Non-small cell lung cancer

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115 regimens on this page 229 variants on this page

Adjuvant therapy

Carboplatin & Paclitaxel

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Regimen

Study	Evidence	Comparator
Strauss et al. 2008 (CALGB 9633)	Phase III	Observation

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. 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 PubMed

Cisplatin & Docetaxel

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Example orders

• Example orders for adjuvant Cisplatin (Platinol) and Docetaxel (Taxotere) in non-small cell lung cancer

Regimen

Study	Evidence	Comparator
Barlesi et al. 2015	Phase III	Cisplatin & Gemcitabine

Treatment begins within 8 weeks of complete R0 resection for Stage IB–III NSCLC.

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

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

Cisplatin & Etoposide

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Regimen

Study	Evidence	Comparator
Arriagada et al. 2004	Phase III	Cisplatin & Vinblastine Cisplatin & Vindesine Cisplatin & Vinorelbine Observation

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. 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

Cisplatin & Gemcitabine

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Regimen

Study	Evidence	Comparator
Barlesi et al. 2015	Phase III	Cisplatin & Docetaxel

Treatment begins within 8 weeks of complete R0 resection for Stage IB–III NSCLC.

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

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

Cisplatin & Pemetrexed

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Regimen

Study	Evidence	Comparator
Kreuter et al. 2013 (TREAT)	Randomized Phase II	Cisplatin & Vinorelbine

Treatment to begin within 4 to 6 weeks after complete resection of pathologically confirmed NSCLC stages (according to the TNM staging system version 6) IB, IIA, IIB or T3N1.

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. 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. 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

Cisplatin & Vinblastine

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Regimen

Study	Evidence	Comparator
Arriagada et al. 2004	Phase III	Cisplatin & Etoposide Cisplatin & Vindesine Cisplatin & Vinorelbine Observation

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.

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. 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 contains verified protocol PubMed

Cisplatin & Vindesine

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Regimen

Study	Evidence	Comparator
Arriagada et al. 2004	Phase III	Cisplatin & Etoposide Cisplatin & Vinblastine Cisplatin & Vinorelbine Observation

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.

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. 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 contains verified protocol PubMed

Cisplatin & Vinorelbine

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Regimen #1

Study	Evidence	Comparator
Winton et al. 2005 (JBR.10)	Phase III	Observation
Kreuter et al. 2013 (TREAT)	Randomized Phase II	Cisplatin & Pemetrexed

Treatment in TREAT to begin within 4 to 6 weeks after complete resection of pathologically confirmed NSCLC stages (according to the TNM staging system version 6) IB, IIA, IIB or T3N1.

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 #2

Study	Evidence	Comparator
Arriagada et al. 2004	Phase III	Cisplatin & Etoposide Cisplatin & Vinblastine Cisplatin & Vindesine Observation
Douillard et al. 2006 (ANITA)	Phase III	Observation

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

Regimen #3

Study	Evidence
Hotta et al. 2001	Phase II

Chemotherapy

• Cisplatin (Platinol) 75 to 80 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 to 30 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

References

1. Hotta K, Sekine I, Tamura T, Sawada M, Watanabe H, Kusaba H, Akiyama Y, Inoue A, Shimoyama T, Nokihara H, Ueda Y, Yamamoto N, Kunitoh H, Ohe Y, Kodama T, Saijo N. A phase I/II study of cisplatin and vinorelbine chemotherapy in patients with advanced non-small cell lung cancer. Jpn J Clin Oncol. 2001 Dec;31(12):596-600. link to original article contains protocol PubMed
2. 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 content property of HemOnc.org
3. 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
4. Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, 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
5. 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. 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

Placebo (Observation)

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Regimen

Study	Evidence	Comparator
Arriagada et al. 2004	Phase III	Cisplatin & Etoposide Cisplatin & Vinblastine Cisplatin & Vindesine Cisplatin & Vinorelbine
Winton et al. 2006 (JBR.10)	Phase III	Cisplatin & Vinorelbine
Douillard et al. 2006 (ANITA)	Phase III	Cisplatin & Vinorelbine
Strauss et al. 2008 (CALGB 9633)	Phase III	Carboplatin & Paclitaxel

No treatment. Placed here because one or more randomized clinical trials included a placebo or observation arm in this disease context.

References

1. 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
2. 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
3. Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, 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. 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 PubMed

Chemotherapy & radiation therapy

Carboplatin, Paclitaxel, concurrent RT

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Regimen

Study	Evidence
Belani et al. 2005	Phase II

Note: This regimen is listed by the NCCN, Non-Small Cell Lung Cancer version 2.2012, but this differs from the Belani et al. 2005 reference, in which additional consolidation chemotherapy is given after completion of concurrent chemotherapy & radiation therapy. That regimen is detailed here.

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 hour once per day on days 1, 8, 15, given first

21-day cycle for 2 cycles, given with concurrent radiation therapy

Concurrent radiation therapy

• Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), given once per day 5 days per week, then 2 Gy fractions x 9 fractions (additional dose: 18 Gy), given once per day 5 days per week. Total dose: 63 Gy over a total 7 week course of treatment.

References

1. 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

Carboplatin, Paclitaxel, concurrent RT -> consolidation chemo

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Regimen

Study	Evidence
Belani et al. 2005	Phase II

Chemoradiotherapy

• 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 hour once per day on days 1, 8, 15, given first

21-day cycle for 2 cycles, given with concurrent radiation therapy

Concurrent radiation therapy

• Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), given once per day 5 days per week, then 2 Gy fractions x 9 fractions (additional dose: 18 Gy), given once per day 5 days per week. Total dose: 63 Gy over a total 7 week course of treatment.

Consolidation 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. 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

Carboplatin, Paclitaxel -> sequential RT

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Regimen

Study	Evidence
Belani et al. 2005	Phase II

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, then proceed to radiation therapy

Radiation therapy

• Sequential radiation therapy, 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), given once per day 5 days per week, then 2 Gy fractions x 9 fractions (additional dose: 18 Gy), given once per day 5 days per week. Total dose: 63 Gy over a total 7 week course of treatment.

References

1. 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

Cisplatin, Etoposide, concurrent RT

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Regimen

Study	Evidence
Albain et al. 2002 (SWOG 9019)	Phase II

Chemoradiotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 1, 8, 29, 36
• Etoposide (Vepesid) 50 mg/m² IV once per day on days 1 to 5, 29 to 33
• Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), given 5 days per week, to start within 24 hours of chemotherapy

5-week initial course of chemoradiotherapy

Patients were reimaged 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 Gy per day x 8 fractions for a total of 61 Gy administered overall.

References

1. 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

Cisplatin, Etoposide, concurrent RT -> consolidation chemo

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Regimen

Study	Evidence
Albain et al. 2002 (SWOG 9019)	Phase II

Note: The NCCN, Non-Small Cell Lung Cancer version 2.2012, describes "two extra cycles" of chemotherapy being given after completion of concurrent RT, but no primary reference can be found for this. It is unclear what the length of each cycle is supposed to be.

Chemoradiotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 1, 8, 29, 36
• Etoposide (Vepesid) 50 mg/m² IV once per day on days 1 to 5, 29 to 33
• Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), given 5 days per week, to start within 24 hours of chemotherapy

5-week initial course of chemotherapy & radiation; patients were reimaged 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 Gy per day x 8 fractions for a total of 61 Gy administered overall

Consolidation 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. 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--see note above PubMed

Cisplatin, Vinblastine, concurrent RT

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Regimen

Study	Evidence	Comparator
Curran et al. 2011 (RTOG 9410)	Phase III	Cisplatin, Vinblastine, sequential RT

Chemoradiotherapy

• 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
• Concurrent radiation therapy

5-week course of chemotherapy

References

1. 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. link to original article PubMed

Cisplatin, Vinblastine, sequential RT

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Regimen

Study	Evidence	Comparator
Curran et al. 2011 (RTOG 9410)	Phase III	Cisplatin, Vinblastine, concurrent RT

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 total course of chemotherapy

• Radiation therapy given after chemotherapy is complete

References

1. 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. link to original article PubMed

Advanced or metastatic disease, ALK-positive

Alectinib (Alecensa)

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Regimen

Study	Evidence
Ou et al. 2015 (NP28673)	Phase II
Gandhi et al. 2015 (NP28761)	Phase II

Patients in NP28673 and NP28761 were ALK mutation positive and had progression of disease on Crizotinib (Xalkori).

Chemotherapy

• Alectinib (Alecensa) 600 mg PO BID, to be taken within 30 minutes of eating

Given until progressive disease, unacceptable toxicity, or withdrawal of consent

References

1. Leena Gandhi, Alice Shaw, Shirish M. Gadgeel, Gregory Riely, Jeremy Cetnar, Howard Jack West, D. Ross Camidge, Mark A. Socinski, Alberto Chiappori, Tarek Mekhail, Bo H. Chao, Hossein Borghaei, Kathryn A. Gold, Ali Hassan Zeaiter, Walter Bordogna, Bogdana Balas, Oscar Puig, Volkmar Henschel, Sai-Hong Ignatius Ou, NP28761 Study Investigators. A phase II, open-label, multicenter study of the ALK inhibitor alectinib in an ALK+ non-small-cell lung cancer (NSCLC) U.S./Canadian population who had progressed on crizotinib (NP28761). 2015 ASCO Annual Meeting abstract 8019. link to abstract
2. Ou SI, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, Lena H, Moro-Sibilot D, Bearz A, Ramirez SV, Mekhail T, Spira A, Bordogna W, Balas B, Morcos PN, Monnet A, Zeaiter A, Kim DW. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol. 2015 Nov 23. link to original article contains verified protocol PubMed

Ceritinib (Zykadia)

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Regimen

Study	Evidence
Shaw et al. 2014	Phase I

Shaw et al. 2014 investigated dose levels of 50 to 750 mg daily; 750 mg is the FDA-approved dose.

Chemotherapy

• Ceritinib (Zykadia) 750 mg PO once per day on an empty stomach

Given until progression of disease

References

1. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27;370(13):1189-97. link to original article contains verified protocol PubMed

Crizotinib (Xalkori)

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Regimen

Study	Evidence	Comparator
Kwak et al. 2010	Phase II
Shaw et al. 2013	Phase III	Pemetrexed Docetaxel

Chemotherapy

• Crizotinib (Xalkori) 250 mg PO BID on days 1 to 28

28-day cycles, given until progression of disease or unacceptable toxicity

Shaw et al. 2013 used 21-day cycles, and crizotinib was similarly given 250 mg PO BID on all days.

References

1. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 Oct 28;363(18):1693-703. link to original article contains verified protocol PubMed
   1. Update: Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ, Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, Gandhi L, Jänne PA, Costa DB, Shapiro GI, Lorusso P, Ruffner K, Stephenson P, Tang Y, Wilner K, Clark JW, Shaw AT. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012 Oct;13(10):1011-9. Epub 2012 Sep 4. link to original article contains verified protocol PubMed
2. Retrospective: Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, Shapiro GI, Costa DB, Ou SH, Butaney M, Salgia R, Maki RG, Varella-Garcia M, Doebele RC, Bang YJ, Kulig K, Selaru P, Tang Y, Wilner KD, Kwak EL, Clark JW, Iafrate AJ, Camidge DR. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 2011 Oct;12(11):1004-12. Epub 2011 Sep 18. link to original article PubMed
3. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94. Epub 2013 Jun 1. link to original article link to supplementary appendix contains verified protocol PubMed

Advanced or metastatic disease

Afatinib (Gliotrif)

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Regimen #1

Study	Evidence	Comparator
Yang et al. 2012 (LUX-Lung 2)	Phase II
Sequist et al. 2013 (LUX-Lung 3)	Phase III	Cisplatin & Pemetrexed

Patients in these trials were EGFR mutation positive.

Chemotherapy

• Afatinib (Gliotrif) 40 mg PO once per day, given 1 hour before eating food (Yang et al. 2012: "no food intake immediately before or after afatinib")
  • In LUX-Lung 3, patients could be increased to 50 mg PO once per day if they did not experience any grade 2 or higher rash, diarrhea, mucositis, or other drug-related adverse event.

Given until progressive disease, unacceptable toxicity, or withdrawal of consent

Regimen #2

Study	Evidence	Comparator
Miller et al. 2012 (LUX-Lung 1)	Phase III	Placebo
Katakami et al. 2013 (LUX-Lung 4)	Phase II

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 (Gliotrif) 50 mg PO once per day, given 1 hour before eating food

Given until progressive disease, unacceptable toxicity, or withdrawal of consent

References

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
2. Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH, Yu CJ, Chang GC, Ho CL, Sequist LV, Dudek AZ, Shahidi M, Cong XJ, Lorence RM, Yang PC, Miller VA. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012 May;13(5):539-48. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
3. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. Epub 2013 Jul 1. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With Advanced Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. Epub 2013 Jul 1. link to original article contains verified protocol PubMed
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

Atezolizumab (Tecentriq)

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Regimen

Study	Evidence	Comparator
Fehrenbacher et al. 2016 (POPLAR)	Randomized Phase II	Docetaxel

Immunotherapy

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

3-week cycles

References

1. 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

Carboplatin & Docetaxel

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Regimen

Study	Evidence	Comparator
Fossella et al. 2003 (TAX 326)	Phase III	Cisplatin & Docetaxel Cisplatin & Vinorelbine

Chemotherapy

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

21-day cycles

References

1. Fossella F, Pereira JR, 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

Carboplatin & Gemcitabine

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Regimen

Study	Evidence	Comparator
Sederholm et al. 2005	Phase III	Gemcitabine
Grønberg et al. 2009	Phase III	Carboplatin & Pemetrexed
Zhou et al. 2015 (OPTIMAL, CTONG-0802)	Phase III	Erlotinib

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1000 to 1250 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. Sederholm C, Hillerdal G, Lamberg K, Kölbeck K, Dufmats M, Westberg R, Gawande SR. 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
2. 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. 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
3. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 2015 Sep;26(9):1877-83. Epub 2015 Jul 3. link to original article PubMed

Carboplatin & Paclitaxel

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Regimen #1

Study	Evidence	Comparator
Johnson et al. 2004	Randomized Phase II	PacCBev
Sandler et al. 2006 (ECOG 4599)	Phase III	PacCBev -> Maintenance Bev
Mok et al. 2009 (IPASS)	Phase III	Gefitinib
Socinski et al. 2012	Phase III	Carboplatin & nabPaclitaxel

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 6 cycles

Patients in Socinski et al. 2012 "could continue in the absence of progressive disease and unacceptable toxicity per the investigator's discretion."

Regimen #2

Study	Evidence	Comparator
Lynch et al. 2012	Randomized Phase II	Carboplatin, Paclitaxel, Ipilimumab

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 infusion.

21-day cycle for up to 6 cycles

Regimen #3, weekly paclitaxel

Study	Evidence	Comparator
Quoix et al. 2011 (IFCT-0501)	Phase III	Gemcitabine Vinorelbine

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 #4

Study	Evidence	Comparator
Mok et al. 2009 (IPASS)	Phase III	Gefitinib

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 6 cycles

Regimen #5

Study	Evidence	Comparator
Schiller et al. 2002	Phase III	Cisplatin & Docetaxel Cisplatin & Gemcitabine Cisplatin & Paclitaxel

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 cycles

References

1. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. 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
2. 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
3. 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. Subset analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. 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
4. 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
5. 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
6. 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
7. 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
8. 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

Carboplatin & Paclitaxel, nanoparticle albumin-bound

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Regimen

Study	Evidence	Comparator
Socinski et al. 2012	Phase III	Carboplatin & Paclitaxel

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. 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

Carboplatin, Paclitaxel, Bevacizumab (PacCBev)

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PacCBev: Paclitaxel, Carboplatin, Bevacizumab

Regimen #1

Study	Evidence	Comparator
Patel et al. 2013 (PointBreak)	Phase III	PemCBev -> Maintenance PemBev

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

Patients with complete response, partial response, or stable disease proceeded to bevacizumab maintenance therapy.

Regimen #2

Study	Evidence	Comparator
Johnson et al. 2004	Randomized Phase II	Carboplatin & Paclitaxel
Sandler et al. 2006 (ECOG 4599)	Phase III	Carboplatin & Paclitaxel

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 on day 1, given third, starting 60 minutes after the completion of carboplatin
  • Infusion time for bevacizumab per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, bevacizumab was given over 30 to 60 minutes for cycles 2 and later

21-day cycle for up to 6 cycles, or until progression of disease, or unacceptable toxicity

After 6 cycles, patients in ECOG 4599 who had stable disease or response continued to bevacizumab maintenance therapy.

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. 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. Subset analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. 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
3. 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 PubMed

Carboplatin, Paclitaxel, Ipilimumab

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Regimen

Study	Evidence	Comparator
Lynch et al. 2012	Randomized Phase II	Carboplatin & Paclitaxel

Chemoimmunotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1
• Ipilimumab (Yervoy) 10 mg/kg IV once on day 1 of cycles 3 to 6

Supportive medications

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

21-day cycle for up to 6 cycles

Patients without progressive disease proceeded to receive maintenance ipilimumab therapy.

References

1. 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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Example orders

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

Regimen #1

Study	Evidence	Comparator
Ardizzoni et al. 2012 (GOIRC 02-2006)	Randomized Phase II	Pemetrexed
Zukin et al. 2013	Phase III	Pemetrexed

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 30 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 BID on the day before, the day of, and day after each dose of pemetrexed
• Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, 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, to be given throughout pemetrexed therapy

21-day cycle for up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal

Regimen #2

Study	Evidence	Comparator
Grønberg et al. 2009	Phase III	Carboplatin & Gemcitabine

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 1 mg PO once per day

21-day cycles

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. 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. 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
3. 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 (PemCBev)

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PemCBev: Pemetrexed, Carboplatin, Bevacizumab

Regimen

Study	Evidence	Comparator
Patel et al. 2013 (PointBreak)	Phase III	PacCBev -> Maintenance Bev

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, and vitamin supplementation per pemetrexed label
• Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycle for 4 cycles

Patients with complete response, partial response, or stable disease proceeded to bevacizumab & pemetrexed maintenance therapy.

References

1. 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 PubMed

Cisplatin & Docetaxel

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Regimen

Study	Evidence	Comparator
Schiller et al. 2002	Phase III	Carboplatin & Paclitaxel Cisplatin & Gemcitabine Cisplatin & Paclitaxel
Fossella et al. 2003 (TAX 326)	Phase III	Carboplatin & Docetaxel Cisplatin & Vinorelbine

Chemotherapy

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

21-day cycles

References

1. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. 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
2. Fossella F, Pereira JR, 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

Cisplatin & Gemcitabine

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Regimen #1

Study	Evidence	Comparator
Thatcher et al. 2015 (SQUIRE)	Phase III	Cisplatin, Gemcitabine, Necitumumab

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 30 minutes once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV over 120 minutes once per day on days 1 & 8

21-day cycles

Regimen #2

Study	Evidence	Comparator
Schiller et al. 2002	Phase III	Carboplatin & Paclitaxel Cisplatin & Docetaxel Cisplatin & Paclitaxel
Scagliotti et al. 2008	Phase III	Cisplatin & Pemetrexed

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

References

1. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. 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
2. 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
3. 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. link to original article contains protocol PubMed

Cisplatin, Gemcitabine, Necitumumab

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Regimen

Study	Evidence	Comparator
Thatcher et al. 2015 (SQUIRE)	Phase III	Cisplatin & Gemcitabine

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

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 120 minutes 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, before gemcitabine

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;

Patients who were free of disease progression proceeded to maintenance necitumumab.

References

1. 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. link to original article contains verified protocol PubMed

Cisplatin & Paclitaxel

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Regimen

Study	Evidence	Comparator
Schiller et al. 2002	Phase III	Carboplatin & Paclitaxel Cisplatin & Docetaxel Cisplatin & Gemcitabine

Chemotherapy

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

21-day cycles

References

1. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. 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

Cisplatin & Pemetrexed

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Regimen #1

Study	Evidence	Comparator
Scagliotti et al. 2008	Phase III	Cisplatin & Gemcitabine
Sequist et al. 2013 (LUX-Lung 3)	Phase III	Afatinib
Paz-Ares et al. 2015 (INSPIRE)	Phase III	Cisplatin, Pemetrexed, Necitumumab

Chemotherapy

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

Supportive medications

• (as described in Scagliotti et al. 2008):
• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to Pemetrexed (Alimta)
• Folic acid 1 mg PO once per day
• In Sequist et al. 2013: Patients "received folic acid, vitamin B12, and dexamethasone, as per package recommendations for Pemetrexed (Alimta)."

21-day cycle for up to 6 cycles

Regimen #2

Study	Evidence
Paz-Ares et al. 2012 (PARAMOUNT)	Non-randomized

Chemotherapy

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

Supportive medications

• Folic acid, Cyanocobalamin (Vitamin B12), prophylactic 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 cycle for 4 cycles

Subsequently patients were randomized to placebo versus pemetrexed maintenance therapy.

References

1. 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
2. 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. 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. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. Epub 2013 Jul 1. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With Advanced Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. Epub 2013 Jul 1. link to original article contains verified protocol PubMed
4. 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

Cisplatin, Pemetrexed, Bevacizumab

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Regimen

Study	Evidence
Barlesi et al. 2013 (AVAPERL (MO22089))	Phase II

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 once on day 1; administered over 90 minutes for the first dose, and 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 350 to 1000 mcg PO once per day, given throughout therapy
• Dexamethasone (Decadron) 4 mg PO BID on days -1, 1, 2 of each cycle

21-day cycle for 4 cycles

Patients with complete response (CR), partial response (PR), or stable disease (SD) were randomized to bevacizumab maintenance versus bevacizumab & pemetrexed maintenance.

References

1. 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

Cisplatin & Vinorelbine

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Regimen #1

Study	Evidence	Comparator
Pirker et al. 2009 (FLEX)	Phase III	Cetuximab, Cisplatin, Vinorelbine

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

Regimen #2

Study	Evidence	Comparator
Fossella et al. 2003 (TAX 326)	Phase III	Carboplatin & Docetaxel Cisplatin & Docetaxel

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once on day 1

28-day cycles

References

1. Fossella F, Pereira JR, 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. Pirker R, Pereira JR, 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 SD article contains verified protocol PubMed

Docetaxel (Taxotere)

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Example orders

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

Regimen #1, 3-week docetaxel

Study	Evidence	Comparator
Hanna et al. 2004	Phase III	Pemetrexed
Chen et al. 2006	Phase III	Weekly paclitaxel
Kim et al. 2008 (INTEREST)	Phase III	Gefitinib
Shaw et al. 2013	Phase III	Crizotinib
Reck et al. 2014 (LUME-Lung 1)	Phase III	Docetaxel & Nintedanib
Garon et al. 2014 (REVEL)	Phase III	Docetaxel & Ramucirumab
Brahmer et al. 2015 (CheckMate 017)	Phase III	Nivolumab
Borghaei et al. 2015 (CheckMate 057)	Phase III	Nivolumab
Herbst et al. 2015 (KEYNOTE-010)	Phase II/III	Pembrolizumab
Fehrenbacher et al. 2016 (POPLAR)	Randomized Phase II	Atezolizumab

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 1 hour once on day 1
  • In Garon, et al. 2014, East Asian patients were later recommended to receive Docetaxel (Taxotere) 60 mg/m² IV once on day 1

Supportive medications

• Per Hanna et al. 2004: Dexamethasone (Decadron) 8 mg PO BID the day before, the day of, and the day after docetaxel
• Per Chem et al. 2006: Dexamethasone (Decadron) 8 mg PO once 12 hours before docetaxel, 10 mg IV once 30 minutes before docetaxel, and 8 mg PO 12 hours after docetaxel

21-day cycles, given until progression of disease, unacceptable toxicity, or patient/physician choice

Regimen #2, weekly docetaxel

Study	Evidence	Comparator
Chen et al. 2006	Phase III	3-week docetaxel

Chemotherapy

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

Supportive medications

• Dexamethasone (Decadron) 8 mg PO once 12 hours before docetaxel, 10 mg IV once 30 minutes before docetaxel, and 8 mg PO 12 hours after docetaxel

28-day cycles

References

1. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, 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
2. 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
3. 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
4. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94. Epub 2013 Jun 1. link to original article link to supplementary appendix contains verified protocol PubMed
5. 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 PubMed
6. 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. link to original article contains verified protocol PubMed
7. 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 PubMed
8. 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
9. 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
10. 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

Docetaxel & Ramucirumab

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Regimen

Study	Evidence	Comparator
Garon et al. 2014 (REVEL/I4T-MC-JVBA)	Phase III	Docetaxel

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
  • East Asian patients were later recommended to receive 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, given until progression of disease, unacceptable toxicity, withdrawal, or death

References

1. 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. link to original article contains verified protocol PubMed

Erlotinib (Tarceva)

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Regimen #1

Study	Evidence	Comparator
Shepherd et al. 2005 (NCIC CTG BR.21)	Phase III	Placebo
Lilenbaum et al. 2008	Phase III	Carboplatin & Paclitaxel
Zhou et al. 2015 (OPTIMAL, CTONG-0802)	Phase III	Carboplatin & Gemcitabine

Chemotherapy

• Erlotinib (Tarceva) 150 mg PO once per day

Continued until progression or intolerance

Regimen #2, low-dose

Study	Evidence
Yeo et al. 2010	Retrospective

Chemotherapy

• Erlotinib (Tarceva) 25 mg PO once per day

Continued until progression or intolerance

References

1. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. link to original article contains protocol PubMed
2. 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
3. Yeo WL, Riely GJ, Yeap BY, Lau MW, Warner JL, Bodio K, Huberman MS, Kris MG, Tenen DG, Pao W, Kobayashi S, Costa DB. Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR mutations. J Thorac Oncol. 2010 Jul;5(7):1048-53. link to PMC article PubMed
4. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 2015 Sep;26(9):1877-83. Epub 2015 Jul 3. link to original article PubMed

Gefitinib (Iressa)

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Regimen

Study	Evidence	Comparator
Kris et al. 2003 (IDEAL2)	Randomized Phase II	Gefitinib 500 mg/day
Kim et al. 2008 (INTEREST)	Phase III	Docetaxel
Mok et al. 2009 (IPASS)	Phase III	Carboplatin & Paclitaxel
Shi et al. 2013 (ICOGEN)	Phase III	Icotinib
Douillard, et al. 2014	Phase IV

Chemotherapy

• Gefitinib (Iressa) 250 mg PO once per day

Given until progression of objective disease or unacceptable toxicity

References

1. 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. 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
3. 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
4. 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
5. Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, Milenkova T. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014 Jan 7;110(1):55-62. link to PMC article contains verified protocol PubMed

Gemcitabine (Gemzar)

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Regimen #1

Study	Evidence	Comparator
Quoix et al. 2011 (IFCT-0501)	Phase III	Carboplatin & Paclitaxel Vinorelbine

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 #2

Study	Evidence	Comparator
Sederholm et al. 2005	Phase III	Carboplatin & Gemcitabine

Chemotherapy

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

21-day cycles

Regimen #3

Study	Evidence	Comparator
Gridelli et al. 2003 (MILES)	Phase III	Gemcitabine & Vinorelbine Vinorelbine

Study involved only patients at least 70 years old

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 up to 6 cycles

References

1. 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. Sederholm C, Hillerdal G, Lamberg K, Kölbeck K, Dufmats M, Westberg R, Gawande SR. 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
3. 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

Gemcitabine & Vinorelbine

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Regimen

Study	Evidence	Comparator
Gridelli et al. 2003 (MILES)	Phase III	Gemcitabine Vinorelbine

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

References

1. 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

Osimertinib (Tagrisso)

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Regimen

Study	Evidence	Comparator
Jänne et al. 2015 (AURA)	Phase I	none
AURA2 (ongoing)	Phase II	none
FLAURA (ongoing)	Phase III	Gefitinib (Iressa) & Erlotinib (Tarceva)

Chemotherapy

• Osimertinib (Tagrisso) 80 mg PO once per day

Given until progression of disease or unacceptable toxicity

References

Non-peer-reviewed references are listed because of a lack of published peer-reviewed articles at the time of osimertinib's 11/13/2015 FDA approval.

1. Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1689-99. link to original article contains verified protocol PubMed
2. Osimertinib (Tagrisso) package insert
3. 16th World Conference on Lung Cancer abstracts MINI16.06, MINI16.07, MINI16.08.
   1. Yang J C-H, et al: World Conf on Lung Cancer. Abst MINI16.06. Sept 8, 2015.
   2. Ramalingam S, et al: World Conf on Lung Cancer. Abst MINI16.07. Sept 8, 2015.
   3. Mitsudomi T, et al: World Conf on Lung Cancer. Abst MINI16.08. Sept 8, 2015.
4. Phase II AZD9291 Open Label Study in NSCLC After Previous EGFR TKI Therapy in EGFR and T790M Mutation Positive Tumours (AURA2) (clinicaltrials.gov)
5. AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA) (clinicaltrials.gov)
6. David Planchard, MD, PhD. AZD9291 a novel EGFR-TKI that overcomes T790M-mediated resistance in NSCLC. (PowerPoint presentation)

Nivolumab (Opdivo)

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Regimen

Study	Evidence	ORR	Comparator	Comparator ORR	Pt Population
Rizvi et al. 2015 (CheckMate 063)	Phase II	14% (95% CI 9 - 22)	None		Chemo exposed
Brahmer et al. 2015 (CheckMate 017)	Phase III	20% (95% CI 14 - 28)	Docetaxel	9% (95% CI 5 - 15)	Squamous only, chemo exposed
Borghaei et al. 2015 (CheckMate 057)	Phase III	19% (95% CI 15 - 24)	Docetaxel	12% (95% CI 9 - 17)	Non-squamous only, chemo exposed

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1

2-week cycles, given until progression of disease or unacceptable toxicity

References

1. 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. 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 PubMed
3. 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

Pembrolizumab (Keytruda)

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Regimen

Study	Evidence	ORR	Comparator	Comparator ORR	Pt Population
Herbst et al. 2015 (KEYNOTE-010)	Phase II/III	2 mg/kg: 18% (95% CI 14 - 23) 10 mg/kg: 19% (95% CI 15 - 23)	Docetaxel	9% (95% CI 7 - 13)	Chemo exposed

Immunotherapy

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

21-day cycles, given until progression of disease or unacceptable toxicity

References

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. 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 (Alimta)

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Example orders

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

Regimen

Study	Evidence	Comparator
Hanna et al. 2004	Phase III	Docetaxel
Ardizzoni et al. 2012 (GOIRC 02-2006)	Randomized Phase II	Carboplatin & Pemetrexed
Shaw et al. 2013	Phase III	Crizotinib
Zukin et al. 2013	Phase III	Carboplatin & Pemetrexed

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 BID on the day before, the day of, and day after each dose of pemetrexed
• Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
  • Hanna et al. 2004 used folic acid 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, to be given throughout pemetrexed therapy

21-day cycles

Ardizzoni et al. 2012 & Zukin et al. 2013 treated patients for up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal.

References

1. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, 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. 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
3. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94. Epub 2013 Jun 1. link to original article link to supplementary appendix contains verified protocol PubMed
4. 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

Placebo (Observation)

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Regimen

Study	Evidence	Comparator
Elderly Lung Cancer Vinorelbine Italian Study Group, 1999	Phase III	Vinorelbine
Shepherd et al. 2005 (NCIC CTG BR.21)	Phase III	Erlotinib
Miller et al. 2012 (LUX-Lung 1)	Phase III	Afatinib

No active antineoplastic treatment. Placed here because one or more randomized clinical trials included a placebo or observation arm in this disease context.

References

1. The 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. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. link to original article contains protocol PubMed
3. 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

Vinorelbine (Navelbine)

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Regimen #1

Study	Evidence	Comparator
Quoix et al. 2011 (IFCT-0501)	Phase III	Carboplatin & Paclitaxel Gemcitabine

Study involved only patients 70 to 89 years old

Chemotherapy

• Vinorelbine (Navelbine) 25 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 #2

Study	Evidence	Comparator
Elderly Lung Cancer Vinorelbine Italian Study Group, 1999	Phase III	Supportive care
Gridelli et al. 2003 (MILES)	Phase III	Gemcitabine Gemcitabine & Vinorelbine

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):
• Elderly Lung Cancer Vinorelbine Italian Study Group, 1999: Metoclopramide (Reglan) 20 mg IV bolus prior to Vinorelbine (Navelbine)
• Gridelli et al. 2003: "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

21-day cycle for up to 6 cycles

Regimen #3

Study	Evidence	Comparator
Jassem et al. 2001	Randomized Phase II	Oral vinorelbine

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV over 5 to 10 minutes once per week

Supportive medications

• 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 (Kytril) (dose/schedule/route not specified) prn nausea

Continued until progression

Regimen #4

Study	Evidence	Comparator
Jassem et al. 2001	Randomized Phase II	Intravenous vinorelbine

Chemotherapy

• Vinorelbine (Navelbine) 60 mg/m² PO once per week, increased to 80 mg/m² PO once per week with 4th dose, if no severe neutropenia

Supportive medications

• 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 (Kytril) (dose/schedule/route not specified) prn nausea

Continued until progression

References

1. The 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. Jassem J, Ramlau R, Karnicka-Mlodkowska H, Krawczyk K, Krzakowski M, Zatloukal P, Lemarié E, Hartmann W, Novakova L, O'Brien M, Depierr A. A multicenter randomized phase II study of oral vs. intravenous vinorelbine in advanced non-small-cell lung cancer patients. Ann Oncol. 2001 Oct;12(10):1375-81. link to original article contains verified protocol PubMed
3. 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
4. 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

Bevacizumab (Avastin)

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Regimen #1

Study	Evidence	Comparator	Efficacy
Barlesi et al. 2013 (AVAPERL (MO22089))	Phase III	Bevacizumab & Pemetrexed maintenance	Inferior PFS

Treatment preceded by cisplatin, pemetrexed, bevacizumab x 4.

Chemotherapy

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

21-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2

Study	Evidence
Sandler et al. 2006 (ECOG 4599)	Non-randomized
Patel et al. 2013 (PointBreak)	Non-randomized

Treatment in ECOG 4599 preceded by PacCBev x 6. Treatment in PointBreak preceded by PacCBev x 4.

Chemotherapy

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

21-day cycles, given until progression of disease or unacceptable toxicity

References

1. 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. Subset analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. 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. 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
3. 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 PubMed

Bevacizumab & Pemetrexed

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Regimen #1

Study	Evidence	Comparator	Efficacy
Barlesi et al. 2013 (AVAPERL (MO22089))	Phase III	Bevacizumab maintenance	Superior PFS

Treatment preceded by cisplatin, pemetrexed, bevacizumab x 4.

Chemotherapy

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

Supportive medications

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

21-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2

Study	Evidence
Patel et al. 2013 (PointBreak)	Non-randomized

Treatment preceded by PemCBev x 4.

Chemotherapy

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

Supportive medications

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

21-day cycles, given until progression of disease or unacceptable toxicity

References

1. 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
2. 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 PubMed

Ipilimumab (Yervoy)

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Regimen

Study	Evidence
Lynch et al. 2012	Non-randomized

Treatment preceded by carboplatin, paclitaxel, ipilimumab x 6.

Immunotherapy

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

12-week cycles, given until progression of disease or unacceptable toxicity

References

1. 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

Necitumumab (Portrazza)

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Regimen

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

Patients had stage IV squamous non-small-cell lung cancer; treatment preceded by 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, given until progression of disease or unacceptable toxicity

References

1. 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. link to original article contains verified protocol PubMed

Pemetrexed (Alimta)

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Example orders

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

Regimen

Study	Evidence	Comparator
Paz-Ares et al. 2012 (PARAMOUNT)	Phase III	Placebo

Treatment preceded by 4 cycles of induction therapy with cisplatin & pemetrexed. Maintenance therapy started 21 to 42 days after cycle 4 day 1 of induction chemotherapy.

Chemotherapy

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

Supportive medications

• Folic acid, Cyanocobalamin (Vitamin B12), prophylactic 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, given until progression of disease, unacceptable toxicity, or physician/patient choice

References

1. 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. 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

Placebo (Observation)

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Regimen

Study	Evidence	Comparator
Paz-Ares et al. 2012 (PARAMOUNT)	Phase III	Pemetrexed

Preceded by 4 cycles of induction therapy with cisplatin & pemetrexed. No further active treatment.

References

1. 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. 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