisplatin vs gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer. 2003 Sep;41(3):321-31. link to original article contains protocol PubMed
4. Rudd RM, Gower NH, Spiro SG, Eisen TG, Harper PG, Littler JA, Hatton M, Johnson PW, Martin WM, Rankin EM, James LE, Gregory WM, Qian W, Lee SM; London Lung Cancer Group. Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group. J Clin Oncol. 2005 Jan 1;23(1):142-53. link to original article contains protocol PubMed
5. Sederholm C, Hillerdal G, Lamberg K, Kölbeck K, Dufmats M, Westberg R, Gawande SR; Swedish Lung Cancer Study Group. Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol. 2005 Nov 20;23(33):8380-8. link to original article contains verified protocol PubMed
6. Helbekkmo N, Sundstrøm SH, Aasebø U, Brunsvig PF, von Plessen C, Hjelde HH, Garpestad OK, Bailey A, Bremnes RM; Norwegian Lung Cancer Study Group. Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity. Br J Cancer. 2007 Aug 6;97(3):283-9. Epub 2007 Jun 26. link to original article link to PMC article contains verified protocol PubMed
7. Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008 Jan;19(1):115-22. Epub 2007 Oct 15. link to original article contains protocol PubMed
8. Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S; Norwegian Lung Cancer Study Group. Phase III study by the Norwegian Lung Cancer Study Group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. link to original article contains verified protocol PubMed
9. ALPHA A1-99002L: Treat JA, Gonin R, Socinski MA, Edelman MJ, Catalano RB, Marinucci DM, Ansari R, Gillenwater HH, Rowland KM, Comis RL, Obasaju CK, Belani CP; Alpha Oncology Research Network. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2010 Mar;21(3):540-7. Epub 2009 Oct 15. link to original article contains protocol PubMed NCT00054392
10. MCC-15005: Bepler G, Williams C, Schell MJ, Chen W, Zheng Z, Simon G, Gadgeel S, Zhao X, Schreiber F, Brahmer J, Chiappori A, Tanvetyanon T, Pinder-Schenck M, Gray J, Haura E, Antonia S, Fischer JR. Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2013 Jul 1;31(19):2404-12. Epub 2013 May 20. link to original article link to PMC article contains verified protocol PubMed
11. FASTACT-2: Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. link to original article contains protocol PubMed
12. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
13. Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M, Shah R, Thompson J, Spicer J, Muthukumar D, Skailes G, Leonard P, Chetiyawardana AD, Wells P, Lewanski C, Crosse B, Hill M, Gaunt P, O'Byrne K; British Thoracic Oncology Group. Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: results from a British Thoracic Oncology Group randomised phase III trial. Eur J Cancer. 2017 Sep;83:302-312. Epub 2017 Aug 4. link to original article contains verified protocol PubMed

Carboplatin & Paclitaxel

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CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin
TC: Taxol (Paclitaxel) & Carboplatin

Regimen variant #1, 5/200

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Mok et al. 2009 (IPASS)		Phase III (C)	Gefitinib	Inferior PFS
Reck et al. 2016 (KEYNOTE-024)	2014-2015	Phase III (C)	Pembrolizumab	Inferior OS	Inferior HRQoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for 4 to 6 cycles

Subsequent treatment

• KEYNOTE-024: Patients with nonsquamous histology could optionally proceed to pemetrexed switch maintenance

Regimen variant #2, 6/175

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Stathopoulos et al. 2004	2006-2008	Phase III (C)	Paclitaxel & Vinorelbine	Did not meet primary endpoints of ORR/OS
Lynch et al. 2012 (CA184-041)		Randomized Phase II (C)	CP & Ipilimumab	Seems to have inferior PFS
Govindan et al. 2017 (CA184-104)		Phase III (C)	CP & Ipilimumab	Did not meet primary endpoint of OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Supportive medications

• Corticosteroids could be used as premedication for Paclitaxel (Taxol) infusion.

21-day cycle for up to 6 cycles

Regimen variant #3, 6/200

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Socinski et al. 2002		Phase III (E-de-esc)	CP; indefinite	Did not meet primary endpoint of OS	Did not meet primary endpoint of QoL
Kosmidis et al. 2002		Phase III (E-switch-ic)	Gemcitabine & Paclitaxel	Did not meet primary endpoint of OS
Rosell et al. 2002	1996-1997	Phase III (E-switch-ic)	Cisplatin & Paclitaxel	Seems to have inferior OS
Johnson et al. 2004		Randomized Phase II (C)	PacCBev	Seems to have inferior TTP
Leighl et al. 2005 (NCIC CTG BR.18)		Phase III (C)	CP & BMS-275291	Did not meet primary endpoint of OS	Less toxic
Herbst et al. 2005 (TRIBUTE)		Phase III (C)	CP & Erlotinib	Did not meet primary endpoint of OS
Schuette et al. 2006		Phase III (C)	CP; weekly	Seems to have non-inferior ORR	Mixed toxicity
Ohe et al. 2006 (FACS)	2000-2002	Phase III (E-switch-ic)	1. Cisplatin & Gemcitabine	Inconclusive whether non-inferior OS
			2. Cisplatin & Irinotecan	Inconclusive whether non-inferior OS
			3. Cisplatin & Vinorelbine	Inconclusive whether non-inferior OS
Blumenschein et al. 2008 (SPIRIT II)		Phase III (C)	CP & Bexarotene	Did not meet primary endpoint of OS
Scagliotti et al. 2010 (ESCAPE)		Phase III (C)	CP & Sorafenib	Did not meet primary endpoint of OS
Okamoto et al. 2010 (LETS)		Phase III (C)	Carboplatin & S-1	Non-inferior OS
Hirsh et al. 2011 (A8501001)	2005-2007	Phase III (C)	CP & Agatolimod	Did not meet primary endpoint of OS
Lara et al. 2011 (ATTRACT-1)	2008-2009	Phase III (C)	CP & Vadimezan	Did not meet primary endpoint of OS
Socinski et al. 2012 (CA031)		Phase III (C)	Carboplatin & nab-Paclitaxel	Inferior ORR
Laurie et al. 2013 (NCIC CTG BR.29)		Phase III (C)	CP & Cediranib	Did not meet primary endpoint of OS	Less toxic
Langer et al. 2014 (A4021016)		Phase III (C)	CP & Figitumumab	Might have superior OS
Reck et al. 2016 (KEYNOTE-024)	2014-2015	Phase III (C)	Pembrolizumab	Inferior OS	Inferior HRQoL
Ramalingam et al. 2016 (M10-898)		Randomized Phase II (C)	CP & Veliparib	Did not meet primary endpoint of PFS
Herbst et al. 2017 (SWOG S0819)		Phase III (C)	CP & Cetuximab	Did not meet primary endpoints of PFS/OS

Note: Patients in TRIBUTE received a maximum of 6 cycles. Patients in SWOG S0819 were EGFR FISH positive.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for 3 or more cycles

Subsequent treatment

• Socinski et al. 2002, upon progression: Paclitaxel
• KEYNOTE-024: Patients with nonsquamous histology could optionally proceed, after 4 to 6 cycles, to pemetrexed switch maintenance

Regimen variant #4, 6/225

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kelly et al. 2001 (SWOG 9509)		Phase III (E-switch-ic)	Cisplatin & Vinorelbine	Did not meet primary endpoint of OS
Schiller et al. 2002 (ECOG E1594)		Phase III (E-switch-ic)	1. Cisplatin & Docetaxel	Did not meet primary endpoint of OS
			2. Cisplatin & Gemcitabine	Did not meet primary endpoint of OS
			3. Cisplatin & Paclitaxel	Did not meet primary endpoint of OS
Herbst et al. 2004 (INTACT 2)		Phase III (C)	CP & Gefitinib	Did not meet primary endpoint of OS
Lilenbaum et al. 2005 (CALGB 9730)		Phase III (E-esc)	Paclitaxel	Superior FFS
Williamson et al. 2005 (SWOG S0003)		Phase III (C)	CP & Tirapazamine	Did not meet primary endpoint of OS
Belani et al. 2008		Phase III (C)	CP; weekly paclitaxel	Did not meet primary endpoint of OS
Kubota et al. 2008 (JMTO LC00-03)		Phase III (C)	Gemcitabine & Vinorelbine, then Docetaxel	Did not meet primary endpoint of OS
Treat et al. 2009 (ALPHA A1-99002L)	2000-2005	Phase III (C)	1. Carboplatin & Gemcitabine 2. Gemcitabine & Paclitaxel	Did not meet primary endpoint of OS
Lynch et al. 2010 (BMS099)		Phase III (C)	CP & Cetuximab	Did not meet primary endpoint of PFS
Weissman et al. 2011		Phase III (C)	GEMOX	Did not meet primary endpoint of PFS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1, given second
• Paclitaxel (Taxol) 225 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for up to 4 cycles (Belani et al. 2008), 6 cycles (Weissman et al. 2011), 10 cycles (SWOG 9509), or indefinitely (ECOG E1594)

Subsequent treatment

• Belani et al. 2008: Paclitaxel maintenance

References

1. SWOG 9509: Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001 Jul 1;19(13):3210-8. link to original article contains verified protocol PubMed
2. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; ECOG. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains protocol PubMed
3. Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, Unger P, Lee J, Lee JH, Tynan M, Moore M, Kies MS. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol. 2002 Mar 1;20(5):1335-43. link to original article contains protocol PubMed
4. Kosmidis P, Mylonakis N, Nicolaides C, Kalophonos C, Samantas E, Boukovinas J, Fountzilas G, Skarlos D, Economopoulos T, Tsavdaridis D, Papakostas P, Bacoyiannis C, Dimopoulos M. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol. 2002 Sep 1;20(17):3578-85. link to original article contains protocol PubMed
5. Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemaissani A, Bogaerts J, Gallant G. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol. 2002 Oct;13(10):1539-49. link to original article contains protocol PubMed
6. INTACT 2: Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol. 2004 Mar 1;22(5):785-94. link to original article contains protocol PubMed
7. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. link to original article PubMed
8. Stathopoulos GP, Veslemes M, Georgatou N, Antoniou D, Giamboudakis P, Katis K, Tsavdaridis D, Rigatos SK, Dimitroulis I, Bastani S, Loukides S, Vergos K, Marossis K, Grigoratou T, Kalatzi E, Charalambatou M, Paspalli A, Michalopoulou P, Stoka M, Gerogianni A. Front-line paclitaxel-vinorelbine versus paclitaxel-carboplatin in patients with advanced non-small-cell lung cancer: a randomized phase III trial. Ann Oncol. 2004 Jul;15(7):1048-55. link to original article link to PMC article contains protocol PubMed
9. CALGB 9730: Lilenbaum RC, Herndon JE 2nd, List MA, Desch C, Watson DM, Miller AA, Graziano SL, Perry MC, Saville W, Chahinian P, Weeks JC, Holland JC, Green MR. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the Cancer and Leukemia Group B (study 9730). J Clin Oncol. 2005 Jan 1;23(1):190-6. link to original articlecontains verified protocol PubMed
10. NCIC CTG BR.18: Leighl NB, Paz-Ares L, Douillard JY, Peschel C, Arnold A, Depierre A, Santoro A, Betticher DC, Gatzemeier U, Jassem J, Crawford J, Tu D, Bezjak A, Humphrey JS, Voi M, Galbraith S, Hann K, Seymour L, Shepherd FA. Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR18. J Clin Oncol. 2005 Apr 20;23(12):2831-9. link to original article contains protocol PubMed
11. TRIBUTE: Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA; TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005 Sep 1;23(25):5892-9. Epub 2005 Jul 25. link to original article contains verified protocol PubMed
12. SWOG S0003: Williamson SK, Crowley JJ, Lara PN Jr, McCoy J, Lau DH, Tucker RW, Mills GM, Gandara DR; SWOG. Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol. 2005 Dec 20;23(36):9097-104. link to original article contains protocol PubMed
13. Schuette W, Blankenburg T, Guschall W, Dittrich I, Schroeder M, Schweisfurth H, Chemaissani A, Schumann C, Dickgreber N, Appel T, Ukena D. Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer. 2006 Mar;7(5):338-43. link to original article contains protocol PubMed
14. FACS: Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. link to original article contains verified protocol PubMed
15. Belani CP, Ramalingam S, Perry MC, LaRocca RV, Rinaldi D, Gable PS, Tester WJ. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol. 2008 Jan 20;26(3):468-73. link to original article contains protocol PubMed
16. SPIRIT II: Blumenschein GR Jr, Khuri FR, von Pawel J, Gatzemeier U, Miller WH Jr, Jotte RM, Le Treut J, Sun SL, Zhang JK, Dziewanowska ZE, Negro-Vilar A. Phase III trial comparing carboplatin, paclitaxel, and bexarotene with carboplatin and paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT II. J Clin Oncol. 2008 Apr 10;26(11):1879-85. link to original article contains verified protocol PubMed
17. JMTO LC00-03: Kubota K, Kawahara M, Ogawara M, Nishiwaki Y, Komuta K, Minato K, Fujita Y, Teramukai S, Fukushima M, Furuse K; Japan Multi-National Trial Organisation. Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study. Lancet Oncol. 2008 Dec;9(12):1135-42. Epub 2008 Nov 13. link to original article contains protocol PubMed
18. ALPHA A1-99002L: Treat JA, Gonin R, Socinski MA, Edelman MJ, Catalano RB, Marinucci DM, Ansari R, Gillenwater HH, Rowland KM, Comis RL, Obasaju CK, Belani CP; Alpha Oncology Research Network. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2010 Mar;21(3):540-7. Epub 2009 Oct 15. link to original article contains protocol PubMed NCT00054392
19. BMS099: Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010 Feb 20;28(6):911-7. Epub 2010 Jan 25. link to original article contains protocol PubMed
20. ESCAPE: Scagliotti G, Novello S, von Pawel J, Reck M, Rodrigues Pereira J, Thomas M, Abrão Miziara JE, Balint B, De Marinis F, Keller A, Arén O, Csollak M, Albert I, Barrios CH, Grossi F, Krzakowski M, Cupit L, Cihon F, Dimatteo S, Hanna N. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010 Apr 10;28(11):1835-42. Epub 2010 Mar 8. link to original article contains protocol PubMed
    1. Dataset: Project Data Sphere
21. LETS: Okamoto I, Yoshioka H, Morita S, Ando M, Takeda K, Seto T, Yamamoto N, Saka H, Asami K, Hirashima T, Kudoh S, Satouchi M, Ikeda N, Iwamoto Y, Sawa T, Miyazaki M, Tamura K, Kurata T, Fukuoka M, Nakagawa K; West Japan Oncology Group. Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer: results of a West Japan Oncology Group study. J Clin Oncol. 2010 Dec 20;28(36):5240-6. Epub 2010 Nov 15. link to original article contains verified protocol PubMed
22. Weissman CH, Reynolds CH, Neubauer MA, Pritchard S, Kobina S, Asmar L. A phase III randomized trial of gemcitabine-oxaliplatin versus carboplatin-paclitaxel as first-line therapy in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2011 Feb;6(2):358-64. link to original article contains protocol PubMed
23. A8501001: Hirsh V, Paz-Ares L, Boyer M, Rosell R, Middleton G, Eberhardt WE, Szczesna A, Reiterer P, Saleh M, Arrieta O, Bajetta E, Webb RT, Raats J, Benner RJ, Fowst C, Meech SJ, Readett D, Schiller JH. Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2011 Jul 1;29(19):2667-74. Epub 2011 May 31. link to original article contains verified protocol PubMed
24. ATTRACT-1: Lara PN Jr, Douillard JY, Nakagawa K, von Pawel J, McKeage MJ, Albert I, Losonczy G, Reck M, Heo DS, Fan X, Fandi A, Scagliotti G. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol. 2011 Aug 1;29(22):2965-71. Epub 2011 Jun 27. link to original article contains verified protocol PubMed
25. CA184-041: Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. link to original article contains verified protocol PubMed
26. CA031: Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. link to original article contains verified protocol PubMed
    1. Dataset: Project Data Sphere
27. NCIC CTG BR.29: Laurie SA, Solomon BJ, Seymour L, Ellis PM, Goss GD, Shepherd FA, Boyer MJ, Arnold AM, Clingan P, Laberge F, Fenton D, Hirsh V, Zukin M, Stockler MR, Lee CW, Chen EX, Montenegro A, Ding K, Bradbury PA. Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29. Eur J Cancer. 2014 Mar;50(4):706-12. Epub 2013 Dec 17. link to original article contains protocol PubMed
28. A4021016: Langer CJ, Novello S, Park K, Krzakowski M, Karp DD, Mok T, Benner RJ, Scranton JR, Olszanski AJ, Jassem J. Randomized, phase III trial of first-line figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2014 Jul 1;32(19):2059-66. Epub 2014 Jun 2. link to original article link to PMC article PubMed
29. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
30. M10-898: Ramalingam SS, Blais N, Mazieres J, Reck M, Jones CM, Juhasz E, Urban L, Orlov S, Barlesi F, Kio E, Keiholz U, Qin Q, Qian J, Nickner C, Dziubinski J, Xiong H, Ansell P, McKee M, Giranda V, Gorbunova V. Randomized, placebo-controlled, phase II study of veliparib in combination with carboplatin and paclitaxel for advanced/metastatic non-small cell lung cancer. Clin Cancer Res. 2017 Apr 15;23(8):1937-1944. Epub 2016 Oct 10. link to original article contains protocol PubMed
31. SWOG S0819: Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. Epub 2017 Nov 20. link to original article contains protocol PubMed

Carboplatin & nab-Paclitaxel

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Socinski et al. 2012 (CA031)	2007-2009	Phase III (E-RT-switch-ic)	Carboplatin & Paclitaxel	Superior ORR

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 mg/mL/min (per Calvert formula) IV once on day 1, given second
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV over 30 minutes once per day on days 1, 8, 15, given first

21-day cycle for 6 cycles; treatment could continue at physician's discretion if there was no progressive disease or unacceptable toxicity

References

1. CA031: Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. link to original article contains verified protocol PubMed
   1. Dataset: Project Data Sphere

Carboplatin, Paclitaxel, Bevacizumab

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PacCBev: Paclitaxel, Carboplatin, Bevacizumab
B+CP: Bevacizumab, Carboplatin, Paclitaxel
BCP: Bevacizumab, Carboplatin, Paclitaxel

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Johnson et al. 2004	Randomized Phase II (E-esc)	Carboplatin & Paclitaxel	Seems to have superior TTP
Herbst et al. 2017 (SWOG S0819)	Phase III (C)	Carboplatin, Paclitaxel, Bevacizumab, Cetuximab	Did not meet primary endpoints of PFS/OS

Note: Patients in SWOG S0819 were EGFR FISH positive.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 30 minutes once on day 1, given second, starting 60 minutes after the completion of paclitaxel
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1, given third, starting 60 minutes after the completion of carboplatin
  • Infusion time per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, given over 30 to 60 minutes for cycles 2 and later

21-day cycle for up to 6 cycles

References

1. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. link to original article PubMed
2. SWOG S0819: Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. Epub 2017 Nov 20. link to original article contains protocol PubMed

Carboplatin, Paclitaxel, Ipilimumab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Lynch et al. 2012 (CA184-041)	Randomized Phase II (E-esc)	Carboplatin & Paclitaxel	Seems to have superior PFS

Note: this is the "phased" approach to this regimen.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Immunotherapy

• Ipilimumab (Yervoy) as follows:
  • Cycles 3 to 6: 10 mg/kg IV once on day 1

Supportive medications

• Corticosteroids could be used as premedication for Paclitaxel (Taxol) infusion or for toxicity management.

21-day cycle for up to 6 cycles

Subsequent treatment

• Maintenance ipilimumab

References

1. CA184-041: Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. link to original article contains verified protocol PubMed

Carboplatin & Pemetrexed

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CP: Carboplatin & Pemetrexed
Carbo-Pem: Carboplatin & Pemetrexed

Example orders

• Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer

Regimen variant #1, 5/500 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Reck et al. 2016 (KEYNOTE-024)	2014-2015	Phase III (C)	Pembrolizumab	Inferior OS	Inferior HRQoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive medications

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be given throughout pemetrexed therapy

21-day cycle for up to 6 cycles

Subsequent treatment

• Optional pemetrexed maintenance

Regimen variant #2, 6/500 x 4

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Grønberg et al. 2009	Phase III (E-switch-ic)	Carboplatin & Gemcitabine		Did not meet primary endpoint of HRQoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive medications

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be given throughout pemetrexed therapy

21-day cycle for up to 4 cycles

Regimen variant #3, 6/500 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Reck et al. 2016 (KEYNOTE-024)	2014-2015	Phase III (C)	Pembrolizumab	Inferior OS	Inferior HRQoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

Supportive medications

• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose prior to Pemetrexed (Alimta)
• Folic acid (Folate) 1 mg PO once per day

21-day cycle for up to 6 cycles

Subsequent treatment

• Optional pemetrexed maintenance

References

1. Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S; Norwegian Lung Cancer Study Group. Phase III study by the Norwegian Lung Cancer Study Group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. link to original article contains protocol PubMed
2. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
   1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
   2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed

Carboplatin, Pemetrexed, Pembrolizumab

Source: Carboplatin, Pemetrexed, Pembrolizumab in advanced or metastatic non-small cell lung cancer

Carboplatin & Vinorelbine

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VC: Vinorelbine & Carboplatin

Regimen variant #1, IV vinorelbine

Study	Evidence	Comparator	Comparative Efficacy
Tan et al. 2005 (GLOB 2)	Phase III (C)	Gemcitabine & Vinorelbine	Did not meet primary endpoint of ORR

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #2, PO vinorelbine

Study	Evidence	Comparator	Comparative Efficacy
Fløtten et al. 2012	Phase III (C)	Gemcitabine & Vinorelbine	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Vinorelbine (Navelbine) 60 mg/m² PO once per day on days 1 & 8

21-day cycle for 3 cycles

References

1. GLOB 2: Tan EH, Szczesna A, Krzakowski M, Macha HN, Gatzemeier U, Mattson K, Wernli M, Reiterer P, Hui R, Pawel JV, Bertetto O, Pouget JC, Burillon JP, Parlier Y, Abratt R; GLOB 2 group. Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2005 Aug;49(2):233-40. link to original article contains protocol PubMed
2. Fløtten Ø, Grønberg BH, Bremnes R, Amundsen T, Sundstrøm S, Rolke H, Hornslien K, Wentzel-Larsen T, Aasebø U, von Plessen C; Norwegian Lung Cancer Study Group. Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC: a phase III randomised controlled trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2012 Jul 24;107(3):442-7. Epub 2012 Jul 3. link to original article link to PMC article contains protocol PubMed

Cisplatin & Docetaxel

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DC: Docetaxel & Cisplatin
DP: Docetaxel & Platinol (Cisplatin)
Doc-Cis: Docetaxel & Cisplatin

Regimen variant #1, 50/75

Study	Evidence	Comparator	Comparative Efficacy
Berghmans et al. 2013 (ELCWP-01041)	Phase III (C)	1. GIP 2. IG	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycles

Regimen variant #2, 75/75

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schiller et al. 2002 (ECOG E1594)		Phase III (E-switch-ic)	1. Carboplatin & Paclitaxel	Did not meet primary endpoint of OS
			2. Cisplatin & Gemcitabine	Did not meet primary endpoint of OS
			3. Cisplatin & Paclitaxel	Did not meet primary endpoint of OS
Fossella et al. 2003 (TAX 326)	1998-2000	Phase III (E-RT-switch-ic)	1. Carboplatin & Docetaxel	Not reported
			2. Cisplatin & Vinorelbine	Seems to have superior OS
Cobo et al. 2007		Phase III (C)	ERCC1 mRNA-guided therapy	Seems to have inferior ORR
Tan et al. 2009 (GLOB3)	2004-2006	Phase III (C)	Cisplatin & Vinorelbine	Did not meet primary endpoint of TTF

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for up to 6 cycles (GLOB3) or indefinitely (E1594, TAX326)

Regimen variant #3, 80/60

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kubota et al. 2004		Phase III (E-switch-ic)	Cisplatin & Vindesine	Seems to have superior OS
Takeda et al. 2009 (WJTOG0203)		Phase III (C)	Platinum doublet x 3, then Gefitinib	Did not meet primary endpoint of OS
Kubota et al. 2015 (TCOG0701 CATS)	2007-2008	Phase III (C)	Cisplatin & S-1	Non-inferior OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 90 minutes once on day 1, given second
• Docetaxel (Taxotere) 60 mg/m² IV over 60 minutes once on day 1, given first

21-day cycle for 3 to 6 cycles

Regimen variant #4, 80/100

Study	Evidence	Comparator	Comparative Efficacy
Georgoulias et al. 2001	Phase III (C)	Docetaxel & Gemcitabine	Did not meet primary endpoints of ORR/TTP
Georgoulias et al. 2003	Phase III (C)	Docetaxel	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 2
• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

21-day cycles

References

1. Georgoulias V, Papadakis E, Alexopoulos A, Tsiafaki X, Rapti A, Veslemes M, Palamidas P, Vlachonikolis I; Greek Oncology Cooperative Group (GOCG) for Lung Cancer. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet. 2001 May 12;357(9267):1478-84. link to original article PubMed
2. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; ECOG. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains protocol PubMed
3. Georgoulias V, Pallis AG, Kourousis C, Alexopoulos A, Ardavanis A, Agelidou A, Agelidou M, Toumbis M, Tzannes S, Pavlakou G, Ziotopoulos P, Tzelepatiotis E, Samaras N; Hellenic Oncology Research Group. Docetaxel versus docetaxel/cisplatin in patients with advanced non-small-cell lung cancer: preliminary analysis of a multicenter, randomized phase III study. Clin Lung Cancer. 2003 Mar;4(5):288-93. link to original article PubMed
   1. Update: Georgoulias V, Ardavanis A, Agelidou A, Agelidou M, Chandrinos V, Tsaroucha E, Toumbis M, Kouroussis C, Syrigos K, Polyzos A, Samaras N, Papakotoulas P, Christofilakis C, Ziras N, Alegakis A. Docetaxel versus docetaxel plus cisplatin as front-line treatment of patients with advanced non-small-cell lung cancer: a randomized, multicenter phase III trial. J Clin Oncol. 2004 Jul 1;22(13):2602-9. link to original article contains protocol PubMed
4. TAX 326: Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed
5. Kubota K, Watanabe K, Kunitoh H, Noda K, Ichinose Y, Katakami N, Sugiura T, Kawahara M, Yokoyama A, Yokota S, Yoneda S, Matsui K, Kudo S, Shibuya M, Isobe T, Segawa Y, Nishiwaki Y, Ohashi Y, Niitani H; Japanese Taxotere Lung Cancer Study Group. Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol. 2004 Jan 15;22(2):254-61. link to original article contains protocol PubMed
6. Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M, Viñolas N, Paz-Ares L, Lopez-Vivanco G, Muñoz MA, Felip E, Alberola V, Camps C, Domine M, Sanchez JJ, Sanchez-Ronco M, Danenberg K, Taron M, Gandara D, Rosell R. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol. 2007 Jul 1;25(19):2747-54. link to original article contains verified protocol PubMed
7. Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. link to original article contains verified protocol PubMed
8. GLOB3: Tan EH, Rolski J, Grodzki T, Schneider CP, Gatzemeier U, Zatloukal P, Aitini E, Carteni G, Riska H, Tsai YH, Abratt R. Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and iv vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol. 2009 Jul;20(7):1249-56. Epub 2009 Mar 10. link to original article contains protocol PubMed
9. WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains verified protocol PubMed
10. ELCWP-01041: Berghmans T, Lafitte JJ, Scherpereel A, Paesmans M, Lecomte J, Marco VG, Meert AP, Leclercq N, Sculier JP; European Lung Cancer Working Party. An ELCWP phase III trial comparing ifosfamide and cisplatin regimens in advanced NSCLC. Anticancer Res. 2013 Dec;33(12):5477-82. link to original article contains verified protocol PubMed
11. TCOG0701 CATS: Kubota K, Sakai H, Katakami N, Nishio M, Inoue A, Okamoto H, Isobe H, Kunitoh H, Takiguchi Y, Kobayashi K, Nakamura Y, Ohmatsu H, Sugawara S, Minato K, Fukuda M, Yokoyama A, Takeuchi M, Michimae H, Gemma A, Kudoh S; Tokyo Cooperative Oncology Group. A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial. Ann Oncol. 2015 Jul;26(7):1401-8. Epub 2015 Apr 23. link to original article link to PMC article contains protocol PubMed UMIN000000608

Cisplatin & Etoposide

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PE: Platinol (Cisplatin) & Etoposide
EC: Etoposide & Cisplatin

Regimen variant #1, 60/360

Study	Evidence	Comparator	Comparative Efficacy
Ruckdeschel et al. 1986 (ECOG E1581)	Phase III (E-switch-ic)	1. CAMP 2. Cisplatin & Vindesine 3. MVP	Did not meet primary endpoint

Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Etoposide (Vepesid) 120 mg/m² IV once per day on days 4, 6, 8

21-day cycles

Regimen variant #2, 75/300

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bonomi et al. 2000 (ECOG E5592)	1993-1994	Phase III (C)	Cisplatin & Paclitaxel	Seems to have inferior OS
Belani et al. 2005	1995-1996	Phase III (C)	Carboplatin & Paclitaxel	Might have superior OS

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 60 minutes once on day 1
• Etoposide (Vepesid) 100 mg/m² IV over 45 minutes once per day on days 1 to 3

21-day cycles

Regimen variant #3, 100/300

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cardenal et al. 1999	1995-1996	Phase III (C)	Cisplatin & Gemcitabine	Inferior TTP

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

21-day cycles

Regimen variant #4, 105/600

Study	Evidence	Comparator	Comparative Efficacy
Font et al. 1999	Phase III (C)	PE; dose-dense	Did not meet primary endpoint of ORR

Chemotherapy

• Cisplatin (Platinol) 35 mg/m² IV once per day on days 1 to 3
• Etoposide (Vepesid) 200 mg/m² IV once per day on days 1 to 3

28-day cycles

Regimen variant #5, 120/300

Study	Evidence	Comparator	Comparative Efficacy
Klastersky et al. 1990 (EORTC 07861)	Phase III (C)	Carboplatin & Etoposide	Might have superior ORR
Comella et al. 1996	Phase III (C)	Carboplatin, Cisplatin, Etoposide, Vinorelbine	Did not meet primary endpoint of ORR

Chemotherapy

• Cisplatin (Platinol) 120 mg/m² IV once on day 1
  • Comella et al. 1996 gave 40 mg/m² IV once per day on days 1 to 3
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

3- to 4-week cycles

References

1. ECOG E1581: Ruckdeschel JC, Finkelstein DM, Ettinger DS, Creech RH, Mason BA, Joss RA, Vogl S. A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol. 1986 Jan;4(1):14-22. link to original article contains verified protocol PubMed
2. EORTC 07861: Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J, Cordier R, Finet C, Berchier MC, Sergysels R, Mommen P, Paesmans M. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organisation for Research and Treatment of Cancer Protocol 07861. J Clin Oncol. 1990 Sep;8(9):1556-62. link to original article contains verified protocol PubMed
3. Comella P, Frasci G, De Cataldis G, Panza N, Cioffi R, Curcio C, Belli M, Bianco A, Ianniello G, Maiorino L, Della Vittoria M, Perchard J, Comella G; Gruppo Oncologico Campano. Cisplatin/carboplatin + etoposide + vinorelbine in advanced non-small-cell lung cancer: a multicentre randomised trial. Br J Cancer. 1996 Dec;74(11):1805-11. link to original article contains protocol PubMed
4. Cardenal F, López-Cabrerizo MP, Antón A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, García M, Lianes P, Montalar J, Vadell C, González-Larriba JL, Nguyen B, Artal A, Rosell R. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999 Jan;17(1):12-8. link to original article contains protocol PubMed
5. Font A, Moyano AJ, Puerto JM, Tres A, Garcia-Giron C, Barneto I, Anton A, Sanchez JJ, Salvador A, Rosell R; Spanish Lung Cancer Group. Increasing dose intensity of cisplatin-etoposide in advanced nonsmall cell lung carcinoma: a phase III randomized trial of the Spanish Lung Cancer Group. Cancer. 1999 Feb 15;85(4):855-63. link to original article PubMed
6. ECOG E5592: Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18(3):623-31. link to original article contains verified protocol PubMed
7. Belani CP, Lee JS, Socinski MA, Robert F, Waterhouse D, Rowland K, Ansari R, Lilenbaum R, Natale RB. Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer. Ann Oncol. 2005 Jul;16(7):1069-75. Epub 2005 Apr 28. link to original article contains protocol PubMed

Cisplatin & Gemcitabine

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GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)

Regimen variant #1, 70/1000

Study	Evidence	Comparator	Comparative Efficacy
Park et al. 2007	Phase III (E-de-esc)	GC; 6 cycles	Non-inferior OS

Chemotherapy

• Cisplatin (Platinol) 70 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Regimen variant #2, 75/1250 q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Bissett et al. 2005		Phase III (C)	GC & Prinomastat	Did not meet primary endpoint of OS
Novello et al. 2007	2001-2004	Phase III (C)	GC x 2, then gemcitabine x 3	Inconclusive whether non-inferior OS
Manegold et al. 2011	2005-2007	Phase III (C)	GC & PF-3512676	Did not meet primary endpoint of OS
Reck et al. 2016 (KEYNOTE-024)	2014-2015	Phase III (C)	Pembrolizumab	Inferior OS	Inferior HRQoL

Note: Patients in Novello et al. 2007 received 5 cycles. Patients in KEYNOTE-024 received 4 to 6 cycles.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 30 minutes once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV over 2 hours once per day on days 1 & 8

21-day cycle for up to 6 cycles (see note)

Regimen variant #3, 75/1250 q4wk

Study	Evidence	Comparator	Comparative Efficacy
Wu et al. 2013 (FASTACT-2)	Phase III (C)	GC/Erlotinib	Seems to have superior OS

Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

28-day cycle for 4 cycles

Regimen variant #4, 80/1000

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ohe et al. 2006 (FACS)	2000-2002	Phase III (E-switch-ic)	1. Carboplatin & Paclitaxel	Inconclusive whether non-inferior OS
			2. Cisplatin & Irinotecan	Inconclusive whether non-inferior OS
			3. Cisplatin & Vinorelbine	Inconclusive whether non-inferior OS
Takeda et al. 2009 (WJTOG0203)		Phase III (C)	Platinum doublet x 3, then Gefitinib	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for 6 cycles (WJTOG0203) or indefinitely (FACS)

Regimen variant #5, 80/1125

Study	Evidence	Comparator	Comparative Efficacy
Wachters et al. 2003	Phase III (C)	Epirubicin & Gemcitabine	Did not meet primary endpoint of PFS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 2
• Gemcitabine (Gemzar) 1125 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 5 cycles

Regimen variant #6, 80/1200 x 6

Study	Evidence	Comparator	Comparative Efficacy
Gridelli et al. 2003	Phase III (C)	Gemcitabine & Vinorelbine	Might have superior OS
Gridelli et al. 2007 (GECO)	Phase III (C)	1. GC & Rofecoxib 2. Cisplatin & PCI Gemcitabine 3. Cisplatin, PCI Gemcitabine, Rofecoxib	Did not meet primary endpoint of OS
Gridelli et al. 2012 (TORCH)	Phase III (C)	Erlotinib	Superior OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Subsequent treatment

• TORCH, at progression: Erlotinib

Regimen variant #7, 80/1250 x 4

Study	Evidence	Comparator	Comparative Efficacy
Pérol et al. 2012 (IFCT-GFPC 0502)	Non-randomized portion of RCT
Ferry et al. 2017 (BTOG2)	Phase III (E-esc)	1. GC; GC50	Seems to have superior OS
		2. GCb6	Non-inferior OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Subsequent treatment

• IFCT-GFPC 0502: Erlotinib switch maintenance versus gemcitabine maintenance versus observation

Regimen variant #8, 80/1250 x 6

Study	Evidence	Comparator	Comparative Efficacy
Giaccone et al. 2004 (INTACT 1)	Phase III (C)	GC & Gefitinib	Did not meet primary endpoint of OS
Paz-Ares et al. 2006	Phase III (C)	GC & Aprinocarsen	Did not meet primary endpoint of OS
Gatzemeier et al. 2007 (TALENT)	Phase III (C)	GC & Erlotinib	Did not meet primary endpoint of OS
Boni et al. 2012 (FAST)	Phase III (C)	1. GIN 2. GN	Seems to have superior OS
		3. GIP	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #9, 100/1000 q3wk

Study	Evidence	Comparator	Comparative Efficacy
Ridolfi et al. 2011	Phase III (C)	GC & LD IL-2	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #10, 100/1000 q4wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Crinò et al. 1999		Phase III (E-switch-ic)	MIC	Seems to have superior ORR
Sandler et al. 2000	1995-1997	Phase III (E-RT-esc)	Cisplatin	Superior OS
Schiller et al. 2002 (ECOG E1594)		Phase III (E-switch-ic)	1. Carboplatin & Paclitaxel	Did not meet primary endpoint of OS
			2. Cisplatin & Docetaxel	Did not meet primary endpoint of OS
			3. Cisplatin & Paclitaxel	Superior PFS
Scagliotti et al. 2008 (JMDB)	2004-2005	Phase III (C)	Cisplatin & Pemetrexed	Seems to have non-inferior OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #11, 100/1250

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cardenal et al. 1999	1995-1996	Phase III (E-RT-switch-ic)	Cisplatin & Etoposide	Superior TTP
Alberola et al. 2003		Phase III (C)	1. CGV 2. GV-VI	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 6 cycles (Alberola et al. 2003) or indefinitely (Cardenal et al. 1999)

Regimen variant #12, 100/1400

Study	Evidence	Comparator	Comparative Efficacy
Gebbia et al. 2003	Phase III (E-switch-ic)	Cisplatin & Vinorelbine	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1400 mg/m² IV once per day on days 1 & 8

28-day cycles

References

1. Cardenal F, López-Cabrerizo MP, Antón A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, García M, Lianes P, Montalar J, Vadell C, González-Larriba JL, Nguyen B, Artal A, Rosell R. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999 Jan;17(1):12-8. link to original article contains protocol PubMed
2. Crinò L, Scagliotti GV, Ricci S, De Marinis F, Rinaldi M, Gridelli C, Ceribelli A, Bianco R, Marangolo M, Di Costanzo F, Sassi M, Barni S, Ravaioli A, Adamo V, Portalone L, Cruciani G, Masotti A, Ferrara G, Gozzelino F, Tonato M. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol. 1999 Nov;17(11):3522-30. link to original article contains protocol PubMed
3. Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, Mattson K, Manegold C, Palmer MC, Gregor A, Nguyen B, Niyikiza C, Einhorn LH. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2000 Jan;18(1):122-30. link to original article contains protocol PubMed
4. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; ECOG. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains protocol PubMed
5. Gebbia V, Galetta D, Caruso M, Verderame F, Pezzella G, Valdesi M, Borsellino N, Pandolfo G, Durini E, Rinaldi M, Loizzi M, Gebbia N, Valenza R, Tirrito ML, Varvara F, Colucci G; Gruppo Ocologico Italia Meridionale. Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide+gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale. Lung Cancer. 2003 Feb;39(2):179-89. link to original article contains protocol PubMed
6. Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. link to original article contains verified protocol PubMed
7. Alberola V, Camps C, Provencio M, Isla D, Rosell R, Vadell C, Bover I, Ruiz-Casado A, Azagra P, Jiménez U, González-Larriba JL, Diz P, Cardenal F, Artal A, Carrato A, Morales S, Sanchez JJ, de las Peñas R, Felip E, López-Vivanco G; Spanish Lung Cancer Group. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol. 2003 Sep 1;21(17):3207-13. link to original article contains protocol PubMed
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9. Wachters FM, Van Putten JW, Kramer H, Erjavec Z, Eppinga P, Strijbos JH, de Leede GP, Boezen HM, de Vries EG, Groen HJ. First-line gemcitabine with cisplatin or epirubicin in advanced non-small-cell lung cancer: a phase III trial. Br J Cancer. 2003 Oct 6;89(7):1192-9. link to original article link to PMC article contains protocol PubMed
10. INTACT 1: Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol. 2004 Mar 1;22(5):777-84. link to original article contains protocol PubMed
11. Bissett D, O'Byrne KJ, von Pawel J, Gatzemeier U, Price A, Nicolson M, Mercier R, Mazabel E, Penning C, Zhang MH, Collier MA, Shepherd FA. Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer. J Clin Oncol. 2005 Feb 1;23(4):842-9. link to original article contains protocol PubMed
12. Paz-Ares L, Douillard JY, Koralewski P, Manegold C, Smit EF, Reyes JM, Chang GC, John WJ, Peterson PM, Obasaju CK, Lahn M, Gandara DR. Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2006 Mar 20;24(9):1428-34. link to original article contains protocol PubMed
13. FACS: Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. link to original article contains verified protocol PubMed
14. Novello S, Bruzzi P, Barone C, Buosi R, Masotti A, Michetti G, Fioretti M, Barbera S, Spatafora M, Garetto L, Mazzanti P, Dongiovanni V, Selvaggi G, Crinò L, Scagliotti GV. Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone. Ann Oncol. 2007 May;18(5):903-8. Epub 2007 Mar 9. link to original article contains protocol PubMed
15. TALENT: Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, Milanowski J, Karnicka-Mlodkowski H, Pesek M, Serwatowski P, Ramlau R, Janaskova T, Vansteenkiste J, Strausz J, Manikhas GM, Von Pawel J. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007 Apr 20;25(12):1545-52. link to original article contains protocol PubMed
16. GECO: Gridelli C, Gallo C, Ceribelli A, Gebbia V, Gamucci T, Ciardiello F, Carozza F, Favaretto A, Daniele B, Galetta D, Barbera S, Rosetti F, Rossi A, Maione P, Cognetti F, Testa A, Di Maio M, Morabito A, Perrone F; GECO investigators. Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study. Lancet Oncol. 2007 Jun;8(6):500-12. link to original article contains protocol PubMed
17. Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. link to original article contains verified protocol PubMed
18. JMDB: Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 27. link to original article contains protocol PubMed
19. WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains verified protocol PubMed
20. Manegold C, van Zandwijk N, Szczesna A, Zatloukal P, Au JS, Blasinska-Morawiec M, Serwatowski P, Krzakowski M, Jassem J, Tan EH, Benner RJ, Ingrosso A, Meech SJ, Readett D, Thatcher N. A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol. 2012 Jan;23(1):72-7. Epub 2011 Apr 4. link to original article contains protocol PubMed
21. Ridolfi L, Bertetto O, Santo A, Naglieri E, Lopez M, Recchia F, Lissoni P, Galliano M, Testore F, Porta C, Maglie M, Dall'agata M, Fumagalli L, Ridolfi R. Chemotherapy with or without low-dose interleukin-2 in advanced non-small cell lung cancer: results from a phase III randomized multicentric trial. Int J Oncol. 2011 Oct;39(4):1011-7. Epub 2011 Jun 24. link to original article contains protocol PubMed
22. FAST: Boni C, Tiseo M, Boni L, Baldini E, Recchia F, Barone C, Grossi F, Germano D, Matano E, Marini G, Labianca R, Di Costanzo F, Bagnulo A, Pennucci C, Caroti C, Mencoboni M, Zanelli F, Prochilo T, Cafferata MA, Ardizzoni A; Gruppo Oncologico Italiano di Ricerca Clinica. Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST). Br J Cancer. 2012 Feb 14;106(4):658-65. Epub 2012 Jan 12. link to original article link to PMC article contains verified protocol PubMed
23. TORCH: Gridelli C, Ciardiello F, Gallo C, Feld R, Butts C, Gebbia V, Maione P, Morgillo F, Genestreti G, Favaretto A, Leighl N, Wierzbicki R, Cinieri S, Alam Y, Siena S, Tortora G, Felletti R, Riccardi F, Mancuso G, Rossi A, Cantile F, Tsao MS, Saieg M, da Cunha Santos G, Piccirillo MC, Di Maio M, Morabito A, Perrone F. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol. 2012 Aug 20;30(24):3002-11. Epub 2012 Jul 9. link to original article contains protocol PubMed
    1. HRQoL analysis: Di Maio M, Leighl NB, Gallo C, Feld R, Ciardiello F, Butts C, Maione P, Gebbia V, Morgillo F, Wierzbicki R, Favaretto A, Alam Y, Cinieri S, Siena S, Bianco R, Riccardi F, Spatafora M, Ravaioli A, Felletti R, Fregoni V, Genestreti G, Rossi A, Mancuso G, Fasano M, Morabito A, Tsao MS, Signoriello S, Perrone F, Gridelli C. Quality of life analysis of TORCH, a randomized trial testing first-line erlotinib followed by second-line cisplatin/gemcitabine chemotherapy in advancednon-small-cell lung cancer. J Thorac Oncol. 2012 Dec;7(12):1830-1844. link to original article PubMed
24. IFCT-GFPC 0502: Pérol M, Chouaid C, Pérol D, Barlési F, Gervais R, Westeel V, Crequit J, Léna H, Vergnenègre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Ségura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012 Oct 1;30(28):3516-24. Epub 2012 Sep 4. link to original articlecontains verified protocol PubMed
25. FASTACT-2: Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. link to original article contains protocol PubMed
26. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
27. BTOG2: Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M, Shah R, Thompson J, Spicer J, Muthukumar D, Skailes G, Leonard P, Chetiyawardana AD, Wells P, Lewanski C, Crosse B, Hill M, Gaunt P, O'Byrne K. Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: results from a British Thoracic Oncology Group randomised phase III trial. Eur J Cancer. 2017 Sep;83:302-312. Epub 2017 Aug 4. link to original article contains verified protocol PubMed

Cisplatin, Gemcitabine, Cetuximab

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Regimen

Study	Years of enrollment	Evidence
Butts et al. 2008	NR	Randomized Phase II (E-esc)

Note: this was a non-comparative study.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8
• Cetuximab (Erbitux) as follows:
  • Cycle 1: 400 mg/m² IV once on day 1, then 250 mg/m² IV once per day on days 8 & 15
  • Cycle 2 onwards: 250 mg/m² IV once per day on days 1, 8, 15

21-day cycle for up to 6 cycles

References

1. Butts CA, Bodkin D, Middleman EL, Englund CW, Ellison D, Alam Y, Kreisman H, Graze P, Maher J, Ross HJ, Ellis PM, McNulty W, Kaplan E, Pautret V, Weber MR, Shepherd FA. Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer. J Clin Oncol. 2007 Dec 20;25(36):5777-84. Erratum in: J Clin Oncol. 2008 Jul 1;26(19): 3295. link to original article contains verified protocol PubMed

Cisplatin & Irinotecan

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IP: Irinotecan & Platinol (Cisplatin)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Negoro et al. 2003		Phase III (E-switch-ic)	Cisplatin & Vindesine	Did not meet primary endpoint of OS
			Irinotecan	Not reported
Ohe et al. 2006 (FACS)	2000-2002	Phase III (C)	1. Carboplatin & Paclitaxel	Inconclusive whether non-inferior OS
			2. Cisplatin & Gemcitabine	Inconclusive whether non-inferior OS
			3. Cisplatin & Vinorelbine	Inconclusive whether non-inferior OS
Takeda et al. 2009 (WJTOG0203)		Phase III (C)	Platinum doublet x 3, then Gefitinib	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Irinotecan (Camptosar) 60 mg/m² IV once per day on days 1, 8, 15

28-day cycle for up to 6 cycles (WJTOG0203) or indefinitely (FACS)

References

1. Negoro S, Masuda N, Takada Y, Sugiura T, Kudoh S, Katakami N, Ariyoshi Y, Ohashi Y, Niitani H, Fukuoka M; CPT-11 Lung Cancer Study Group West. Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer. Br J Cancer. 2003 Feb 10;88(3):335-41. link to original article link to PMC article contains verified protocol PubMed
2. FACS: Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. link to original article contains verified protocol PubMed
3. WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains verified protocol PubMed

Cisplatin & Paclitaxel

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PC: Paclitaxel & Cisplatin

Regimen variant #1, 70/175 x 4

Study	Evidence	Comparator	Comparative Efficacy
Park et al. 2007	Phase III (E-de-esc)	Cisplatin & Paclitaxel x 6	Non-inferior OS

Chemotherapy

• Cisplatin (Platinol) 70 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 4 cycles

Regimen variant #2, 75/135, q2wk

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Stathopoulos et al. 2010a	Phase III (C)	Liposomal Cisplatin & Paclitaxel	Did not meet secondary endpoints	More toxic

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1, given second
• Paclitaxel (Taxol) 135 mg/m² IV over 3 hours once on day 1, given first

14-day cycle for up to 9 cycles

Regimen variant #3, 75/135, q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bonomi et al. 2000 (ECOG E5592)	1993-1994	Phase III (E-RT-switch-ic)	Cisplatin & Etoposide	Seems to have superior OS
Schiller et al. 2002 (ECOG E1594)		Phase III (C)	1. Carboplatin & Paclitaxel	Did not meet primary endpoint of OS
			2. Cisplatin & Docetaxel	Did not meet primary endpoint of OS
			3. Cisplatin & Gemcitabine	Inferior PFS

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 2, given second
• Paclitaxel (Taxol) 135 mg/m² IV continuous infusion over 24 hours, started on day 1, given first

21-day cycles

Regimen variant #4, 80/175

Study	Evidence	Comparator	Comparative Efficacy
Gatzemeier et al. 2000	Phase III (E-esc)	Cisplatin	Seems to have superior TTP
Smit et al. 2003 (EORTC 08975)	Phase III (C)	1. Cisplatin & Gemcitabine 2. Gemcitabine & Paclitaxel	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

21-day cycle for up to 6 cycles

Regimen variant #5, 80/200

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rosell et al. 2002	1996-1997	Phase III (E-switch-ic)	Carboplatin & Paclitaxel	Seems to have superior OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

21-day cycles

References

1. ECOG E5592: Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18(3):623-31. link to original article contains protocol PubMed
2. Gatzemeier U, von Pawel J, Gottfried M, ten Velde GP, Mattson K, de Marinis F, Harper P, Salvati F, Robinet G, Lucenti A, Bogaerts J, Gallant G. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Oct 1;18(19):3390-9. link to original article contains protocol PubMed
3. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; ECOG. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains verified protocol PubMed
4. Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemaissani A, Bogaerts J, Gallant G. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol. 2002 Oct;13(10):1539-49. link to original article contains protocol PubMed
5. EORTC 08975: Smit EF, van Meerbeeck JP, Lianes P, Debruyne C, Legrand C, Schramel F, Smit H, Gaafar R, Biesma B, Manegold C, Neymark N, Giaccone G; EORTC Lung Cancer Group. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organisation for Research and Treatment of Cancer Lung Cancer Group--EORTC 08975. J Clin Oncol. 2003 Nov 1;21(21):3909-17. link to original article contains protocol PubMed
6. Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. link to original article contains verified protocol PubMed
7. Stathopoulos GP, Antoniou D, Dimitroulis J, Michalopoulou P, Bastas A, Marosis K, Stathopoulos J, Provata A, Yiamboudakis P, Veldekis D, Lolis N, Georgatou N, Toubis M, Pappas Ch, Tsoukalas G. Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial. Ann Oncol. 2010 Nov;21(11):2227-32. Epub 2010 May 3. link to original article link to PMC article contains verified protocol PubMed

Cisplatin & Vinorelbine

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CV: Cisplatin & Vinorelbine
NP: Navelbine (Vinorelbine) & Platinol (Cisplatin)
PV: Platinol (Cisplatin) & Vinorelbine
VC: Vinorelbine & Cisplatin

Regimen variant #1, 75/25

Study	Evidence	Comparator	Comparative Efficacy
Martoni et al. 2005	Phase III (E-switch-ic)	Cisplatin & Gemcitabine	Did not meet primary endpoint of ORR

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Subsequent treatment

• Vinorelbine maintenance

Regimen variant #2, 80/25

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ohe et al. 2006 (FACS)	2000-2002	Phase III (E-switch-ic)	1. Carboplatin & Paclitaxel	Inconclusive whether non-inferior OS
			2. Cisplatin & Gemcitabine	Inconclusive whether non-inferior OS
			3. Cisplatin & Irinotecan	Inconclusive whether non-inferior OS
Pirker et al. 2009 (FLEX)		Phase III (C)	Cisplatin, Vinorelbine, Cetuximab	Seems to have inferior OS
Takeda et al. 2009 (WJTOG0203)		Phase III (C)	Platinum doublet x 3, then Gefitinib	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles (FLEX; WJTOG0203) or indefinitely (FACS)

Regimen variant #3, 80/30, 2 out of 3 weeks vinorelbine

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Gridelli et al. 2003	Phase III (C)	Gemcitabine & Vinorelbine	Might have superior OS
Georgoulias et al. 2005	Phase III (C)	Docetaxel & Gemcitabine	Did not meet primary endpoint of OS
Gebbia et al. 2008	Phase III (C)	Cisplatin & Vinorelbine; 3 out of 4 weeks	Did not meet primary endpoint of OS	Less toxic

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 8
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycle for 6 cycles (Gridelli et al. 2003) or up to 9 cycles (Georgoulias et al. 2005)

Regimen variant #4, 80/30, weekly vinorelbine

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Depierre et al. 1994	1989-1991	Phase III (E-esc)	Vinorelbine	Superior TTP
Souquet et al. 2002 (GLOB-1)	1998-1999	Phase III (C)	NIP	Did not meet primary endpoint of OS1

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1, 8, 15

21-day cycles

Regimen variant #5, 100/25

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Wozniak et al. 1998	1993-1995	Phase III (E-RT-esc)	Cisplatin	Superior OS
Kelly et al. 2001 (SWOG 9509)		Phase III (C)	Carboplatin & Paclitaxel	Did not meet primary endpoint of OS
Scagliotti et al. 2002		Phase III (C)	1. Carboplatin & Paclitaxel 2. Cisplatin & Gemcitabine	Did not meet primary endpoint of ORR
Fossella et al. 2003 (TAX 326)	1998-2000	Phase III (C)	1. Carboplatin & Docetaxel	Did not meet primary endpoint of OS
			2. Cisplatin & Docetaxel	Seems to have inferior OS
Ramlau et al. 2008 (SPIRIT I)		Phase III (C)	CV & Bexarotene	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for up to 10 cycles (SWOG 9509) or indefinitely (TAX 326, SPIRIT I)

Regimen variant #6, 100/30

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robinet et al. 2001 (GFPC 95-1)	1995-1997	Phase III (C)	CV & concurrent WBRT	Did not meet primary endpoint of
Pujol et al. 2005	1999-2001	Phase III (C)	Docetaxel & Gemcitabine	Did not meet primary endpoint of OS

Note: patients in GFPC 95-1 had intracranial metastases.

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV over 60 to 120 minutes once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV over 10 to 20 minutes once per day on days 1, 8, 15, 22

28-day cycle for 6 cycles

Subsequent treatment

• GFPC 95-1: WBRT

Regimen variant #7, 120/30

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Le Chevalier et al. 1994	1989-1991	Phase III (E-RT-esc)	1. Cisplatin & Vindesine	Seems to have superior OS
			2. Vinorelbine	Superior OS
Comella et al. 2000		Phase III (C)	1. Cisplatin & Gemcitabine	Not reported
			2. PGV	Inferior OS

Note: in Comella et al. 2000, vinorelbine was given for a total of 10 weeks.

Chemotherapy

• Cisplatin (Platinol) 120 mg/m² IV once on day 1
• Vinorelbine (Navelbine) as follows:
  • Cycle 1: 30 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycle 2 onwards: 30 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

28-day cycle for 1 cycle, then 42-day cycles (see note)

References

1. Depierre A, Chastang C, Quoix E, Lebeau B, Blanchon F, Paillot N, Lemarie E, Milleron B, Moro D, Clavier J, Herman D, Tuchais E, Jacoulet P, Brechot JM, Cordier JF, Solal-Celigny P, Badri N, Besenval M. Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: a randomized trial. Ann Oncol. 1994 Jan;5(1):37-42. link to original article contains protocol PubMed
2. Le Chevalier T, Brisgand D, Douillard JY, Pujol JL, Alberola V, Monnier A, Riviere A, Lianes P, Chomy P, Cigolari S, Gottfried M, Ruffle P, Panizo A, Gaspard MH, Ravaioli A, Besenval M, Besson F, Martinez A, Berthaud P, Tursz T. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol. 1994 Feb;12(2):360-7. link to original article contains protocol PubMed
3. Wozniak AJ, Crowley JJ, Balcerzak SP, Weiss GR, Spiridonidis CH, Baker LH, Albain KS, Kelly K, Taylor SA, Gandara DR, Livingston RB; SWOG. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1998 Jul;16(7):2459-65. link to original article PubMed
4. Comella P, Frasci G, Panza N, Manzione L, De Cataldis G, Cioffi R, Maiorino L, Micillo E, Lorusso V, Di Rienzo G, Filippelli G, Lamberti A, Natale M, Bilancia D, Nicolella G, Di Nota A, Comella G; Southern Italy Cooperative Oncology Group. Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol. 2000 Apr;18(7):1451-7. link to original article contains verified protocol PubMed
5. GFPC 95-1: Robinet G, Thomas P, Breton JL, Léna H, Gouva S, Dabouis G, Bennouna J, Souquet PJ, Balmes P, Thiberville L, Fournel P, Quoix E, Riou R, Rebattu P, Pérol M, Paillotin D, Mornex F. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol. 2001 Jan;12(1):59-67. link to original article contains protocol PubMed
6. SWOG 9509: Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001 Jul 1;19(13):3210-8. link to original article contains verified protocol PubMed
7. Scagliotti GV, De Marinis F, Rinaldi M, Crinò L, Gridelli C, Ricci S, Matano E, Boni C, Marangolo M, Failla G, Altavilla G, Adamo V, Ceribelli A, Clerici M, Di Costanzo F, Frontini L, Tonato M; Italian Lung Cancer Project. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol. 2002 Nov 1;20(21):4285-91. link to original article PubMed
8. GLOB-1: Souquet PJ, Tan EH, Rodrigues Pereira J, Van Klaveren R, Price A, Gatzemeier U, Jaworski M, Burillon JP, Aubert D. GLOB-1: a prospective randomised clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine-ifosfamide-cisplatin in metastatic non-small-cell lung cancer patients. Ann Oncol. 2002 Dec;13(12):1853-61. Erratum in: Ann Oncol. 2003 Feb;14(2):347. link to original article contains protocol PubMed
9. TAX 326: Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed
10. Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. link to original article contains verified protocol PubMed
11. Martoni A, Marino A, Sperandi F, Giaquinta S, Di Fabio F, Melotti B, Guaraldi M, Palomba G, Preti P, Petralia A, Artioli F, Picece V, Farris A, Mantovani L. Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer. Eur J Cancer. 2005 Jan;41(1):81-92. link to original article contains protocol PubMed
12. Georgoulias V, Ardavanis A, Tsiafaki X, Agelidou A, Mixalopoulou P, Anagnostopoulou O, Ziotopoulos P, Toubis M, Syrigos K, Samaras N, Polyzos A, Christou A, Kakolyris S, Kouroussis C, Androulakis N, Samonis G, Chatzidaki D. Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol. 2005 May 1;23(13):2937-45. Epub 2005 Feb 22. link to original article contains verified protocol PubMed
13. Pujol JL, Breton JL, Gervais R, Rebattu P, Depierre A, Morère JF, Milleron B, Debieuvre D, Castéra D, Souquet PJ, Moro-Sibilot D, Lemarié E, Kessler R, Janicot H, Braun D, Spaeth D, Quantin X, Clary C. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin. Ann Oncol. 2005 Apr;16(4):602-10. Epub 2005 Mar 1. link to original article contains verified protocol PubMed
14. FACS: Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. link to original article contains verified protocol PubMed
15. Gebbia V, Galetta D, Lorusso V, Caruso M, Verderame F, Pezzella G, Borsellino N, Durini E, Valenza R, Agostara B, Colucci G; Gruppo Oncologico Italia Meridionale. Cisplatin plus weekly vinorelbine versus cisplatin plus vinorelbine on days 1 and 8 in advanced non-small cell lung cancer: a prospective randomized phase III trial of the GOIM (Gruppo Oncologico Italia Meridionale). Lung Cancer. 2008 Sep;61(3):369-77. Epub 2008 Mar 4. link to original article contains protocol PubMed
16. SPIRIT I: Ramlau R, Zatloukal P, Jassem J, Schwarzenberger P, Orlov SV, Gottfried M, Rodrigues Pereira J, Temperley G, Negro-Vilar R, Rahal S, Zhang JK, Negro-Vilar A, Dziewanowska ZE. Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I. J Clin Oncol. 2008 Apr 10;26(11):1886-92. link to original article contains verified protocol PubMed
17. FLEX: Pirker R, Rodrigues Pereira J, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. link to original article contains verified protocol PubMed
18. WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains verified protocol PubMed

Cisplatin, Vinorelbine, Cetuximab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Pirker et al. 2009 (FLEX)	Phase III (E-esc)	Cisplatin & Vinorelbine	Seems to have superior OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8
• Cetuximab (Erbitux) as follows:
  • Cycle 1: 400 mg/m² IV over 2 hours once on day 1, then 250 mg/m² IV over 60 minutes once per day on days 8 & 15
  • Cycles 2 to 6: 250 mg/m² IV over 60 minutes once per day on days 1, 8, 15

21-day cycle for up to 6 cycles

Subsequent treatment

• Cetuximab maintenance

References

1. FLEX: Pirker R, Rodrigues Pereira J, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. link to original article contains protocol PubMed

Docetaxel & Vinorelbine

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Regimen

Study	Evidence
Miller et al. 2000	Phase II

Chemotherapy

• Docetaxel (Taxotere)
• Vinorelbine (Navelbine)

References

1. Miller VA, Krug LM, Ng KK, Pizzo B, Perez W, Heelan RT, Kris MG. Phase II trial of docetaxel and vinorelbine in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Mar;18(6):1346-50. link to original article PubMed

Gemcitabine & Paclitaxel

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GT: Gemcitabine & Taxol (Paclitaxel)

Regimen variant #1, 1000/125

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kosmidis et al. 2002		Phase III (E-switch-ic)	Carboplatin & Paclitaxel	Did not meet primary endpoint of OS
Kosmidis et al. 2007	2000-2004	Phase III (E-switch-ic)	Carboplatin & Gemcitabine	Did not meet primary endpoint of OS
Comella et al. 2006 (SICOG 0101)	2001-2005	Phase III (C)	1. GV 2. PGT 3. PGV	Did not meet primary endpoint of OS

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Paclitaxel (Taxol) 125 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #2, 1000/200

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kosmidis et al. 2010	2004-2008	Phase III (C)	Paclitaxel & Vinorelbine	Did not meet primary endpoint of OS

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycles

References

1. Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008 Jan;19(1):115-22. Epub 2007 Oct 15. link to original article contains protocol PubMed
2. SICOG 0101: Comella P, Filippelli G, De Cataldis G, Massidda B, Frasci G, Maiorino L, Putzu C, Mancarella S, Palmeri S, Cioffi R, Roselli M, Buzzi F, Milia V, Gambardella A, Natale D, Bianco M, Ghiani M, Masullo P; Southern Italy Cooperative Oncology Group. Efficacy of the combination of cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101). Ann Oncol. 2007 Feb;18(2):324-30. Epub 2006 Oct 27. link to original article contains protocol PubMed
3. Kosmidis PA, Fountzilas G, Eleftheraki AG, Kalofonos HP, Pentheroudakis G, Skarlos D, Dimopoulos MA, Bafaloukos D, Pectasides D, Samantas E, Boukovinas J, Lambaki S, Katirtzoglou N, Bakogiannis C, Syrigos KN; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus paclitaxel and vinorelbine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol. 2011 Apr;22(4):827-34. Epub 2010 Sep 29. link to original article contains protocol PubMed ACTRN12609000946213

Gemcitabine & Vinorelbine

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VG: Vinorelbine & Gemcitabine G+V: Gemcitabine & Vinorelbine

Regimen variant #1, 1000/25, 2 weeks out of 3 (IV vinorelbine)

Study	Evidence	Comparator	Comparative Efficacy
Laack et al. 2004	Phase III (E-de-esc)	GVP	Did not meet primary endpoint of OS
Tan et al. 2005 (GLOB 2)	Phase III (E-switch-ic)	Carboplatin & Vinorelbine	Did not meet primary endpoint of ORR

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

Supportive medications

• "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

21-day cycles

Regimen variant #2, 1000/25, 3 weeks out of 4 (IV vinorelbine)

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Greco et al. 2007	Phase III (E-switch-ic)	PCG	Did not meet primary endpoint of OS	Less toxic

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #3, 1000/60 (PO vinorelbine)

Study	Evidence	Comparator	Comparative Efficacy
Fløtten et al. 2012	Phase III (E-switch-ic)	Carboplatin & Vinorelbine	Did not meet primary endpoint of OS

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 60 mg/m² PO once per day on days 1 & 8

21-day cycle for 3 cycles

Regimen variant #4, 1200/30

Study	Evidence	Comparator	Comparative Efficacy
Frasci et al. 2001	Phase III (E-esc)	Vinorelbine	Superior OS

Chemotherapy

• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, DeCataldis G, Belli M, Iannelli N, Massidda B, Mascia V, Comella G, De Lena M; Southern Italy Cooperative Oncology Group. Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer: a Southern Italy Cooperative Oncology Group (SICOG) phase III trial. Lung Cancer. 2001 Dec;34 Suppl 4:S65-9. link to original article contains protocol PubMed
2. Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. link to original article contains verified protocol PubMed
3. Laack E, Dickgreber N, Müller T, Knuth A, Benk J, Lorenz C, Gieseler F, Dürk H, Engel-Riedel W, Dalhoff K, Kortsik C, Graeven U, Burk M, Dierlamm T, Welte T, Burkholder I, Edler L, Hossfeld DK; German and Swiss Lung Cancer Study Group. Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group. J Clin Oncol. 2004 Jun 15;22(12):2348-56. link to original article contains protocol PubMed
4. GLOB 2: Tan EH, Szczesna A, Krzakowski M, Macha HN, Gatzemeier U, Mattson K, Wernli M, Reiterer P, Hui R, Pawel JV, Bertetto O, Pouget JC, Burillon JP, Parlier Y, Abratt R; GLOB 2 group. Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2005 Aug;49(2):233-40. link to original article contains protocol PubMed
5. Greco FA, Spigel DR, Kuzur ME, Shipley D, Gray JR, Thompson DS, Burris HA, Yardley DA, Pati A, Webb CD, Gandhi JG, Hainsworth JD. Paclitaxel/Carboplatin/gemcitabine versus gemcitabine/vinorelbine in advanced non-small-cell lung cancer: a phase II/III study of the Minnie Pearl Cancer Research Network. Clin Lung Cancer. 2007 Sep;8(8):483-7. link to original article PubMed
6. Fløtten Ø, Grønberg BH, Bremnes R, Amundsen T, Sundstrøm S, Rolke H, Hornslien K, Wentzel-Larsen T, Aasebø U, von Plessen C; Norwegian Lung Cancer Study Group. Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC: a phase III randomised controlled trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2012 Jul 24;107(3):442-7. Epub 2012 Jul 3. link to original article link to PMC article contains protocol PubMed

Ipilimumab & Nivolumab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Hellmann et al. 2018 (CheckMate 227)	Phase III (E-RT-switch-ooc)	1. Nivolumab	Not reported
		2. Platinum doublet	Superior OS (*)

Note: reported efficacy is based on the 2019 update.

Immunotherapy

• Ipilimumab (Yervoy) 1 mg/kg IV once on day 1
• Nivolumab (Opdivo) 3 mg/kg IV once per day on days 1, 15, 29

42-day cycles

References

1. CheckMate 227: Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018 May 31;378(22):2093-2104. Epub 2018 Apr 16. link to original article contains verified protocol PubMed
   1. Update: Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, Sakai H, Albert I, Vergnenegre A, Peters S, Syrigos K, Barlesi F, Reck M, Borghaei H, Brahmer JR, O'Byrne KJ, Geese WJ, Bhagavatheeswaran P, Rabindran SK, Kasinathan RS, Nathan FE, Ramalingam SS. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019 Nov 21;381(21):2020-2031. Epub 2019 Sep 28. link to original article PubMed

Nivolumab monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	ORR
Carbone et al. 2017 (CheckMate 026)	Phase III (E-switch-ooc)	Platinum doublet	Did not meet primary endpoint of PFS	26% (95% CI 20 - 33)

Note: control arm patients in CheckMate 026 received investigator's choice of platinum doublet; the most commonly used regimen was carboplatin & paclitaxel.

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1
  • Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

14-day cycles

References

1. CheckMate 026: Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017 Jun 22;376(25):2415-2426. link to original articlecontains verified protocol PubMed
2. CheckMate 227: Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018 May 31;378(22):2093-2104. Epub 2018 Apr 16. link to original article contains verified protocol PubMed

Pembrolizumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Garon et al. 2015 (KEYNOTE-001)		Phase 1, >20 pts in dosing cohort
Reck et al. 2016 (KEYNOTE-024)	2014-2015	Phase III (E-RT-switch-ooc)	1. Carboplatin & Gemcitabine 2. Carboplatin & Paclitaxel 3. Carboplatin & Pemetrexed 4. Cisplatin & Gemcitabine 5. Cisplatin & Pemetrexed	Superior OS	Superior HRQoL
Mok et al. 2019 (KEYNOTE-042)	2014-2017	Phase III (E-RT-switch-ooc)	1. Carboplatin & Paclitaxel 2. Carboplatin & Pemetrexed	Superior OS

KEYNOTE-024 required PD-L1 to be expressed on at least 50% of tumor cells, no EGFR/ALK mutations. Treatment choice for patients in the comparator arm was up to the investigators; most with nonsquamous histology received carboplatin & pemetrexed, whereas most with squamous histology received carboplatin & gemcitabine. Patients could receive a maximum of 35 cycles. ORR was 45% (95% CI: 37-53).
KEYNOTE-042 required PD-L1 to be expressed on at least 1% of tumor cells. Treatment choice for patients in the comparator arm was carboplatin & paclitaxel for patients with squamous histology, and carboplatin & pemetrexed for patients with nonsquamous histology.

Immunotherapy

• Pembrolizumab (Keytruda) 200 IV once on day 1

21-day cycles

References

1. Phase 1: Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. Epub 2015 Apr 19. link to original article PubMed
2. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
   1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
   2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
3. KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed

Advanced or metastatic disease, first-line, nonsquamous

ABCP

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ABCP: Atezolizumab, Bevacizumab, Carboplatin, Paclitaxel

Regimen variant #1, 1200/15/6/175 x 4

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Socinski et al. 2018 (IMpower150)	2015-2016	Phase III (E-RT-esc)	1. ACP	Not reported
			2. BCP	Seems to have superior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1

Chemotherapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1
• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Atezolizumab & Bevacizumab maintenance

Regimen variant #2, 1200/15/6/175 x 6

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Socinski et al. 2018 (IMpower150)	2015-2016	Phase III (E-RT-esc)	1. ACP	Not reported
			2. BCP	Seems to have superior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1

Chemotherapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1
• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• Atezolizumab & Bevacizumab maintenance

Regimen variant #3, 1200/15/6/200 x 4

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Socinski et al. 2018 (IMpower150)	2015-2016	Phase III (E-RT-esc)	1. ACP	Not reported
			2. BCP	Seems to have superior OS

Note: the total number of cycles given in IMpower150 was determined prior to randomization. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1

Chemotherapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1
• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Atezolizumab & Bevacizumab maintenance

Regimen variant #4, 1200/15/6/200 x 6

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Socinski et al. 2018 (IMpower150)	2015-2016	Phase III (E-RT-esc)	1. ACP	Not reported
			2. BCP	Seems to have superior OS

Note: the total number of cycles given in IMpower150 was determined prior to randomization. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1

Chemotherapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1
• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• Atezolizumab & Bevacizumab maintenance

References

1. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed

Carboplatin & Docetaxel

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DCb: Docetaxel & Carboplatin

Regimen

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Rodrigues-Pereira et al. 2011 (H3E-CR-S380)	Phase III (C)	Carboplatin & Pemetrexed	Did not meet primary endpoint of OS	Inferior survival without treatment-emergent grade 3/4 toxicity

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

References

1. H3E-CR-S380: Rodrigues-Pereira J, Kim JH, Magallanes M, Lee DH, Wang J, Ganju V, Martínez-Barrera L, Barraclough H, van Kooten M, Orlando M. A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol. 2011 Nov;6(11):1907-14. link to original article contains protocol PubMed

Carboplatin & Gemcitabine

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CG: Carboplatin & Gemcitabine

Regimen

Study	Evidence
Jian et al. 2017	Non-randomized portion of RCT

Note: the manuscript does not specify whether gemcitabine is given more than once per cycle.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once on day 1

28-day cycle for 2 cycles

Subsequent treatment

• Continued CG x 4 versus CG & Gefitinib

References

1. Jian H, Li W, Ma Z, Huang J, Feng J, Song Y, Gao B, Zhu H, Tao M, Bai C, Ma S, Pan H, Qin S, Hua D, Yu Y, Lu S. Intercalating and maintenance gefitinib plus chemotherapy versus chemotherapy alone in selected advanced non-small cell lung cancer with unknown EGFR status. Sci Rep. 2017 Aug 16;7(1):8483. link to original article link to PMC article contains verified protocol PubMed

Carboplatin, nab-Paclitaxel, Atezolizumab

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
West et al. 2019 (IMpower130)	2015-2017	Phase III (E-RT-esc)	Carboplatin & nab-Paclitaxel	Seems to have superior OS

Note: the FDA-recommended dose is specific to the atezolizumab dosing.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycle for 4 to 6 cycles

Subsequent treatment

• Atezolizumab maintenance

References

1. IMpower130: West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, Kopp HG, Daniel D, McCune S, Mekhail T, Zer A, Reinmuth N, Sadiq A, Sandler A, Lin W, Ochi Lohmann T, Archer V, Wang L, Kowanetz M, Cappuzzo F. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):924-937. Epub 2019 May 20. link to original article contains protocol PubMed

Carboplatin & Paclitaxel

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TC: Taxol (Paclitaxel) & Carboplatin
CP: Carboplatin & Paclitaxel

Regimen variant #1, 6/175

Study	Evidence	Comparator	Comparative Efficacy
Zhou et al. 2015 (BEYOND)	Phase III (C)	Carboplatin, Paclitaxel, Bevacizumab	Seems to have inferior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Supportive medications

• Corticosteroids could be used as premedication for Paclitaxel (Taxol) infusion

21-day cycle for up to 6 cycles

Regimen variant #2, 6/200

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sandler et al. 2006 (ECOG E4599)	2001-2004	Phase III (C)	PacCBev, then Maintenance Bev	Inferior OS
Mok et al. 2009 (IPASS)	2006-2007	Phase III (C)	Gefitinib	Inferior PFS
Scagliotti et al. 2012 (MONET1)		Phase III (C)	TC & Motesanib	Did not meet primary endpoint of OS
Kubota et al. 2017 (MONET-A)		Phase III (C)	TC & Motesanib	Might have inferior PFS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for 3 or more cycles

References

1. ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; ECOG. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article contains verified protocol PubMed
2. IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article contains verified protocol PubMed
   1. Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article PubMed
   2. Dataset: Project Data Sphere
3. MONET1: Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, Pirker R, Galiulin R, Ciuleanu TE, Sydorenko O, Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, Hei YJ, Galimi F, Spigel DR. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol. 2012 Aug 10;30(23):2829-36. Epub 2012 Jul 2. link to original article contains protocol PubMed
4. BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article contains protocol PubMed
5. MONET-A: Kubota K, Yoshioka H, Oshita F, Hida T, Yoh K, Hayashi H, Kato T, Kaneda H, Yamada K, Tanaka H, Ichinose Y, Park K, Cho EK, Lee KH, Lin CB, Yang JC, Hara K, Asato T, Nakagawa K. Phase III, randomized, placebo-controlled, double-blind trial of motesanib (AMG-706) in combination with paclitaxel and carboplatin in East Asian patients with advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2017 Nov 10;35(32):3662-3670. Epub 2017 Sep 13. link to original article contains verified protocol PubMed

Carboplatin, Paclitaxel, Bevacizumab

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PacCBev: Paclitaxel, Carboplatin, Bevacizumab
B+CP: Bevacizumab, Carboplatin, Paclitaxel
BCP: Bevacizumab, Carboplatin, Paclitaxel
CbTB: Carboplatin, Taxol (Paclitaxel), Bevacizumab

Regimen variant #1, 6/175/15 x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Socinski et al. 2018 (IMpower150)	2015-2016	Phase III (C)	1. ACP	Not reported
			2. ABCP	Seems to have inferior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Bevacizumab maintenance

Regimen variant #2, 6/175/15 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Socinski et al. 2018 (IMpower150)	2015-2016	Phase III (C)	1. ACP	Not reported
			2. ABCP	Seems to have inferior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• Bevacizumab maintenance

Regimen variant #3, 6/200/15 x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Patel et al. 2013 (PointBreak)		Phase III (C)	PemCBev, then PemBev maint.	Seems to have inferior PFS
Zinner et al. 2015 (PRONOUNCE)		Phase III (C)	See link	See link
Socinski et al. 2018 (IMpower150)	2015-2016	Phase III (C)	1. ACP	Not reported
			2. ABCP	Seems to have inferior OS

Note: the total number of cycles given in IMpower150 was determined prior to randomization.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

Supportive medications

• Premedications per paclitaxel label
• Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycle for 4 cycles

Subsequent treatment

• Bevacizumab maintenance

Regimen variant #4, 6/200/15 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sandler et al. 2006 (ECOG E4599)	2001-2004	Phase III (E-RT-esc)	See link	See link
Zhou et al. 2015 (BEYOND)		Phase III (E-esc)	Carboplatin & Paclitaxel	Seems to have superior OS
Socinski et al. 2018 (IMpower150)	2015-2016	Phase III (C)	1. ACP	Not reported
			2. ABCP	Seems to have inferior OS

Note: the total number of cycles given in IMpower150 was determined prior to randomization. Patients in SWOG S0819 were EGFR FISH positive.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 30 minutes once on day 1, given second, starting 60 minutes after the completion of paclitaxel
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1, given third, starting 60 minutes after the completion of carboplatin
  • Infusion time per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, given over 30 to 60 minutes for cycles 2 and later

21-day cycle for up to 6 cycles

Subsequent treatment

• Bevacizumab maintenance

References

1. ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; ECOG. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article contains verified protocol PubMed
2. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed
   1. Dataset: Project Data Sphere
3. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed
4. BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article contains protocol PubMed
5. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed

Carboplatin & Pemetrexed

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CP: Carboplatin & Pemetrexed
Carbo-Pem: Carboplatin & Pemetrexed

Example orders

• Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer

Regimen variant #1, 5/500 x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Langer et al. 2016 (KEYNOTE-021)		Randomized Phase II (C)	See link	See link
Gandhi et al. 2018 (KEYNOTE-189)	2016-2017	Phase III (C)	See link	See link

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive medications

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be given throughout pemetrexed therapy

21-day cycle for up to 4 cycles

Subsequent treatment

• Pemetrexed maintenance (optional in KEYNOTE-021)

Regimen variant #2, 5/500 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Rodrigues-Pereira et al. 2011 (H3E-CR-S380)		Phase III (E-switch-ic)	Carboplatin & Docetaxel	Did not meet primary endpoint of OS	Superior survival without treatment-emergent grade 3/4 toxicity
Mok et al. 2019 (KEYNOTE-042)	2014-2017	Phase III (C)	Pembrolizumab	Inferior OS

Patients in KEYNOTE-042 receiving this treatment had nonsquamous NSCLC.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive medications

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be taken throughout pemetrexed therapy.
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be given throughout pemetrexed therapy

21-day cycle for up to 6 cycles

Subsequent treatment

• Optional pemetrexed maintenance

Regimen variant #3, 6/500 x 4

Study	Evidence	Comparator	Comparative Efficacy
Zinner et al. 2015 (PRONOUNCE)	Phase III (E-switch-ooc)	See link	See link

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive medications

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be given throughout pemetrexed therapy

21-day cycle for up to 4 cycles

Subsequent treatment

• Pemetrexed maintenance

Regimen variant #4, 6/500 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Mok et al. 2019 (KEYNOTE-042)	2014-2017	Phase III (C)	Pembrolizumab	Inferior OS

Patients in KEYNOTE-042 receiving this treatment had nonsquamous NSCLC.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

Supportive medications

• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose prior to Pemetrexed (Alimta)
• Folic acid (Folate) 1 mg PO once per day

21-day cycle for up to 6 cycles

Subsequent treatment

• Optional pemetrexed maintenance

Regimen variant #5, 6/500 indefinitely

Study	Evidence	Comparator	Comparative Efficacy
Edelman et al. 2017 (CALGB 30801)	Phase III (C)	CP & Celecoxib	Did not meet primary endpoint of PFS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

21-day cycles

References

1. H3E-CR-S380: Rodrigues-Pereira J, Kim JH, Magallanes M, Lee DH, Wang J, Ganju V, Martínez-Barrera L, Barraclough H, van Kooten M, Orlando M. A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol. 2011 Nov;6(11):1907-14. link to original article contains protocol PubMed
2. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed
3. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol PubMed
4. CALGB 30801: Edelman MJ, Wang X, Hodgson L, Cheney RT, Baggstrom MQ, Thomas SP, Gajra A, Bertino E, Reckamp KL, Molina J, Schiller JH, Mitchell-Richards K, Friedman PN, Ritter J, Milne G, Hahn OM, Stinchcombe TE, Vokes EE; Alliance for Clinical Trials in Oncology. Phase III randomized, placebo-controlled, double-blind trial of celecoxib in addition to standard chemotherapy for advanced non-small-cell lung cancer with cyclooxygenase-2 overexpression: CALGB 30801 (Alliance). J Clin Oncol. 2017 Jul 1;35(19):2184-2192. Epub 2017 May 10. link to original article link to PMC article contains verified protocol PubMed
5. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed
6. KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed

Carboplatin, Pemetrexed, Bevacizumab

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PemCBev: Pemetrexed, Carboplatin, Bevacizumab

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Patel et al. 2013 (PointBreak)	Phase III (E-switch-ic)	PacCBev, then Maintenance Bev	Seems to have superior PFS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

Supportive medications

• Premedications, Folic acid (Folate), and vitamin supplementation per pemetrexed label
• Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycle for 4 cycles

Subsequent treatment

• Patients with complete response, partial response, or stable disease: Pemetrexed & Bevacizumab maintenance

References

1. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed
   1. Dataset: Project Data Sphere

Cisplatin & Docetaxel

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DC: Docetaxel & Cisplatin
DP: Docetaxel & Platinol (Cisplatin)
Doc-Cis: Docetaxel & Cisplatin

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Park et al. 2017	Phase III (C)	Cisplatin & Pemetrexed	Inconclusive whether non-inferior PFS

Chemotherapy

• Cisplatin (Platinol) 70 mg/m² IV once on day 1
• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

21-day cycle for up to 4 cycles

References

1. Park CK, Oh IJ, Kim KS, Choi YD, Jang TW, Kim YS, Lee KH, Shin KC, Jung CY, Yang SH, Ryu JS, Jang SH, Yoo SS, Yong SJ, Lee KY, In KH, Lee MK, Kim YC. Randomized phase III study of docetaxel plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of nonsquamous non-small-cell lung cancer: a TRAIL trial. Clin Lung Cancer. 2017 Jul;18(4):e289-e296. Epub 2017 Jan 11. link to original article contains protocol PubMed

Cisplatin & Gemcitabine

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GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)

Regimen variant #1, 75/1250

Study	Evidence	Comparator	Comparative Efficacy
Paz-Ares et al. 2012 (NExUS)	Phase III (C)	GC & Sorafenib	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 30 minutes once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV over 2 hours once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #2, 80/1250 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Reck et al. 2009 (AVAil)	2005-2006	Phase III (C)	1. GC & Bevacizumab; low-dose	Inferior PFS
			2. GC & Bevacizumab; standard-dose	Seems to have inferior PFS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #3, 80/1250 x 9

Study	Evidence	Comparator	Comparative Efficacy
Han et al. 2012 (First-SIGNAL)	Phase III (C)	Gefitinib	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 9 cycles

References

1. AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains protocol PubMed NCT00806923
   1. Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed
2. First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article contains protocol PubMed
3. NExUS: Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, Zhang L, Liao M, Sun Y, Gans S, Syrigos K, Le Marie E, Gottfried M, Vansteenkiste J, Alberola V, Strauss UP, Montegriffo E, Ong TJ, Santoro A; NSCLC [non–small-cell lung cancer] Research Experience Utilizing Sorafenib (NExUS) Investigators Study Group. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol. 2012 Sep 1;30(25):3084-92. Epub 2012 Jul 30. link to original article contains protocol PubMed
   1. Dataset: Project Data Sphere

Cisplatin, Gemcitabine, Bevacizumab

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Regimen variant #1, low-dose bev

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Reck et al. 2009 (AVAil)	2005-2006	Phase III (E-RT-esc)	Cisplatin & Gemcitabine	Superior PFS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycle for up to 6 cycles

Subsequent treatment

• Bevacizumab maintenance

Regimen variant #2, standard-dose bev

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Reck et al. 2009 (AVAil)	2005-2006	Phase III (E-RT-esc)	Cisplatin & Gemcitabine	Seems to have superior PFS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for up to 6 cycles

Subsequent treatment

• Bevacizumab maintenance

References

1. AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains verified protocol PubMed NCT00806923
   1. Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed

Cisplatin & Pemetrexed

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Pem-Cis: Pemetrexed & Cisplatin
Cis-Pem: Cisplatin & Pemetrexed

Regimen variant #1, 70/500

Study	Evidence	Comparator	Comparative Efficacy
Park et al. 2017	Phase III (E-switch-ic)	Cisplatin & Docetaxel	Inconclusive whether non-inferior PFS

Chemotherapy

• Cisplatin (Platinol) 70 mg/m² IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

21-day cycle for up to 4 cycles

Regimen variant #2, 75/500

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Paz-Ares et al. 2012 (PARAMOUNT)		Non-randomized portion of RCT
Wu et al. 2014 (JMIL)		Phase III (C)	GC	Did not meet primary endpoint of OS
Paz-Ares et al. 2015 (INSPIRE)		Phase III (C)	Pem-Cis & Necitumumab	Did not meet primary endpoint of OS
Reck et al. 2016 (KEYNOTE-024)	2014-2015	Phase III (C)	Pembrolizumab	Inferior OS	Inferior HRQoL
Gandhi et al. 2018 (KEYNOTE-189)		Phase III (C)	See link	See link

Note: Selection of platinum agent in KEYNOTE-189 was per investigator choice.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive medications

• (as described in JMDB):
• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to Pemetrexed (Alimta)
• Folic acid (Folate) 1 mg PO once per day
• In Sequist et al. 2013: Patients "received Folic acid (Folate), vitamin B12, and dexamethasone, as per package recommendations for Pemetrexed (Alimta)."

21-day cycle for 4 to 6 cycles

Subsequent treatment

• PARAMOUNT: Placebo versus pemetrexed maintenance
• KEYNOTE-024 & KEYNOTE-189: Pemetrexed maintenance (optional in KEYNOTE-024)

References

1. PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article contains verified protocol PubMed
   1. HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article PubMed
   2. Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
2. JMIL: Wu YL, Lu S, Cheng Y, Zhou C, Wang M, Qin S, Lu Y, Zhang Y, Zhu Y, Song X, Wang X, Barraclough H, Zhang X, Chi H, Orlando M. Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer. Lung Cancer. 2014 Sep;85(3):401-7. Epub 2014 Jul 17. link to original article PubMed
3. INSPIRE: Paz-Ares L, Mezger J, Ciuleanu TE, Fischer JR, von Pawel J, Provencio M, Kazarnowicz A, Losonczy G, de Castro G Jr, Szczesna A, Crino L, Reck M, Ramlau R, Ulsperger E, Schumann C, Miziara JE, Lessa ÁE, Dediu M, Bálint B, Depenbrock H, Soldatenkova V, Kurek R, Hirsch FR, Thatcher N, Socinski MA; INSPIRE investigators. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncol. 2015 Mar;16(3):328-37. Epub 2015 Feb 18. link to original article PubMed
4. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
   1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
   2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
5. Park CK, Oh IJ, Kim KS, Choi YD, Jang TW, Kim YS, Lee KH, Shin KC, Jung CY, Yang SH, Ryu JS, Jang SH, Yoo SS, Yong SJ, Lee KY, In KH, Lee MK, Kim YC. Randomized phase III study of docetaxel plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of nonsquamous non-small-cell lung cancer: a TRAIL trial. Clin Lung Cancer. 2017 Jul;18(4):e289-e296. Epub 2017 Jan 11. link to original article contains protocol PubMed
6. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed

Cisplatin, Pemetrexed, Bevacizumab

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Regimen

Study	Evidence
Barlesi et al. 2013 (AVAPERL)	Non-randomized portion of RCT

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 2 hours once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1
• Bevacizumab (Avastin) 7.5 mg/kg IV over 90 minutes once on day 1
  • If well tolerated, subsequent infusions were given over 60 minutes, then 30 minutes

Supportive medications

• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 3 cycles (i.e. every 9 weeks), given throughout therapy
• Folic acid (Folate) 350 to 1000 mcg PO once per day, given throughout therapy
• Dexamethasone (Decadron) 4 mg PO twice per day on days -1 to 2 (3 days)

21-day cycle for 4 cycles

Subsequent treatment

• Patients with complete response (CR), partial response (PR), or stable disease (SD): Bevacizumab versus Pemetrexed & Bevacizumab maintenance

References

1. AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
   1. Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article PubMed

Cisplatin, Pemetrexed, Pembrolizumab

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gandhi et al. 2018 (KEYNOTE-189)	2016-2017	Phase III (E-RT-esc)	See link	See link

Note: selection of platinum agent in KEYNOTE-189 was per investigator choice.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV over 30 minutes once on day 1, at least 30 minutes prior to chemotherapy

Supportive medications

• "Premedication with folic acid, vitamin B12, and corticosteroids was administered according to local guidelines."

21-day cycle for 4 cycles

Subsequent treatment

• Pemetrexed & Pembrolizumab maintenance

References

1. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed

Gefitinib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Mok et al. 2009 (IPASS)	2006-2007	Phase III (E-RT-switch-ooc)	Carboplatin & Paclitaxel	Superior PFS
Han et al. 2012 (First-SIGNAL)		Phase III (E-switch-ooc)	Cisplatin & Gemcitabine	Did not meet primary endpoint of OS
Yang et al. 2014 (H3E-CR-S131)		Phase III (E-de-esc)	Cisplatin & Pemetrexed, then Gefitinib maint.	Did not meet primary endpoint of PFS

Chemotherapy

• Gefitinib (Iressa) 250 mg PO once per day

Continued indefinitely

References

1. IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article contains verified protocol PubMed
   1. Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article PubMed
   2. Dataset: Project Data Sphere
2. First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article contains protocol PubMed
3. H3E-CR-S131: Yang JC, Kang JH, Mok T, Ahn MJ, Srimuninnimit V, Lin CC, Kim DW, Tsai CM, Barraclough H, Altug S, Orlando M, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial. Eur J Cancer. 2014 Sep;50(13):2219-30. Epub 2014 Jun 18. link to original article PubMed
   1. Update: Yang JC, Srimuninnimit V, Ahn MJ, Lin CC, Kim SW, Tsai CM, Mok T, Orlando M, Puri T, Wang X, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian never-smoker patients with locally advanced or metastatic nonsquamous non-small cell lung cancer: final overall survival results from a randomized phase 3 study. J Thorac Oncol. 2016 Mar;11(3):370-9. Epub 2015 Dec 25. link to original article PubMed

Advanced or metastatic disease, first-line, squamous

Carboplatin & Gemcitabine

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Regimen variant #1, 5/1000

Study	Evidence	Comparator	Comparative Efficacy
Patil et al. 2019	Phase III (C)	Carboplatin & low-dose Gemcitabine	Non-inferior OS

Note: CrCl was calculated using Cockcroft–Gault.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #2, 5.5/1000

Study	Evidence	Comparator	Comparative Efficacy
Edelman et al. 2017 (CALGB 30801)	Phase III (C)	CG & Celecoxib	Did not meet primary endpoint of PFS

Chemotherapy

• Carboplatin (Paraplatin) AUC 5.5 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 8

21-day cycles

References

1. CALGB 30801: Edelman MJ, Wang X, Hodgson L, Cheney RT, Baggstrom MQ, Thomas SP, Gajra A, Bertino E, Reckamp KL, Molina J, Schiller JH, Mitchell-Richards K, Friedman PN, Ritter J, Milne G, Hahn OM, Stinchcombe TE, Vokes EE; Alliance for Clinical Trials in Oncology. Phase III randomized, placebo-controlled, double-blind trial of celecoxib in addition to standard chemotherapy for advanced non-small-cell lung cancer with cyclooxygenase-2 overexpression: CALGB 30801 (Alliance). J Clin Oncol. 2017 Jul 1;35(19):2184-2192. Epub 2017 May 10. link to original article link to PMC article contains verified protocol PubMed
2. Patil V, Noronha V, Joshi A, Chougule A, Kannan S, Bhattacharjee A, Goud S, More S, Chandrasekharan A, Menon N, Srinivas S, Vallathol DH, Dsouza H, Majumdar S, Das S, Zawar A, Khaddar S, Kumar A, Singh G, Kumar KAP, Ravind R, Trivedi V, Behel V, Mahajan A, Janu A, Purandare N, Prabhash K. Phase III non-inferiority study evaluating efficacy and safety of low dose gemcitabine compared to standard dose gemcitabine with platinum in advanced squamous lung cancer. EClinicalMedicine. 2019 Apr 9;9:19-25. link to PMC article contains verified protocol PubMed

Carboplatin & nab-Paclitaxel

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Paz-Ares et al. 2018 (KEYNOTE-407)	2016-2017	Phase III (C)	Carboplatin, nab-Paclitaxel, Pembrolizumab x 4, then Pembrolizumab maint.	Inferior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

References

1. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains verified protocol PubMed

Carboplatin, nab-Paclitaxel, Pembrolizumab

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Paz-Ares et al. 2018 (KEYNOTE-407)	2016-2017	Phase III (E-RT-esc)	See link	See link

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1, given first

21-day cycle for 4 cycles

Subsequent treatment

• Pembrolizumab maintenance

References

1. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains verified protocol PubMed

Carboplatin & Paclitaxel

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TC: Taxol (Paclitaxel) & Carboplatin
CP: Carboplatin & Paclitaxel

Regimen variant #1, 5/200

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Mok et al. 2019 (KEYNOTE-042)	2014-2017	Phase III (C)	Pembrolizumab	Inferior OS

Patients enrolled in this arm of KEYNOTE-042 had squamous histology.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for 4 to 6 cycles

Regimen variant #2, 6/175

Study	Evidence	Comparator	Comparative Efficacy
Govindan et al. 2017 (CA184-104)	Phase III (C)	TC & Ipilimumab	Did not meet primary endpoint of OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Supportive medications

• Corticosteroids could be used as premedication for Paclitaxel (Taxol) infusion.

21-day cycle for up to 6 cycles

Regimen variant #3, 6/200

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Mok et al. 2019 (KEYNOTE-042)	2014-2017	Phase III (C)	Pembrolizumab	Inferior OS
Paz-Ares et al. 2018 (KEYNOTE-407)	2016-2017	Phase III (C)	CP & Pembrolizumab x 4, then Pembrolizumab maint.	Inferior OS

Patients enrolled in this arm of KEYNOTE-042 had squamous histology.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for 4 cycles (KEYNOTE-407) or up to 6 cycles (KEYNOTE-042)

References

1. CA184-104: Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, Barlesi F, Han B, Ganea DE, Von Pawel J, Vladimirov V, Fadeeva N, Lee KH, Kurata T, Zhang L, Tamura T, Postmus PE, Jassem J, O'Byrne K, Kopit J, Li M, Tschaika M, Reck M. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol. 2017 Oct 20;35(30):3449-3457. Epub 2017 Aug 30. link to original article contains verified protocol PubMed
2. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains verified protocol PubMed
3. KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed

Carboplatin, Paclitaxel, Ipilimumab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Govindan et al. 2017 (CA184-104)	Phase III (E-esc)	Carboplatin & Paclitaxel	Did not meet primary endpoint of OS

Note: this is the "phased" approach to this regimen.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Immunotherapy

• Ipilimumab (Yervoy) as follows:
  • Cycles 3 to 6: 10 mg/kg IV once on day 1

Supportive medications

• Corticosteroids could be used as premedication for Paclitaxel (Taxol) infusion or for toxicity management.

21-day cycle for up to 6 cycles

Subsequent treatment

• Maintenance ipilimumab

References

1. CA184-104: Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, Barlesi F, Han B, Ganea DE, Von Pawel J, Vladimirov V, Fadeeva N, Lee KH, Kurata T, Zhang L, Tamura T, Postmus PE, Jassem J, O'Byrne K, Kopit J, Li M, Tschaika M, Reck M. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol. 2017 Oct 20;35(30):3449-3457. Epub 2017 Aug 30. link to original article contains verified protocol PubMed

Carboplatin, Paclitaxel, Pembrolizumab

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Paz-Ares et al. 2018 (KEYNOTE-407)	2016-2017	Phase III (E-RT-esc)	See link	See link

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1, given first

21-day cycle for 4 cycles

Subsequent treatment

• Pembrolizumab maintenance

References

1. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains verified protocol PubMed

Cisplatin & Docetaxel

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DC: Docetaxel & Cisplatin
CD: Cisplatin & Docetaxel

Regimen variant #1, 75/75

Study	Evidence	Comparator	Comparative Efficacy
Lu et al. 2018 (5501068)	Phase III (C)	Docetaxel & Nedaplatin	Might have inferior PFS

Note: the cycle length is not specified in the abstract; 21-day cycles are standard.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycles

Regimen variant #2, 80/60

Study	Evidence	Comparator	Comparative Efficacy
Shukuya et al. 2015 (WJOG5208L)	Phase III (C)	Docetaxel & Nedaplatin	Seems to have inferior OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

21-day cycle for 4 to 6 cycles

References

1. WJOG5208L: Shukuya T, Yamanaka T, Seto T, Daga H, Goto K, Saka H, Sugawara S, Takahashi T, Yokota S, Kaneda H, Kawaguchi T, Nagase S, Oguri T, Iwamoto Y, Nishimura T, Hattori Y, Nakagawa K, Nakanishi Y, Yamamoto N; West Japan Oncology Group. Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1630-8. Epub 2015 Oct 28. link to original article contains protocol PubMed
2. 5501068: Lu S, Chen Z, Hu C, Zhang J, Chen Y, Song Y, Zhao Q, Fan Y, Wu G, Ma Z, Fang J, Yu Q, Liu Z. Nedaplatin plus docetaxel versus cisplatin plus docetaxel as first-line chemotherapy for advanced squamous cell carcinoma of the lung - a multicenter, open-label, randomized, phase III trial. J Thorac Oncol. 2018 Nov;13(11):1743-1749. Epub 2018 Jul 11. link to original article contains protocol PubMed

Cisplatin & Gemcitabine

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GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Thatcher et al. 2015 (SQUIRE)	2010-2012	Phase III (C)	Cisplatin, Gemcitabine, Necitumumab	Seems to have inferior OS

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 30 minutes once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV over 2 hours once per day on days 1 & 8

21-day cycle for up to 6 cycles

References

1. SQUIRE: Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA; SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 Jul;16(7):763-74. Epub 2015 Jun 1. link to original article contains protocol PubMed
   1. Dataset: Project Data Sphere

Cisplatin, Gemcitabine, Necitumumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Thatcher et al. 2015 (SQUIRE)	2010-2012	Phase III (E-RT-esc)	Cisplatin & Gemcitabine	Seems to have superior OS

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 2 hours once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV over 30 minutes once per day on days 1 & 8
• Necitumumab (Portrazza) 800 mg IV over at least 50 minutes once per day on days 1 & 8

Supportive medications

• Antiemetic premedications for gemcitabine and cisplatin "according to local practice."
• "Pre-emptive treatment for skin toxicity was allowed only after the first cycle."

21-day cycle for 6 cycles

Subsequent treatment

• Necitumumab maintenance

References

1. SQUIRE: Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA; SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 Jul;16(7):763-74. Epub 2015 Jun 1. link to original article contains verified protocol PubMed
   1. Dataset: Project Data Sphere

Docetaxel & Nedaplatin

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Shukuya et al. 2015 (WJOG5208L)	Phase III (E-switch-ic)	Cisplatin & Docetaxel	Seems to have superior OS

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1
• Nedaplatin (Aqupla) 100 mg/m² IV once on day 1

21-day cycle for 4 to 6 cycles

References

1. WJOG5208L: Shukuya T, Yamanaka T, Seto T, Daga H, Goto K, Saka H, Sugawara S, Takahashi T, Yokota S, Kaneda H, Kawaguchi T, Nagase S, Oguri T, Iwamoto Y, Nishimura T, Hattori Y, Nakagawa K, Nakanishi Y, Yamamoto N; West Japan Oncology Group. Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1630-8. Epub 2015 Oct 28. link to original article contains protocol PubMed

Advanced or metastatic disease, first-line, elderly or poor performance status

Carboplatin & Gemcitabine

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CG: Carboplatin & Gemcitabine

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Biesma et al. 2011 (NVALT-3)	2003-2006	Phase III (C)	CP		Similar QoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 4 cycles

References

1. NVALT-3: Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, Smit EF, van Felius CL, van Putten JW, Slaets JP, Groen HJ; Dutch Chest Physician Study Group. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011 Jul;22(7):1520-7. Epub 2011 Jan 20. link to original article contains verified protocol PubMed

Carboplatin & Paclitaxel

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TC: Taxol (Paclitaxel) & Carboplatin
CP: Carboplatin & Paclitaxel

Regimen variant #1, 5/175

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Biesma et al. 2011 (NVALT-3)	2003-2006	Phase III (C)	CG		Similar QoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for up to 4 cycles

Regimen variant #2, 6/90

Study	Evidence	Comparator	Comparative Efficacy
Quoix et al. 2011 (IFCT-0501)	Phase III (E-esc)	1. Gemcitabine	Superior OS
		2. Vinorelbine	Superior OS

Study involved only patients 70 to 89 years old

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 90 mg/m² IV once per day on days 1, 8, 15

Supportive medications

• Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3-4 neutropenia

28-day cycle for up to 4 cycles

Regimen variant #3, 6/200

Study	Evidence	Comparator	Comparative Efficacy
Lilenbaum et al. 2008	Phase III (C)	Erlotinib	Seems to have superior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for up to 4 cycles

Regimen variant #4, 6/225

Study	Evidence	Comparator	Comparative Efficacy
Langer et al. 2008	Phase III (C)	Carboplatin & PPX	Did not meet primary endpoint of OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 225 mg/m² IV once on day 1

21-day cycles

References

1. Lilenbaum R, Axelrod R, Thomas S, Dowlati A, Seigel L, Albert D, Witt K, Botkin D. Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2. J Clin Oncol. 2008 Feb 20;26(6):863-9. link to original article contains protocol PubMed
2. Langer CJ, O'Byrne KJ, Socinski MA, Mikhailov SM, Leśniewski-Kmak K, Smakal M, Ciuleanu TE, Orlov SV, Dediu M, Heigener D, Eisenfeld AJ, Sandalic L, Oldham FB, Singer JW, Ross HJ. Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol. 2008 Jun;3(6):623-30. link to original article contains protocol PubMed
3. NVALT-3: Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, Smit EF, van Felius CL, van Putten JW, Slaets JP, Groen HJ; Dutch Chest Physician Study Group. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011 Jul;22(7):1520-7. Epub 2011 Jan 20. link to original article contains verified protocol PubMed
4. IFCT-0501: Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains verified protocol PubMed

Carboplatin & Pemetrexed

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Example orders

• Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Zukin et al. 2013 (INCA-Lung001)	Phase III (E-esc)	Pemetrexed	Superior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive medications

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be given throughout pemetrexed therapy

21-day cycle for up to 4 cycles

References

1. INCA-Lung001: Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Da Rocha Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. Epub 2013 Jun 17. link to original article contains verified protocol PubMed

Carboplatin, Pemetrexed, Bevacizumab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Spigel et al. 2018	Randomized Phase II (E-esc)	1. Pemetrexed 2. Pemetrexed & Bevacizumab	PFS: 4.8 mo

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

Supportive medications

• Premedications, Folic acid (Folate), and vitamin supplementation per standard guidelines
• Antiemetics per standard guidelines

21-day cycle for 4 cycles

Subsequent treatment

• Pemetrexed & Bevacizumab maintenance

References

1. Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. link to original article contains verified protocol PubMed

Cisplatin & Gemcitabine

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Morabito et al. 2013 (CAPPA-2)	Phase III (E-esc)	Gemcitabine	Seems to have superior OS
Gridelli et al. 2018 (MILES-3)	Phase III (E-esc)	Gemcitabine	Did not meet primary endpoint of OS
Gridelli et al. 2018 (MILES-4)	Phase III (E-esc)	Gemcitabine	Did not meet primary endpoint of OS

MILES studies involved only patients at least 70 years old. CAPPA-2 allowed patients aged 18-70 with ECOG PS = 2.

Chemotherapy

• Cisplatin (Platinol)
• Gemcitabine (Gemzar)

References

1. CAPPA-2: Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, Barbera S, Cavanna L, De Marinis F, Montesarchio V, Costanzo R, Sandomenico C, Montanino A, Mancuso G, Russo P, Nacci A, Giordano P, Daniele G, Piccirillo MC, Rocco G, Gridelli C, Gallo C, Perrone F. Randomized phase III trial of gemcitabine and cisplatin vs gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013 Jul;81(1):77-83. Epub 2013 May 1. link to original article contains protocol PubMed
2. MILES-3/MILES-4: Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. link to original article contains verified protocol PubMed

Docetaxel monotherapy

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Example orders

• Example orders for Docetaxel (Taxotere) in non-small cell lung cancer

Regimen variant #1, 25 mg/m², 3 out of 4 weeks

Study	Evidence	Comparator	Comparative Efficacy
Tsukada et al. 2014 (JCOG0207)	Phase III (C)	Cisplatin & Docetaxel	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 25 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 36 mg/m², 3 out of 4 weeks

Study	Evidence	Comparator	Comparative Efficacy
Hainsworth et al. 2007	Phase III (C)	Docetaxel & Gemcitabine	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 36 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #3, 38 mg/m², 2 out of 3 weeks

Study	Evidence	Comparator	Comparative Efficacy
Karampeazis et al. 2011	Phase III (E-switch-ic)	Vinorelbine	Might have superior OS

Chemotherapy

• Docetaxel (Taxotere) 38 mg/m² IV over 60 minutes once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #4, 60 mg/m² q3wk

Study	Evidence	Comparator	Comparative Efficacy
Kudoh et al. 2006 (WJTOG 9904)	Phase III (E-switch-ic)	Vinorelbine	Did not meet primary endpoint of OS
Abe et al. 2015 (JCOG0803/WJOG4307L)	Phase III (C)	Cisplatin & Docetaxel	Did not meet primary endpoint of OS

This is the PMDA-approved dose.

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV over 60 minutes once on day 1

21-day cycle for up to 4 cycles (WJTOG 9904) or indefinitely

References

1. WJTOG 9904: Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, Shinkai T, Sawa T, Goto I, Semba H, Seto T, Ando M, Satoh T, Yoshimura N, Negoro S, Fukuoka M. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006 Aug 1;24(22):3657-63. link to original article contains protocol PubMed
2. Hainsworth JD, Spigel DR, Farley C, Shipley DL, Bearden JD, Gandhi J, Houston GA, Greco FA. Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network. Cancer. 2007 Nov 1;110(9):2027-34. link to original article contains protocol PubMed
3. Karampeazis A, Vamvakas L, Agelidou A, Kentepozidis N, Chainis K, Chandrinos V, Vardakis N, Pallis AG, Christophyllakis C, Georgoulias V; Hellenic Oncology Research Group. Docetaxel vs vinorelbine in elderly patients with advanced non--small-cell lung cancer: a Hellenic Oncology Research Group randomized phase III study. Clin Lung Cancer. 2011 May;12(3):155-60. Epub 2011 Apr 27. link to original article contains verified protocol PubMed
4. JCOG0207: Tsukada H, Yokoyama A, Goto K, Shinkai T, Harada M, Ando M, Shibata T, Ohe Y, Tamura T, Saijo N; Lung Cancer Study Group of the Japan Clinical Oncology Group (JCOG). Randomized controlled trial comparing docetaxel-cisplatin combination with weekly docetaxel alone in elderly patients with advanced non-small-cell lung cancer: Japan Clinical Oncology Group (JCOG) 0207. Jpn J Clin Oncol. 2015 Jan;45(1):88-95. Epub 2014 Nov 6. link to original article contains protocol PubMed
5. JCOG0803/WJOG4307L: Abe T, Takeda K, Ohe Y, Kudoh S, Ichinose Y, Okamoto H, Yamamoto N, Yoshioka H, Minato K, Sawa T, Iwamoto Y, Saka H, Mizusawa J, Shibata T, Nakamura S, Ando M, Yokoyama A, Nakagawa K, Saijo N, Tamura T. Randomized phase III trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non-small-cell lung cancer: the intergroup trial JCOG0803/WJOG4307L. J Clin Oncol. 2015 Feb 20;33(6):575-81. Epub 2015 Jan 12. link to original article contains verified protocol PubMed

Gemcitabine monotherapy

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Regimen variant #1, 1000 mg/m², 3 out of 4 weeks

Study	Evidence	Comparator	Comparative Efficacy
O'Brien et al. 2008	Phase III (C)	Paclitaxel poliglumex	Did not meet primary endpoint of OS

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycle for up to 6 cycles

Regimen variant #2, 1150 mg/m², 2 out of 3 weeks

Study	Evidence	Comparator	Comparative Efficacy
Quoix et al. 2011 (IFCT-0501)	Phase III (C)	Carboplatin & Paclitaxel	Inferior OS

Study involved only patients 70 to 89 years old

Chemotherapy

• Gemcitabine (Gemzar) 1150 mg/m² IV once per day on days 1 & 8

Supportive medications

• Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3 to 4 neutropenia

21-day cycle for up to 5 cycles

Regimen variant #3, 1200 mg/m², 2 out of 3 weeks

Study	Evidence	Comparator	Comparative Efficacy
Gridelli et al. 2003 (MILES)	Phase III (E-switch-ic)	1. Gemcitabine & Vinorelbine	Did not meet primary endpoint of OS
		2. Vinorelbine	Did not meet primary endpoint of OS
Reynolds et al. 2009 (USO-03012)	Phase III (C)	Carboplatin & Gemcitabine	Did not meet primary endpoint of OS
Morabito et al. 2013 (CAPPA-2)	Phase III (C)	Cisplatin & Gemcitabine	Seems to have inferior OS
Gridelli et al. 2018 (MILES-3)	Phase III (C)	Cisplatin & Gemcitabine	Did not meet primary endpoint of OS
Gridelli et al. 2018 (MILES-4)	Phase III (C)	Cisplatin & Gemcitabine	Did not meet primary endpoint of OS

MILES studies involved only patients at least 70 years old. CAPPA-2 allowed patients aged 18-70 with ECOG PS = 2.

Chemotherapy

• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8

Supportive medications

• "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

21-day cycle for 4 to 6 cycles

References

1. MILES: Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. link to original article contains verified protocol PubMed
2. SICOG 9909: Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. link to original article link to PMC article contains protocol PubMed
3. O'Brien ME, Socinski MA, Popovich AY, Bondarenko IN, Tomova A, Bilynsky BT, Hotko YS, Ganul VL, Kostinsky IY, Eisenfeld AJ, Sandalic L, Oldham FB, Bandstra B, Sandler AB, Singer JW. Randomized phase III trial comparing single-agent paclitaxel Poliglumex (CT-2103, PPX) with single-agent gemcitabine or vinorelbine for the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol. 2008 Jul;3(7):728-34. link to original article contains verified protocol PubMed
4. USO-03012: Reynolds C, Obasaju C, Schell MJ, Li X, Zheng Z, Boulware D, Caton JR, Demarco LC, O'Rourke MA, Shaw Wright G, Boehm KA, Asmar L, Bromund J, Peng G, Monberg MJ, Bepler G. Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer. J Clin Oncol. 2009 Dec 1;27(34):5808-15. Epub 2009 Nov 2. link to original article link to PMC article contains verified protocol PubMed
5. IFCT-0501: Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains verified protocol PubMed
6. CAPPA-2: Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, Barbera S, Cavanna L, De Marinis F, Montesarchio V, Costanzo R, Sandomenico C, Montanino A, Mancuso G, Russo P, Nacci A, Giordano P, Daniele G, Piccirillo MC, Rocco G, Gridelli C, Gallo C, Perrone F. Randomized phase III trial of gemcitabine and cisplatin vs gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013 Jul;81(1):77-83. Epub 2013 May 1. link to original article contains protocol PubMed
7. MILES-3/MILES-4: Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. link to original article contains verified protocol PubMed

Gemcitabine & Paclitaxel

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GT: Gemcitabine & Taxol (Paclitaxel)

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Comella et al. 2004 (SICOG 9909)	Phase III (E-esc)	1. Gemcitabine 2. Paclitaxel	Seems to have superior OS
		3. GV	Not reported

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

References

1. SICOG 9909: Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. link to original article link to PMC article contains protocol PubMed

Gemcitabine & Vinorelbine

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GV: Gemcitabine & Vinorelbine
VG: Vinorelbine & Gemcitabine

Regimen variant #1, 1000/25

Study	Evidence	Comparator	Comparative Efficacy
Gridelli et al. 2003 (MILES)	Phase III (E-esc)	1. Gemcitabine	Did not meet primary endpoint of OS
		2. Vinorelbine	Did not meet primary endpoint of OS

This study involved only patients at least 70 years old

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

Supportive medications

• "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

21-day cycle for up to 6 cycles

Regimen variant #2, 1200/30

Study	Evidence	Comparator	Comparative Efficacy
Frasci et al. 2000	Phase III (E-esc)	Vinorelbine	Superior OS

This study involved only patients at least 70 years old

Chemotherapy

• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

References

1. Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, De Cataldis G, Iannelli A, Bilancia D, Belli M, Massidda B, Piantedosi F, Comella G, De Lena M. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Jul;18(13):2529-36. link to original article contains protocol PubMed
2. MILES: Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. link to original article contains verified protocol PubMed
3. SICOG 9909: Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. link to original article link to PMC article contains protocol PubMed

Pemetrexed monotherapy

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Example orders

• Example orders for Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Zukin et al. 2013 (INCA-Lung001)	Phase III (C)	Carboplatin & Pemetrexed	Inferior OS
Gridelli et al. 2018 (MILES-4)	Phase III (C)	1. Cisplatin & Gemcitabine 2. Cisplatin & Pemetrexed	Did not meet primary endpoint of OS

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

21-day cycle for up to 4 cycles (INCA-Lung001) or 6 cycles (MILES-4)

References

1. INCA-Lung001: Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Da Rocha Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. Epub 2013 Jun 17. link to original article contains verified protocol PubMed
2. Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. link to original article contains verified protocol PubMed
3. MILES-4: Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. link to original article contains verified protocol PubMed

Pemetrexed & Bevacizumab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Spigel et al. 2018	Randomized Phase II (E-esc)	1. Pemetrexed 2. Carboplatin, Pemetrexed, Bevacizumab	PFS: 4.0 mo

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

Supportive medications

• Premedications, Folic acid (Folate), and vitamin supplementation per standard guidelines
• Antiemetics per standard guidelines

21-day cycles

References

1. Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. link to original article contains verified protocol PubMed

Vinorelbine monotherapy

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Regimen variant #1, 25 mg/m²

Study	Evidence	Comparator	Comparative Efficacy
Kudoh et al. 2006 (WJTOG 9904)	Phase III (C)	Docetaxel	Did not meet primary endpoint of OS
Karampeazis et al. 2011	Phase III (E-switch-ic)	Docetaxel	Might have inferior OS
Quoix et al. 2011 (IFCT-0501)	Phase III (C)	Carboplatin & Paclitaxel	Inferior OS

IFCT-0501 involved only patients 70 to 89 years old

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV over 30 minutes once per day on days 1 & 8

Supportive medications

• Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3 to 4 neutropenia

21-day cycle for up to 4 cycles (WJTOG 9904), 5 cycles (IFCT-0501), or 6 cycles (Karampeazis et al. 2011)

Regimen variant #2, 30 mg/m²

Study	Evidence	Comparator	Comparative Efficacy
Gridelli et al. 1999 (ELVIS)	Phase III (E-esc)	Best supportive care	Seems to have superior OS
Gridelli et al. 2003 (MILES)	Phase III (C)	1. Gemcitabine	Did not meet primary endpoint of OS
		2. Gemcitabine & Vinorelbine	Did not meet primary endpoint of OS

Study involved only patients at least 70 years old

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

Supportive medications

• (varies depending on reference):
• ELVIS: Metoclopramide (Reglan) 20 mg IV bolus once per day on days 1 & 8, prior to Vinorelbine (Navelbine)
• MILES: "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

21-day cycle for up to 6 cycles

References

1. ELVIS: Gridelli C, Perrone F, Gallo C; Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999 Jan 6;91(1):66-72. link to original article contains verified protocol PubMed
2. MILES: Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. link to original article contains verified protocol PubMed
3. WJTOG 9904: Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, Shinkai T, Sawa T, Goto I, Semba H, Seto T, Ando M, Satoh T, Yoshimura N, Negoro S, Fukuoka M. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006 Aug 1;24(22):3657-63. link to original article contains protocol PubMed
4. Karampeazis A, Vamvakas L, Agelidou A, Kentepozidis N, Chainis K, Chandrinos V, Vardakis N, Pallis AG, Christophyllakis C, Georgoulias V; Hellenic Oncology Research Group. Docetaxel vs vinorelbine in elderly patients with advanced non--small-cell lung cancer: a Hellenic Oncology Research Group randomized phase III study. Clin Lung Cancer. 2011 May;12(3):155-60. Epub 2011 Apr 27. link to original article contains verified protocol PubMed
5. IFCT-0501: Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains verified protocol PubMed

Maintenance after first-line therapy

Atezolizumab & Bevacizumab

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence
Socinski et al. 2018 (IMpower150)	2015-2016	Non-randomized portion of RCT

Note: this is the FDA-recommended dose for atezolizumab.

Preceding treatment

• ABCP x 4 or ABCP x 6

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1

Chemotherapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed

Bevacizumab monotherapy

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Regimen variant #1, 7.5 mg/kg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Reck et al. 2009 (AVAil)	2005-2006	Non-randomized portion of RCT
Barlesi et al. 2013 (AVAPERL)		Phase III (C)	Bevacizumab & Pemetrexed maintenance	Inferior PFS

Preceding treatment

• AVAil: Cisplatin, Gemcitabine, Bevacizumab x 6
• AVAPERL: Cisplatin, Pemetrexed, Bevacizumab x 4

Chemotherapy

• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, 15 mg/kg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Sandler et al. 2006 (ECOG E4599)	2001-2004	Phase III (E-RT-esc)	See link	See link
Reck et al. 2009 (AVAil)	2005-2006	Non-randomized portion of RCT
Johnson et al. 2013 (ATLAS-NSCLC)		Phase III (C)	Erlotinib & Bevacizumab maintenance	Inferior PFS (*)	Less toxic
Patel et al. 2013 (PointBreak)		Non-randomized portion of RCT
Zinner et al. 2015 (PRONOUNCE)		Phase III (C)	See link	See link
Socinski et al. 2018 (IMpower150)	2015-2016	Non-randomized portion of RCT

Note that while this arm was inferior in ATLAS, the authors note that, due to toxicity, the "two-drug maintenance regimen will not lead to a new postchemotherapy standard of care." Also, this trial should not be confused with the ones with the same name in breast cancer and in renal cell carcinoma.

Preceding treatment

• ECOG E4599: PacCBev x 6
• AVAil: Cisplatin, Gemcitabine, Bevacizumab x 6
• ATLAS: Carboplatin, Docetaxel, Bevacizumab x 4 or Carboplatin, Gemcitabine, Bevacizumab x 4 or PacCBev x 4 or Cisplatin, Docetaxel, Bevacizumab x 4 or Cisplatin, Gemcitabine, Bevacizumab x 4 or Cisplatin, Vinorelbine, Bevacizumab x 4
• PointBreak and PRONOUNCE: PacCBev x 4
• IMpower150: BCP x 4 or BCP x 6

Chemotherapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; ECOG. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article contains verified protocol PubMed
2. AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains verified protocol PubMed NCT00806923
   1. Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed
3. AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
   1. Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article PubMed
4. ATLAS: Johnson BE, Kabbinavar F, Fehrenbacher L, Hainsworth J, Kasubhai S, Kressel B, Lin CY, Marsland T, Patel T, Polikoff J, Rubin M, White L, Yang JC, Bowden C, Miller V. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2013 Nov 1;31(31):3926-34. Epub 2013 Oct 7. link to original article contains verified protocol in supplement PubMed
5. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed
   1. Dataset: Project Data Sphere
6. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed
7. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed

Gemcitabine monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Brodowicz et al. 2006	Phase III (E-esc)	Observation	Superior TTP
Pérol et al. 2012 (IFCT-GFPC 0502)	Phase III (E-esc)	1. Erlotinib	Not reported
		2. Observation	Superior PFS

Preceding treatment

• Cisplatin & Gemcitabine x 4

Chemotherapy

• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. Brodowicz T, Krzakowski M, Zwitter M, Tzekova V, Ramlau R, Ghilezan N, Ciuleanu T, Cucevic B, Gyurkovits K, Ulsperger E, Jassem J, Grgic M, Saip P, Szilasi M, Wiltschke C, Wagnerova M, Oskina N, Soldatenkova V, Zielinski C, Wenczl M; Central European Cooperative Oncology Group. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006 May;52(2):155-63. Epub 2006 Mar 29. link to original article contains protocol PubMed
2. IFCT-GFPC 0502: Pérol M, Chouaid C, Pérol D, Barlési F, Gervais R, Westeel V, Crequit J, Léna H, Vergnenègre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Ségura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012 Oct 1;30(28):3516-24. Epub 2012 Sep 4. link to original articlecontains verified protocol PubMed

Ipilimumab monotherapy

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Regimen

Study	Evidence
Lynch et al. 2012 (CA184-041)	Non-randomized portion of RCT
Govindan et al. 2017 (CA184-104)	Non-randomized portion of RCT

Preceding treatment

• Carboplatin, Paclitaxel, Ipilimumab x 6

Immunotherapy

• Ipilimumab (Yervoy) 10 mg/kg IV once on day 1

12-week cycles

References

1. CA184-041: Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. link to original article contains verified protocol PubMed
2. CA184-104: Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, Barlesi F, Han B, Ganea DE, Von Pawel J, Vladimirov V, Fadeeva N, Lee KH, Kurata T, Zhang L, Tamura T, Postmus PE, Jassem J, O'Byrne K, Kopit J, Li M, Tschaika M, Reck M. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol. 2017 Oct 20;35(30):3449-3457. Epub 2017 Aug 30. link to original article contains verified protocol PubMed

Necitumumab monotherapy

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Regimen

Study	Evidence
Thatcher et al. 2015 (SQUIRE)	Non-randomized portion of RCT

Patients had stage IV squamous non-small-cell lung cancer.

Preceding treatment

• Cisplatin, Gemcitabine, Necitumumab x 6

Chemotherapy

• Necitumumab (Portrazza) 800 mg IV over at least 50 minutes once per day on days 1 & 8

21-day cycles

References

1. SQUIRE: Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA; SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 Jul;16(7):763-74. Epub 2015 Jun 1. link to original article contains verified protocol PubMed
   1. Dataset: Project Data Sphere

Pembrolizumab monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Paz-Ares et al. 2018 (KEYNOTE-407)	2016-2017	Phase III (E-RT-esc)	See link	See link

Preceding treatment

• Carboplatin, nab-Paclitaxel, Pembrolizumab x 4 or Carboplatin, Paclitaxel, Pembrolizumab x 4

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 35 cycles (including induction)

References

1. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains verified protocol PubMed

Pemetrexed monotherapy

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Example orders

• Example orders for Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ciuleanu et al. 2009 (JMEN)	2005-2007	Phase III (E-RT-esc)	Placebo	Seems to have superior OS
Paz-Ares et al. 2012 (PARAMOUNT)	2008-2010	Phase III (E-RT-esc)	Placebo	Superior PFS
Zinner et al. 2015 (PRONOUNCE)		Phase III (E-switch-ooc)	See link	See link
Reck et al. 2016 (KEYNOTE-024)	2014-2015	Non-randomized portion of RCT
Mok et al. 2019 (KEYNOTE-042)	2014-2017	Non-randomized portion of RCT
Langer et al. 2016 (KEYNOTE-021)		Non-randomized portion of RCT
Gandhi et al. 2018 (KEYNOTE-189)	2016-2017	Non-randomized portion of RCT

Preceding treatment

• JMEN: Platinum-based chemotherapy x 4
• PARAMOUNT: Cisplatin & Pemetrexed x 4; maintenance therapy started 21 to 42 days after cycle 4 day 1 of induction chemotherapy
• PRONOUNCE & KEYNOTE-021 (control arm): Carboplatin & Pemetrexed x 4
• KEYNOTE-024: Carboplatin & Paclitaxel or Carboplatin & Pemetrexed or Cisplatin & Pemetrexed
• KEYNOTE-189 (control arm): Carboplatin & Pemetrexed x 4 or Cisplatin & Pemetrexed x 4
• KEYNOTE-021 & KEYNOTE-189 (experimental arm): Pemetrexed & Pembrolizumab maintenance x 2 y
• KEYNOTE-042: Carboplatin & Pemetrexed x 6

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

Supportive medications

• Folic acid (Folate)
• Cyanocobalamin (Vitamin B12)
• Dexamethasone (Decadron)
• "Investigators followed current American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) guidelines for use of colony-stimulating factors and erythropoiesis-stimulating agents."

21-day cycles

References

1. JMEN: Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Rodrigues Pereira J, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 Oct 24;374(9699):1432-40. Epub 2009 Sep 18. link to original article contains protocol PubMed
2. PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article contains verified protocol PubMed
   1. HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article PubMed
   2. Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
3. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed
4. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
   1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
   2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
5. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol PubMed
6. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed
7. KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed

Pemetrexed & Bevacizumab

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Regimen variant #1, 500/7.5

Study	Evidence	Comparator	Comparative Efficacy
Barlesi et al. 2013 (AVAPERL)	Phase III (E-esc)	Bevacizumab maintenance	Superior PFS

Preceding treatment

• Cisplatin, Pemetrexed, Bevacizumab x 4

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

Supportive medications

• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, given throughout therapy
• Folic acid (Folate) 350 to 1000 mcg PO once per day, given throughout therapy
• Dexamethasone (Decadron) 4 mg PO twice per day on days -1 to 2 (3 days)

21-day cycles

Regimen variant #2, 500/15

Study	Evidence
Patel et al. 2013 (PointBreak)	Non-randomized portion of RCT
Spigel et al. 2018	Non-randomized portion of RCT

Preceding treatment

• PointBreak: PemCBev (AUC 6) x 4
• Spigel et al. 2018: PemCBev (AUC 5) x 4

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

Supportive medications

• Premedications, Folic acid (Folate), and vitamin supplementation per pemetrexed label
• Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycles

References

1. AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
   1. Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article PubMed
2. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed
   1. Dataset: Project Data Sphere
3. Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. link to original article contains verified protocol PubMed

Pemetrexed & Pembrolizumab

Pembrolizumab & Pemetrexed maintenance therapy for advanced or metastatic non-small cell lung cancer

Advanced or metastatic disease, second-line

Afatinib monotherapy

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Regimen variant #1, 30 mg/day

FDA-recommended dose

This is the FDA-recommended dose for patients with "severe renal impairment".

Chemotherapy

• Afatinib (Gilotrif) 30 mg PO once per day

Continued indefinitely

Regimen variant #2, 40 mg/day

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Soria et al. 2015 (LUX-Lung 8)	2012-2014	Phase III (E-RT-switch-ic)	Erlotinib	Superior OS

Chemotherapy

• Afatinib (Gilotrif) 40 mg PO once per day, given 1 hour before eating food

Continued indefinitely

References

1. LUX-Lung 8: Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Göker E, Georgoulias V, Li W, Isla D, Guclu SZ, Morabito A, Min YJ, Ardizzoni A, Gadgeel SM, Wang B, Chand VK, Goss GD; LUX-Lung 8 Investigators. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015 Aug;16(8):897-907. Epub 2015 Jul 5. link to original article contains protocol PubMed

Cabozantinib monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512)	Randomized Phase II (E-switch-ic)	1. Cabozantinib & Erlotinib	Not reported
		2. Erlotinib	Superior PFS

Chemotherapy

• Cabozantinib (Cometriq) 60 mg PO once per day

Continued indefinitely

References

1. ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains protocol link to PMC article PubMed

Cabozantinib & Erlotinib

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512)	Randomized Phase II (E-esc)	1. Cabozantinib	Not reported
		2. Erlotinib	Superior PFS

Chemotherapy

• Cabozantinib (Cometriq) 40 mg PO once per day
• Erlotinib (Tarceva) 150 mg PO once per day

Continued indefinitely

References

1. ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains protocol link to PMC article PubMed

Carboplatin & Pemetrexed

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Example orders

• Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Ardizzoni et al. 2012 (GOIRC 02-2006)	Randomized Phase II (E-esc)	Pemetrexed	Did not meet primary endpoint of PFS

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive medications

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be given throughout pemetrexed therapy

21-day cycle for 4 to 6 cycles

References

1. GOIRC 02-2006: Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. Epub 2012 Oct 29. link to original article contains verified protocol PubMed

Docetaxel monotherapy

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Example orders

• Example orders for Docetaxel (Taxotere) in non-small cell lung cancer

Regimen variant #1, 33.3 mg/m², 3 out of 4 weeks

Study	Evidence	Comparator	Comparative Efficacy
Gebbia et al. 2008 (DISTAL-2)	Phase III (C)	1. Capecitabine & Docetaxel 2. Docetaxel & Gemcitabine 3. Docetaxel & Vinorelbine	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 33.3 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 35 mg/m², 3 out of 4 weeks

Study	Evidence	Comparator	Comparative Efficacy
Schuette et al. 2005	Phase III (E-switch-ic)	Docetaxel; 75 mg/m2, every 3 wks	Might have superior OS
Garassino et al. 2013 (TAILORNSCLC)	Phase III (C)	Erlotinib	Seems to have superior OS

Note that there is another trial named TAILOR in colorectal cancer.

Chemotherapy

• Docetaxel (Taxotere) 35 mg/m² IV once per day on days 1, 8, 15

Supportive medications

• Dexamethasone (Decadron) as follows:
  • 8 mg PO once per day on days 1, 8, 15; 12 hours prior to Docetaxel (Taxotere)
  • 10 mg IV once per day on days 1, 8, 15; 30 minutes prior to Docetaxel (Taxotere)
  • 8 mg PO once per day on days 1, 8, 15; 12 hours after Docetaxel (Taxotere)

28-day cycles

Regimen variant #3, 50 mg/m² q2wk, limited duration

Study	Evidence	Comparator	Comparative Efficacy
Pallis et al. 2010	Phase III (C)	Carboplatin & Docetaxel	Did not meet primary endpoint of OS

These patients had previously been treated with a platinum-free regimen.

Chemotherapy

• Docetaxel (Taxotere) 50 mg/m² IV once per day on days 1 & 15

28-day cycle for up to 6 cycles

Regimen variant #4, 60 mg/m² q3wk, limited duration

Study	Evidence	Comparator	Comparative Efficacy
Herbst et al. 2010 (ZODIAC)	Phase III (C)	Docetaxel & Vandetanib	Inferior PFS

This is the PMDA-approved dose. While statistically inferior, the median PFS difference was only 0.8 months.

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

Regimen variant #5, 60 mg/m² q3wk, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Takeda et al. 2009 (JCOG 0104)	2002-2003	Phase III (C)	Docetaxel & Gemcitabine	Did not meet primary endpoint of OS
Kawaguchi et al. 2014 (DELTANSCLC)		Phase III (C)	Erlotinib	Might have superior PFS
Garon et al. 2014 (REVEL)	2010-2013	Phase III (C)	Docetaxel & Ramucirumab	Seems to have inferior OS
Gridelli et al. 2018 (AvaALL)		Phase III (C)	Investigator's choice of: 1. Docetaxel & Bevacizumab 2. Erlotinib & Bevacizumab 3. Pemetrexed & Bevacizumab	Did not meet primary endpoint of OS

This is the PMDA-approved dose, the dose used for East Asian patients in REVEL, and the dose used in Japanese patients in EAST-LC. Note that there is another trial named DELTA in indolent lymphoma.

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV over at least 60 minutes once on day 1

21-day cycles

Regimen variant #6, 75 mg/m² q3wk, limited duration

Study	Evidence	Comparator	Comparative Efficacy
Herbst et al. 2010 (ZODIAC)	Phase III (C)	Docetaxel & Vandetanib	Inferior PFS

Note: while statistically inferior, the median PFS difference in ZODIAC was only 0.8 months.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

Regimen variant #7, 75 mg/m² q3wk, indefinite

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Gridelli et al. 2004 (DISTAL 01)	Phase III (C)	Docetaxel; 33.3 mg/m2, 6 out of 8 wks		Did not meet primary endpoint of QoL
Schuette et al. 2005	Phase III (C)	Docetaxel; 35 mg/m2, 3 out of 4 wks	Might have inferior OS
Paz-Ares et al. 2008 (STELLAR 2)	Phase III (C)	Paclitaxel poliglumex	Did not meet primary endpoint of OS
Krzakowski et al. 2010	Phase III (C)	Vinflunine	Non-inferior PFS
Ciuleanu et al. 2012 (TITAN)	Phase III (C)	Erlotinib	Did not meet primary endpoint of OS
Sun et al. 2012 (JMID)	Phase III (C)	Pemetrexed	Inconclusive whether non-inferior OS
Garassino et al. 2013 (TAILORNSCLC)	Phase III (C)	Erlotinib	Seems to have superior OS
Garon et al. 2014 (REVEL)	Phase III (C)	Docetaxel & Ramucirumab	Seems to have inferior OS
Gridelli et al. 2018 (AvaALL)	Phase III (C)	Investigator's choice of: 1. Docetaxel & Bevacizumab 2. Erlotinib & Bevacizumab 3. Pemetrexed & Bevacizumab	Did not meet primary endpoint of OS
Pillai et al. 2019 (GALAXY-2)	Phase III (C)	Docetaxel & Ganetespib	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Supportive medications

• Per JMEI: Dexamethasone (Decadron) 8 mg PO twice per day on days -1 to 2 (3 days)
• Per Chem et al. 2006: Dexamethasone (Decadron) as follows:
  • 8 mg PO once per day on days 1, 8, 15; 12 hours prior to Docetaxel (Taxotere)
  • 10 mg IV once per day on days 1, 8, 15; 30 minutes prior to Docetaxel (Taxotere)
  • 8 mg PO once per day on days 1, 8, 15; 12 hours after Docetaxel (Taxotere)

21-day cycles

References

1. DISTAL 01: Gridelli C, Gallo C, Di Maio M, Barletta E, Illiano A, Maione P, Salvagni S, Piantedosi FV, Palazzolo G, Caffo O, Ceribelli A, Falcone A, Mazzanti P, Brancaccio L, Capuano MA, Isa L, Barbera S, Perrone F. A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer: the DISTAL 01 study. Br J Cancer. 2004 Dec 13;91(12):1996-2004. link to original article link to PMC article contains protocol PubMed
2. Schuette W, Nagel S, Blankenburg T, Lautenschlaeger C, Hans K, Schmidt EW, Dittrich I, Schweisfurth H, von Weikersthal LF, Raghavachar A, Reissig A, Serke M. Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel. J Clin Oncol. 2005 Nov 20;23(33):8389-95. link to original article contains protocol PubMed
3. STELLAR 2: Paz-Ares L, Ross H, O'Brien M, Riviere A, Gatzemeier U, Von Pawel J, Kaukel E, Freitag L, Digel W, Bischoff H, García-Campelo R, Iannotti N, Reiterer P, Bover I, Prendiville J, Eisenfeld AJ, Oldham FB, Bandstra B, Singer JW, Bonomi P. Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer. Br J Cancer. 2008 May 20;98(10):1608-13. Epub 2008 May 13. link to original article link to PMC article contains protocol PubMed
4. DISTAL-2: Gebbia V, Gridelli C, Verusio C, Frontini L, Aitini E, Daniele B, Gamucci T, Mancuso G, Di Maio M, Gallo C, Perrone F, Morabito A. Weekly docetaxel vs docetaxel-based combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer patients: the DISTAL-2 randomized trial. Lung Cancer. 2009 Feb;63(2):251-8. Epub 2008 Jul 15. link to original article contains protocol PubMed
5. JCOG 0104: Takeda K, Negoro S, Tamura T, Nishiwaki Y, Kudoh S, Yokota S, Matsui K, Semba H, Nakagawa K, Takada Y, Ando M, Shibata T, Saijo N. Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104). Ann Oncol. 2009 May;20(5):835-41. Epub 2009 Jan 22. link to original article contains protocol PubMed
6. Krzakowski M, Ramlau R, Jassem J, Szczesna A, Zatloukal P, Von Pawel J, Sun X, Bennouna J, Santoro A, Biesma B, Delgado FM, Salhi Y, Vaissiere N, Hansen O, Tan EH, Quoix E, Garrido P, Douillard JY. Phase III trial comparing vinflunine with docetaxel in second-line advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy. J Clin Oncol. 2010 May 1;28(13):2167-73. Epub 2010 Mar 29. link to original article contains protocol PubMed
7. ZODIAC: Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010 Jul;11(7):619-26. link to original article link to PMC article contains verified protocol PubMed
   1. Dataset: Project Data Sphere
8. Pallis AG, Agelaki S, Agelidou A, Varthalitis I, Syrigos K, Kentepozidis N, Pavlakou G, Kotsakis A, Kontopodis E, Georgoulias V. A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic non-small cell lung cancer. BMC Cancer. 2010 Nov 19;10:633. link to original article link to PMC article contains verified protocol PubMed
9. TITAN: Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012 Mar;13(3):300-8. Epub 2012 Jan 24. link to original article contains protocol PubMed
10. JMID: Sun Y, Wu YL, Zhou CC, Zhang L, Zhang L, Liu XY, Yu SY, Jiang GL, Li K, Qin SK, Ma SL, Han L, Quinlivan M, Orlando M, Zhang XQ. Second-line pemetrexed versus docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer: a randomized, open-label study. Lung Cancer. 2013 Feb;79(2):143-50. Epub 2012 Nov 20. link to original article PubMed
11. TAILOR: Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, Bianchi F, Bettini A, Longo F, Moscetti L, Tomirotti M, Marabese M, Ganzinelli M, Lauricella C, Labianca R, Floriani I, Giaccone G, Torri V, Scanni A, Marsoni S; TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013 Sep;14(10):981-8. Epub 2013 Jul 22. link to original article contains verified protocol PubMed
12. DELTA: Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8. Epub 2014 May 19. link to original article contains verified protocol PubMed
13. REVEL: Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. Epub 2014 Jun 2. link to original article contains verified protocol PubMed
14. AvaALL: Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. Epub 2018 Dec 13. Erratum in: JAMA Oncol. 2018 Dec 1;4(12):1792. link to original article link to PMC article contains verified protocol in supplement PubMed
15. GALAXY-2: Pillai RN, Fennell DA, Kovcin V, Ciuleanu TE, Ramlau R, Kowalski D, Schenker M, Yalcin I, Teofilovici F, Vukovic VM, Ramalingam SS. Randomized Phase III Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, With Docetaxel Versus Docetaxel in Advanced Non-Small-Cell Lung Cancer (GALAXY-2). J Clin Oncol. 2020 Feb 20;38(6):613-622. Epub 2019 Dec 12. link to original article contains protocol PubMed

Docetaxel & Ramucirumab

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Regimen variant #1, 60 mg/m² docetaxel

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Garon et al. 2014 (REVEL)	2010-2013	Phase III (E-RT-esc)	Docetaxel	Seems to have superior OS

Note: This is the PMDA-approved dose and the dose recommended for East Asians. The FDA only provides recommendations for ramucirumab dosing.

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1
• Ramucirumab (Cyramza) 10 mg/kg IV once on day 1

Supportive medications

• Colony-stimulating factors and erythroid-stimulating factor use per investigator discretion.

21-day cycles

Regimen variant #2, 75 mg/m² docetaxel

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Garon et al. 2014 (REVEL)	2010-2013	Phase III (E-RT-esc)	Docetaxel	Seems to have superior OS

Note: The FDA only provides recommendations for ramucirumab dosing.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Ramucirumab (Cyramza) 10 mg/kg IV once on day 1

Supportive medications

• Colony-stimulating factors and erythroid-stimulating factor use per investigator discretion.

21-day cycles

References

1. REVEL: Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. Epub 2014 Jun 2. link to original article contains verified protocol PubMed

Docetaxel & Vandetanib

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Regimen variant #1, 60 mg/m² docetaxel

Study	Evidence	Comparator	Comparative Efficacy
Herbst et al. 2010 (ZODIAC)	Phase III (E-esc)	Docetaxel	Superior PFS

This is the PMDA-approved dose of docetaxel. While statistically superior, the median PFS difference was only 0.8 months. Vandetanib is continued until disease progression, unacceptable toxicity, or withdrawal of consent.

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1
• Vandetanib (Caprelsa) 100 mg PO once per day

21-day cycle for up to 6 cycles (*)

Regimen variant #2, 75 mg/m² docetaxel

Study	Evidence	Comparator	Comparative Efficacy
Herbst et al. 2010 (ZODIAC)	Phase III (E-esc)	Docetaxel	Superior PFS

While statistically superior, the median PFS difference was only 0.8 months. Vandetanib is continued until disease progression, unacceptable toxicity, or withdrawal of consent.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Vandetanib (Caprelsa) 100 mg PO once per day

21-day cycle for up to 6 cycles (see note)

References

1. Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010 Jul;11(7):619-26. link to original article link to PMC article contains verified protocol PubMed

Gefitinib monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Sun et al. 2012 (KCSG-LU08-01)	Phase III (E-switch-ooc)	Pemetrexed	Superior PFS

Chemotherapy

• Gefitinib (Iressa) 250 mg PO once per day

Continued indefinitely

References

1. KCSG-LU08-01: Sun JM, Lee KH, Kim SW, Lee DH, Min YJ, Yun HJ, Kim HK, Song HS, Kim YH, Kim BS, Hwang IG, Lee K, Jo SJ, Lee JW, Ahn JS, Park K, Ahn MJ; Korean Cancer Study Group. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012 Dec 15;118(24):6234-42. Epub 2012 Jun 6. link to original article contains protocol PubMed

Gemcitabine monotherapy

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Regimen

Study	Evidence
Crinò et al. 1999a	Phase II

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycles

References

1. Crinò L, Mosconi AM, Scagliotti G, Selvaggi G, Novello S, Rinaldi M, Della Giulia M, Gridelli C, Rossi A, Calandri C, De Marinis F, Noseda M, Tonato M. Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol. 1999 Jul;17(7):2081-5. link to original article contains protocol PubMed

Pemetrexed monotherapy

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Example orders

• Example orders for Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cullen et al. 2008	2004-2005	Phase III (C)	Pemetrexed; high-dose	Did not meet primary endpoint of OS
de Boer et al. 2011 (ZEAL)		Phase III (C)	Pemetrexed & Vandetanib	Did not meet primary endpoint of PFS
Ciuleanu et al. 2012 (TITAN)		Phase III (C)	Erlotinib	Did not meet primary endpoint of OS
Sun et al. 2012 (KCSG-LU08-01)		Phase III (C)	Gefitinib	Inferior PFS
Ardizzoni et al. 2012 (GOIRC 02-2006)		Randomized Phase II (C)	Carboplatin & Pemetrexed	Did not meet primary endpoint of PFS
Sun et al. 2012 (JMID)		Phase III (E-switch-ic)	Docetaxel	Inconclusive whether non-inferior OS
Gridelli et al. 2018 (AvaALL)		Phase III (C)	Investigator's choice of: 1. Docetaxel & Bevacizumab 2. Erlotinib & Bevacizumab 3. Pemetrexed & Bevacizumab	Did not meet primary endpoint of OS

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

Supportive medications

• (per Ardizzoni et al. 2012):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be given throughout pemetrexed therapy

21-day cycles

GOIRC 02-2006 treated patients for up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal.

References

1. Cullen MH, Zatloukal P, Sörenson S, Novello S, Fischer JR, Joy AA, Zereu M, Peterson P, Visseren-Grul CM, Iscoe N. A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2008 May;19(5):939-45. Epub 2008 Feb 17. link to original article contains protocol PubMed
2. ZEAL: de Boer RH, Arrieta Ó, Yang CH, Gottfried M, Chan V, Raats J, de Marinis F, Abratt RP, Wolf J, Blackhall FH, Langmuir P, Milenkova T, Read J, Vansteenkiste JF. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2011 Mar 10;29(8):1067-74. Epub 2011 Jan 31. link to original article contains protocol PubMed
3. TITAN: Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012 Mar;13(3):300-8. Epub 2012 Jan 24. link to original article contains protocol PubMed
4. KCSG-LU08-01: Sun JM, Lee KH, Kim SW, Lee DH, Min YJ, Yun HJ, Kim HK, Song HS, Kim YH, Kim BS, Hwang IG, Lee K, Jo SJ, Lee JW, Ahn JS, Park K, Ahn MJ; Korean Cancer Study Group. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012 Dec 15;118(24):6234-42. Epub 2012 Jun 6. link to original article contains protocol PubMed
5. GOIRC 02-2006: Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. Epub 2012 Oct 29. link to original article contains verified protocol PubMed
6. JMID: Sun Y, Wu YL, Zhou CC, Zhang L, Zhang L, Liu XY, Yu SY, Jiang GL, Li K, Qin SK, Ma SL, Han L, Quinlivan M, Orlando M, Zhang XQ. Second-line pemetrexed versus docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer: a randomized, open-label study. Lung Cancer. 2013 Feb;79(2):143-50. Epub 2012 Nov 20. link to original article PubMed
7. AvaALL: Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. Epub 2018 Dec 13. Erratum in: JAMA Oncol. 2018 Dec 1;4(12):1792. link to original article link to PMC article contains verified protocol in supplement PubMed

Advanced or metastatic disease, third-line

Cabozantinib monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512)	Randomized Phase II (E-switch-ic)	1. Cabozantinib & Erlotinib	Not reported
		2. Erlotinib	Superior PFS

Chemotherapy

• Cabozantinib (Cometriq) 60 mg PO once per day

Continued indefinitely

References

1. ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains protocol link to PMC article PubMed

Cabozantinib & Erlotinib

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512)	Randomized Phase II (E-esc)	1. Cabozantinib	Not reported
		2. Erlotinib	Superior PFS

Chemotherapy

• Cabozantinib (Cometriq) 40 mg PO once per day
• Erlotinib (Tarceva) 150 mg PO once per day

Continued indefinitely

References

1. ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains protocol link to PMC article PubMed

Docetaxel monotherapy

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Example orders

• Example orders for Docetaxel (Taxotere) in non-small cell lung cancer

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Kawaguchi et al. 2014 (DELTANSCLC)	Phase III (C)	Erlotinib	Might have superior PFS

This is the PMDA-approved dose. Note that there is another trial named DELTA in indolent lymphoma.

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV over at least 60 minutes once on day 1

21-day cycles

References

1. DELTA: Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8. Epub 2014 May 19. link to original article contains verified protocol PubMed

Advanced or metastatic disease, subsequent lines of therapy

Note: this section includes regimens that were tested in second-line and beyond; those tested specifically in the second-line or third-line are to be found above.

Afatinib monotherapy

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Regimen variant #1, 30 mg/day

FDA-recommended dose

This is the FDA-recommended dose for patients with "severe renal impairment".

Chemotherapy

• Afatinib (Gilotrif) 30 mg PO once per day

Continued indefinitely

Regimen variant #2, 50 mg/day

Study	Evidence	Comparator	Comparative Efficacy
Miller et al. 2012 (LUX-Lung 1)	Phase III (E-esc)	Placebo	Superior PFS
Katakami et al. 2013 (LUX-Lung 4)	Phase II		ORR: 8% (95% CI: 3-18)

In LUX-Lung 4, 72.6% of patients were EGFR mutation positive. This was third or fourth line therapy for participants, who had progressed while receiving erlotinib and/or gefitinib and had received one or two previous lines of chemotherapy, including at least one platinum-based regimen.

Chemotherapy

• Afatinib (Gilotrif) 50 mg PO once per day, given 1 hour before eating food

Continued indefinitely

References

1. LUX-Lung 1: Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
   1. HRQoL analysis: Hirsh V, Cadranel J, Cong XJ, Fairclough D, Finnern HW, Lorence RM, Miller VA, Palmer M, Yang JC. Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1). J Thorac Oncol. 2013 Feb;8(2):229-37. link to original article PubMed
2. LUX-Lung 4: Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013 Sep 20;31(27):3335-41. Epub 2013 Jul 1. link to original article contains verified protocol PubMed

Afatinib & Paclitaxel

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schuler et al. 2015 (LUX-Lung 5)	2010-2011	Phase III (E-esc)	Single-agent chemotherapy	Superior PFS

Chemotherapy

• Afatinib (Gilotrif)
• Paclitaxel (Taxol)

References

1. LUX-Lung 5: Schuler M, Yang JC, Park K, Kim JH, Bennouna J, Chen YM, Chouaid C, De Marinis F, Feng JF, Grossi F, Kim DW, Liu X, Lu S, Strausz J, Vinnyk Y, Wiewrodt R, Zhou C, Wang B, Chand VK, Planchard D; LUX-Lung 5 Investigators. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. Ann Oncol. 2016 Mar;27(3):417-23. Epub 2015 Dec 8. link to original article link to PMC article PubMed NCT01085136

Amrubicin monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Yoshioka et al. 2017 (D0702035)	2010-2012	Phase III (E-switch-ic)	Docetaxel	Did not meet primary endpoint of PFS

Chemotherapy

• Amrubicin (Calsed) 35 mg/m² IV over 5 minutes once per day on days 1 to 3

21-day cycles

References

1. D0702035: Yoshioka H, Katakami N, Okamoto H, Iwamoto Y, Seto T, Takahashi T, Sunaga N, Kudoh S, Chikamori K, Harada M, Tanaka H, Saito H, Saka H, Takeda K, Nogami N, Masuda N, Harada T, Kitagawa H, Horio H, Yamanaka T, Fukuoka M, Yamamoto N, Nakagawa K. A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer. Ann Oncol. 2017 Feb 1;28(2):285-291. link to original article contains verified protocol PubMed NCT01207011

Atezolizumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fehrenbacher et al. 2016 (POPLAR)	2013-2014	Randomized Phase II (E-switch-ooc)	Docetaxel	Seems to have superior OS
Rittmeyer et al. 2016 (OAK)	2014-2015	Phase III (E-RT-switch-ooc)	Docetaxel	Superior OS

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycles

References

1. POPLAR: Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. link to original article contains protocol PubMed
2. OAK: Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. link to original article PubMed
   1. Update: von Pawel J, Bordoni R, Satouchi M, Fehrenbacher L, Cobo M, Han JY, Hida T, Moro-Sibilot D, Conkling P, Gandara DR, Rittmeyer A, Gandhi M, Yu W, Matheny C, Patel H, Sandler A, Ballinger M, Kowanetz M, Park K. Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study. Eur J Cancer. 2019 Jan;107:124-132. Epub 2018 Dec 17. link to original article PubMed
   2. Update: Fehrenbacher L, von Pawel J, Park K, Rittmeyer A, Gandara DR, Ponce Aix S, Han JY, Gadgeel SM, Hida T, Cortinovis DL, Cobo M, Kowalski DM, De Marinis F, Gandhi M, Danner B, Matheny C, Kowanetz M, He P, Felizzi F, Patel H, Sandler A, Ballinger M, Barlesi F. Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer. J Thorac Oncol. 2018 Aug;13(8):1156-1170. Epub 2018 May 17. Erratum in: J Thorac Oncol. 2018 Nov;13(11):1800. link to original article PubMed

Docetaxel monotherapy

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Example orders

• Example orders for Docetaxel (Taxotere) in non-small cell lung cancer

Regimen variant #1, 35 mg/m², 3 out of 4 weeks

Study	Evidence	Comparator	Comparative Efficacy
Chen et al. 2006	Phase III (E-switch-ic)	1. Docetaxel; 40 mg/m2, 2 out of 3 wks	Did not meet efficacy endpoint
		2. Docetaxel; 75 mg/m2, every 3 wks	Did not meet efficacy endpoint

Chemotherapy

• Docetaxel (Taxotere) 35 mg/m² IV once per day on days 1, 8, 15

Supportive medications

• Dexamethasone (Decadron) as follows:
  • 8 mg PO once per day on days 1, 8, 15; 12 hours prior to Docetaxel (Taxotere)
  • 10 mg IV once per day on days 1, 8, 15; 30 minutes prior to Docetaxel (Taxotere)
  • 8 mg PO once per day on days 1, 8, 15; 12 hours after Docetaxel (Taxotere)

28-day cycles

Regimen variant #2, 60 mg/m² q3wk, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Maruyama et al. 2008 (V-15-32)		Phase III (C)	Gefitinib	Inconclusive whether non-inferior OS
Kawaguchi et al. 2014 (DELTANSCLC)		Phase III (C)	Erlotinib	Might have superior PFS
Yoshioka et al. 2017 (D0702035)	2010-2012	Phase III (C)	Amrubicin	Did not meet primary endpoint of PFS
Nokihara et al. 2017 (EAST-LC)	2010-2014	Phase III (C)	S-1	Non-inferior OS

This is the PMDA-approved dose, the dose used for East Asian patients in REVEL, and the dose used in Japanese patients in EAST-LC.

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV over at least 60 minutes once on day 1

21-day cycles

Regimen variant #3, 75 mg/m² q3wk, limited duration

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gerber et al. 2018 (SUNRISE)	2013-2016	Phase III (C)	Docetaxel & Bavituximab	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

Regimen variant #4, 75 mg/m² q3wk, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Shepherd et al. 2000 (TAX 317)	1994-1998	Phase III (E-RT-esc)	Best supportive care	Seems to have superior OS
Fossella et al. 2000 (TAX 320)	1995-1998	Phase III (E-RT-switch-ic)	1. Docetaxel; 100 mg/m2	Did not meet primary endpoint of OS
			2. Ifosfamide 3. Vinorelbine	Did not meet primary endpoint of OS
Camps et al. 2005	2000-2003	Phase III (C)	Docetaxel; 36 mg/m2, 6 out of 8 wks	Might have superior OS
Hanna et al. 2004 (JMEI)	2001-2002	Phase III (C)	Pemetrexed	Inconclusive whether non-inferior OS
Chen et al. 2006		Phase III (C)	1. Docetaxel; 35 mg/m2, 3 out of 4 wks	Did not meet efficacy endpoint
			2. Docetaxel; 40 mg/m2, 2 out of 3 wks	Did not meet efficacy endpoint
Ramlau et al. 2006		Phase III (C)	Topotecan	Might have superior OS
Kim et al. 2008 (INTEREST)		Phase III (C)	Gefitinib	Seems to have non-inferior OS
Fidias et al. 2008		Phase III (C)	Docetaxel consolidation	Might have inferior OS
Lee et al. 2010 (ISTANA)		Phase III (C)	Gefitinib	Seems to have inferior PFS
Ramlau et al. 2012 (EFC10261)		Phase III (C)	Docetaxel & ziv-Aflibercept	Did not meet primary endpoint of OS
Reck et al. 2014 (LUME-Lung 1)		Phase III (C)	Docetaxel & Nintedanib	Inferior PFS
Nokihara et al. 2017 (EAST-LC)	2010-2014	Phase III (C)	S-1	Non-inferior OS
Katakami et al. 2017 (E7389-G000-302)	2011-2014	Phase III (C)	Eribulin	Did not meet primary endpoint of OS
Brahmer et al. 2015 (CheckMate 017)	2012-2013	Phase III (C)	Nivolumab	Inferior OS
Borghaei et al. 2015 (CheckMate 057)	NR-2015	Phase III (C)	Nivolumab	Inferior OS
Herbst et al. 2015 (KEYNOTE-010)	2013-2015	Phase II/III (C)	Pembrolizumab	Inferior OS
Fehrenbacher et al. 2016 (POPLAR)	2013-2014	Randomized Phase II (C)	Atezolizumab	Seems to have inferior OS
Rittmeyer et al. 2016 (OAK)	2014-2015	Phase III (C)	Atezolizumab	Inferior OS
Barlesi et al. 2018 (JAVELIN Lung 200)		Phase III (C)	Avelumab	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Supportive medications

• Per JMEI: Dexamethasone (Decadron) 8 mg PO twice per day on days -1 to 2 (3 days)
• Per Chem et al. 2006: Dexamethasone (Decadron) as follows:
  • 8 mg PO once per day on days 1, 8, 15; 12 hours prior to Docetaxel (Taxotere)
  • 10 mg IV once per day on days 1, 8, 15; 30 minutes prior to Docetaxel (Taxotere)
  • 8 mg PO once per day on days 1, 8, 15; 12 hours after Docetaxel (Taxotere)

21-day cycles

Regimen variant #5, 100 mg/m² q3wk

Study	Evidence
Fossella et al. 1995	Phase II

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

21-day cycles

References

1. Fossella FV, Lee JS, Shin DM, Calayag M, Huber M, Perez-Soler R, Murphy WK, Lippman S, Benner S, Glisson B, Chasen M, Hong WK, Raber M. Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer. J Clin Oncol. 1995 Mar;13(3):645-51. link to original article contains protocol PubMed
2. TAX 317: Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000 May;18(10):2095-103. link to original article contains protocol PubMed
3. TAX 320: Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. link to original article contains verified protocol PubMed
4. JMEI: Hanna N, Shepherd FA, Fossella FV, Rodrigues Pereira J, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. link to original article contains verified protocol PubMed
5. Camps C, Massuti B, Jiménez A, Maestu I, Gómez RG, Isla D, González JL, Almenar D, Blasco A, Rosell R, Carrato A, Viñolas N, Batista N, Girón CG, Galán A, López M, Blanco R, Provencio M, Diz P, Felip E; Spanish Lung Cancer Group. Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: a Spanish Lung Cancer Group trial. Ann Oncol. 2006 Mar;17(3):467-72. Epub 2005 Dec 21. link to original article contains protocol PubMed
6. Chen YM, Shih JF, Perng RP, Tsai CM, Whang-Peng J. A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy. Chest. 2006 Apr;129(4):1031-8. link to original article contains verified protocol PubMed
7. Ramlau R, Gervais R, Krzakowski M, von Pawel J, Kaukel E, Abratt RP, Dharan B, Grotzinger KM, Ross G, Dane G, Shepherd FA. Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non-small-cell lung cancer. J Clin Oncol. 2006 Jun 20;24(18):2800-7. Epub 2006 May 8. link to original article contains protocol PubMed
8. V-15-32: Maruyama R, Nishiwaki Y, Tamura T, Yamamoto N, Tsuboi M, Nakagawa K, Shinkai T, Negoro S, Imamura F, Eguchi K, Takeda K, Inoue A, Tomii K, Harada M, Masuda N, Jiang H, Itoh Y, Ichinose Y, Saijo N, Fukuoka M. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol. 2008 Sep 10;26(26):4244-52. link to original article contains verified protocol PubMed
   1. HRQoL analysis: Sekine I, Ichinose Y, Nishiwaki Y, Yamamoto N, Tsuboi M, Nakagawa K, Shinkai T, Negoro S, Imamura F, Eguchi K, Takeda K, Itoh Y, Tamura T, Saijo N, Fukuoka M. Quality of life and disease-related symptoms in previously treated Japanese patients with non-small-cell lung cancer: results of a randomized phase III study (V-15-32) of gefitinib versus docetaxel. Ann Oncol. 2009 Sep;20(9):1483-8. Epub 2009 Mar 12. link to original article PubMed
9. INTEREST: Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. link to original article contains protocol PubMed
   1. Dataset: Project Data Sphere
10. Fidias PM, Dakhil SR, Lyss AP, Loesch DM, Waterhouse DM, Bromund JL, Chen R, Hristova-Kazmierski M, Treat J, Obasaju CK, Marciniak M, Gill J, Schiller JH. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Feb 1;27(4):591-8. Epub 2008 Dec 15. link to original articlecontains verified protocol PubMed
11. ISTANA: Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, Ahn MJ, Ahn JS, Suh C, Kim SW. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010 Feb 15;16(4):1307-14. Epub 2010 Feb 9. link to original article contains protocol PubMed
12. EFC10261: Ramlau R, Gorbunova V, Ciuleanu TE, Novello S, Ozguroglu M, Goksel T, Baldotto C, Bennouna J, Shepherd FA, Le-Guennec S, Rey A, Miller V, Thatcher N, Scagliotti G. Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol. 2012 Oct 10;30(29):3640-7. Epub 2012 Sep 10. link to original article contains protocol PubMed
    1. Dataset: Project Data Sphere
13. LUME-Lung 1: Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55. 2. Epub 2014 Jan 9. link to original article contains protocol PubMed
14. CheckMate 017: Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. Epub 2015 May 31. link to original article link to PMC article PubMed
    1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article PubMed
    2. HRQoL analysis: Reck M, Taylor F, Penrod JR, DeRosa M, Morrissey L, Dastani H, Orsini L, Gralla RJ. Impact of nivolumab versus docetaxel on health-related quality of life and symptoms in patients with advanced squamous non-small cell lung cancer: results from the CheckMate 017 study. J Thorac Oncol. 2018 Feb;13(2):194-204. Epub 2017 Nov 10. link to original article PubMed
15. CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article PubMed NCT01673867
    1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article PubMed
    2. HRQoL analysis: Reck M, Brahmer J, Bennett B, Taylor F, Penrod JR, DeRosa M, Dastani H, Spigel DR, Gralla RJ. Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. Eur J Cancer. 2018 Oct;102:23-30. Epub 2018 Aug 10. link to original article PubMed
16. KEYNOTE-010: Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. link to original article contains protocol PubMed
17. POPLAR: Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. link to original article contains protocol PubMed
18. OAK: Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. Epub 2016 Dec 13. link to original article contains protocol PubMed
    1. Update: von Pawel J, Bordoni R, Satouchi M, Fehrenbacher L, Cobo M, Han JY, Hida T, Moro-Sibilot D, Conkling P, Gandara DR, Rittmeyer A, Gandhi M, Yu W, Matheny C, Patel H, Sandler A, Ballinger M, Kowanetz M, Park K. Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study. Eur J Cancer. 2019 Jan;107:124-132. Epub 2018 Dec 17. link to original article PubMed
    2. Update: Fehrenbacher L, von Pawel J, Park K, Rittmeyer A, Gandara DR, Ponce Aix S, Han JY, Gadgeel SM, Hida T, Cortinovis DL, Cobo M, Kowalski DM, De Marinis F, Gandhi M, Danner B, Matheny C, Kowanetz M, He P, Felizzi F, Patel H, Sandler A, Ballinger M, Barlesi F. Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer. J Thorac Oncol. 2018 Aug;13(8):1156-1170. Epub 2018 May 17. Erratum in: J Thorac Oncol. 2018 Nov;13(11):1800. link to original article PubMed
19. D0702035: Yoshioka H, Katakami N, Okamoto H, Iwamoto Y, Seto T, Takahashi T, Sunaga N, Kudoh S, Chikamori K, Harada M, Tanaka H, Saito H, Saka H, Takeda K, Nogami N, Masuda N, Harada T, Kitagawa H, Horio H, Yamanaka T, Fukuoka M, Yamamoto N, Nakagawa K. A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer. Ann Oncol. 2017 Feb 1;28(2):285-291. link to original article contains verified protocol PubMed NCT01207011
20. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed NCT01454934
21. EAST-LC: Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. link to original article link to PMC article contains verified protocol PubMed JapicCTI-101155
22. SUNRISE: Gerber DE, Horn L, Boyer M, Sanborn R, Natale R, Palmero R, Bidoli P, Bondarenko I, Germonpre P, Ghizdavescu D, Kotsakis A, Lena H, Losonczy G, Park K, Su WC, Tang M, Lai J, Kallinteris NL, Shan JS, Reck M, Spigel DR. Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer. Ann Oncol. 2018 Jul 1;29(7):1548-1553. link to original article contains verified protocol link to PMC article PubMed NCT01999673
23. JAVELIN Lung 200: Barlesi F, Vansteenkiste J, Spigel D, Ishii H, Garassino M, de Marinis F, Özgüroğlu M, Szczesna A, Polychronis A, Uslu R, Krzakowski M, Lee JS, Calabrò L, Arén Frontera O, Ellers-Lenz B, Bajars M, Ruisi M, Park K. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol. 2018 Nov;19(11):1468-79. Epub 2018 Sep 21. link to original article contains protocol PubMed

Docetaxel & Nintedanib

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Reck et al. 2014 (LUME-Lung 1)	Phase III (E-esc)	Docetaxel	Superior PFS

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Nintedanib (Vargatef) 200 mg PO twice per day on days 2 to 21

21-day cycles

References

1. LUME-Lung 1: Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55. 2. Epub 2014 Jan 9. link to original article contains protocol PubMed

Gefitinib monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Kris et al. 2003 (IDEAL2)	Randomized Phase II (E-de-esc)	Gefitinib; 500 mg/day	Did not meet primary endpoint of ORR
Thatcher et al. 2005 (ISEL)	Phase III (E-esc)	Placebo	Might have superior OS
Kim et al. 2008 (INTEREST)	Phase III (E-switch-ooc)	Docetaxel	Seems to have non-inferior OS
Lee et al. 2010 (ISTANA)	Phase III (E-switch-ooc)	Docetaxel	Seems to have superior PFS
Han et al. 2011	Randomized Phase II (C)	Gefitinib & Simvastatin	Did not meet primary endpoint of ORR
Shi et al. 2013 (ICOGEN)	Phase III (C)	Icotinib	Seems to have non-inferior PFS
Urata et al. 2016 (WJOG 5108L)	Phase III (C)	Erlotinib	Inconclusive whether non-inferior PFS

Chemotherapy

• Gefitinib (Iressa) 250 mg PO once per day

Continued indefinitely

References

1. IDEAL2: Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003 Oct 22;290(16):2149-58. link to original article PubMed
2. ISEL: Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37. link to original article PubMed
3. INTEREST: Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. link to original article contains verified protocol PubMed
   1. Dataset: Project Data Sphere
4. ISTANA: Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, Ahn MJ, Ahn JS, Suh C, Kim SW. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010 Feb 15;16(4):1307-14. Epub 2010 Feb 9. link to original article contains protocol PubMed
5. Han JY, Lee SH, Yoo NJ, Hyung LS, Moon YJ, Yun T, Kim HT, Lee JS. A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2011 Mar 15;17(6):1553-60. link to orinigal article contains protocol PubMed
6. ICOGEN: Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. link to original article PubMed
7. WJOG 5108L: Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, Satouchi M, Iwamoto Y, Kanehara M, Fujimoto D, Ikeda N, Murakami H, Daga H, Oguri T, Goto I, Imamura F, Sugawara S, Saka H, Nogami N, Negoro S, Nakagawa K, Nakanishi Y. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016 Sep 20;34(27):3248-57. Epub 2016 Mar 28. link to original article contains verified protocol PubMed

Gemcitabine monotherapy

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Regimen variant #1, 1000 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Katakami et al. 2017 (E7389-G000-302)	2011-2014	Phase III (C)	Eribulin	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 1250 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Katakami et al. 2017 (E7389-G000-302)	2011-2014	Phase III (C)	Eribulin	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed NCT01454934

Icotinib monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Shi et al. 2013 (ICOGEN)	Phase III (E-switch-ic)	Gefitinib	Seems to have non-inferior PFS

Note: this drug is only approved in China.

Chemotherapy

• Icotinib (Conmana) 125 mg PO three times per day

Continued indefinitely

References

1. ICOGEN: Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. link to original article contains protocol PubMed

Nintedanib & Pemetrexed

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Hanna et al. 2016 (LUME-Lung 2)	Phase III (E-esc)	Pemetrexed	Seems to have superior PFS

Chemotherapy

• Nintedanib (Vargatef) 200 mg PO twice per day on days 2 to 21
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

21-day cycles

References

1. LUME-Lung 2: Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Voccia I, Pawel JV, Kovcin V, Agulnik J, Gaschler-Markefski B, Barrueco J, Sikken P, Schloss C, Kim JH; LUME-Lung 2 Study group. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. Lung Cancer. 2016 Dec;102:65-73. Epub 2016 Oct 27. link to original article PubMed

Nivolumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rizvi et al. 2015 (CheckMate 063)		Phase II
Brahmer et al. 2015 (CheckMate 017)	2012-2013	Phase III (E-RT-switch-ooc)	Docetaxel	Superior OS
Borghaei et al. 2015 (CheckMate 057)	NR-2015	Phase III (E-RT-switch-ooc)	Docetaxel	Superior OS

Patients in CheckMate 017 had squamous histology. Patients in CheckMate 057 had non-squamous histology.

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1
  • Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

14-day cycles

References

1. CheckMate 063: Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Feb 19. link to original article contains verified protocol PubMed
2. CheckMate 017: Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. Epub 2015 May 31. link to original article link to PMC article PubMed
   1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article PubMed
   2. HRQoL analysis: Reck M, Taylor F, Penrod JR, DeRosa M, Morrissey L, Dastani H, Orsini L, Gralla RJ. Impact of nivolumab versus docetaxel on health-related quality of life and symptoms in patients with advanced squamous non-small cell lung cancer: results from the CheckMate 017 study. J Thorac Oncol. 2018 Feb;13(2):194-204. Epub 2017 Nov 10. link to original article PubMed
3. CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article PubMed NCT01673867
   1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article PubMed
   2. HRQoL analysis: Reck M, Brahmer J, Bennett B, Taylor F, Penrod JR, DeRosa M, Dastani H, Spigel DR, Gralla RJ. Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. Eur J Cancer. 2018 Oct;102:23-30. Epub 2018 Aug 10. link to original article PubMed

Pembrolizumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Garon et al. 2015 (KEYNOTE-001)		Phase 1, >20 pts in dosing cohort
Herbst et al. 2015 (KEYNOTE-010)	2013-2015	Phase II/III (E-RT-switch-ooc)	Docetaxel	Superior OS

Note: patients had previously received chemotherapy.

Immunotherapy

• Pembrolizumab (Keytruda) 2 mg/kg or 10 mg/kg IV once on day 1

21-day cycles

References

1. Phase 1: Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. Epub 2015 Apr 19. link to original article PubMed
2. KEYNOTE-010: Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. link to original article contains protocol PubMed

Pemetrexed monotherapy

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Example orders

• Example orders for Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hanna et al. 2004 (JMEI)	2001-2002	Phase III (E-RT-switch-ic)	Docetaxel	Inconclusive whether non-inferior OS
Karampeazis et al. 2013 (CT/06.05)		Phase III (E-switch-ooc)	Erlotinib	Did not meet primary endpoint of TTP
Kim et al. 2013 (JXBC)		Phase III (C)	Pemetrexed & Cetuximab	Did not meet primary endpoint of PFS
Hanna et al. 2016 (LUME-Lung 2)		Phase III (C)	Nintedanib & Pemetrexed	Seems to have inferior PFS
Katakami et al. 2017 (E7389-G000-302)	2011-2014	Phase III (C)	Eribulin	Did not meet primary endpoint of OS

Note: JXBC also evaluated docetaxel versus docetaxel & cetuximab, but did not report the efficacy of this comparison; see paper for details.

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

Supportive medications

• (per Ardizzoni et al. 2012):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be taken throughout pemetrexed therapy
  • JMEI used Folic acid (Folate) 1 mg PO once per day
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be given throughout pemetrexed therapy

21-day cycles

References

1. JMEI: Hanna N, Shepherd FA, Fossella FV, Rodrigues Pereira J, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. link to original article contains protocol PubMed
2. CT/06.05: Karampeazis A, Voutsina A, Souglakos J, Kentepozidis N, Giassas S, Christofillakis C, Kotsakis A, Papakotoulas P, Rapti A, Agelidou M, Agelaki S, Vamvakas L, Samonis G, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer. 2013 Aug 1;119(15):2754-64. Epub 2013 May 9. link to original article contains verified protocol PubMed
3. JXBC: Kim ES, Neubauer M, Cohn A, Schwartzberg L, Garbo L, Caton J, Robert F, Reynolds C, Katz T, Chittoor S, Simms L, Saxman S. Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial. Lancet Oncol. 2013 Dec;14(13):1326-36. Epub 2013 Nov 12. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. link to original article contains protocol PubMed
4. LUME-Lung 2: Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Voccia I, Pawel JV, Kovcin V, Agulnik J, Gaschler-Markefski B, Barrueco J, Sikken P, Schloss C, Kim JH; LUME-Lung 2 Study group. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. Lung Cancer. 2016 Dec;102:65-73. Epub 2016 Oct 27. link to original article PubMed
5. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed NCT01454934

S-1 monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Nokihara et al. 2017 (EAST-LC)	2010-2014	Phase III (E-switch-ic)	Docetaxel	Non-inferior OS

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) as follows:
  • BSA less than 1.25 m²: 40 mg PO twice per day on days 1 to 28
  • BSA at least 1.25 m² and less than 1.5 m²: 50 mg PO twice per day on days 1 to 28
  • BSA 1.5 m² or more: 60 mg PO twice per day on days 1 to 28

42-day cycles

References

1. EAST-LC: Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. link to original article link to PMC article PubMed JapicCTI-101155

Sorafenib monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Paz-Ares et al. 2015 (MISSION)	Phase III (E-esc)	Placebo	Superior PFS

Note: although the primary endpoint (OS) was negative overall, the authors note that the subgroup of patients with known EGFR mutations treated with sorafenib had significantly superior survival (p=0.002).

Chemotherapy

• Sorafenib (Nexavar) 400 mg PO twice per day

Continued indefinitely

References

1. MISSION: Paz-Ares L, Hirsh V, Zhang L, de Marinis F, Yang JC, Wakelee HA, Seto T, Wu YL, Novello S, Juhász E, Arén O, Sun Y, Schmelter T, Ong TJ, Peña C, Smit EF, Mok TS. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: A phase III, multicenter, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung cancer after 2 or 3 previous treatment regimens. J Thorac Oncol. 2015 Dec;10(12):1745-53. link to original article contains verified protocol PubMed

Vinorelbine monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fossella et al. 2000 (TAX 320)	1995-1998	Phase III (C)	1. Docetaxel 100 mg/m2	Did not meet primary endpoint of OS
			2. Docetaxel 75 mg/m2	Did not meet primary endpoint of OS
Katakami et al. 2017 (E7389-G000-302)	2011-2014	Phase III (C)	Eribulin	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV over 5 to 10 minutes once per day on days 1, 8, 15, 22

Supportive medications

• Per TAX 320:
• Patients who had either grade 4 neutropenia lasting at least 5 days or both fever and grade 3 or 4 neutropenia could receive G-CSF (dose/schedule/duration not specified)
• Metoclopramide (Reglan) (dose/schedule/route not specified) used first for nausea
• Nausea despite metoclopramide was treated with a 5-HT3 antagonist such as Ondansetron (Zofran) or Granisetron (dose/schedule/route not specified) prn nausea

28-day cycles

References

1. TAX 320: Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. link to original article contains verified protocol PubMed
2. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed NCT01454934

Investigational agents

Drugs with some degree of promising activity in clinical trials.

• Sacituzumab govitecan (IMMU-132)