Non-small cell lung cancer, ALK-positive

Page editor		Section editor
	Eric K. Singhi, MD MD Anderson Cancer Center Houston, TX, USA LinkedIn		Amit Kulkarni, MBBS University of Minnesota Minneapolis, MN, USA LinkedIn

Note: these are regimens tested in biomarker-specific populations, please see the main NSCLC page for other regimens.
There are several related dedicated pages:

• Site-specific:
  • NSCLC, CNS metastases

22 regimens on this page 27 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

• 2022: Singh et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline PubMed

ESMO

• 2023: Hendriks et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up PubMed

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Non-Small Cell Lung Cancer.

Adjuvant therapy

Alectinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2024 (ALINA)	2018-08 to 2021-12	Phase 3 (E-RT-switch-ooc)	1a. CVb 1b. Cisplatin & Pemetrexed 1c. GC 1d. GCb 1e. Carboplatin & Pemetrexed 1f. Carboplatin & Vinorelbine	Superior DFS (primary endpoint) DFS24: 93.6% vs 63.7% (HR 0.24, 95% CI 0.13-0.43)

Preceding treatment

• Resection

Targeted therapy

• Alectinib (Alecensa) 600 mg PO twice per day

24-month course

References

1. ALINA: Wu YL, Dziadziuszko R, Ahn JS, Barlesi F, Nishio M, Lee DH, Lee JS, Zhong W, Horinouchi H, Mao W, Hochmair M, de Marinis F, Migliorino MR, Bondarenko I, Lu S, Wang Q, Ochi Lohmann T, Xu T, Cardona A, Ruf T, Noe J, Solomon BJ; ALINA Investigators. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024 Apr 11;390(14):1265-1276. link to original article contains dosing details in manuscript PubMed NCT03456076

Carboplatin & Gemcitabine (GCb)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2024 (ALINA)	2018-08 to 2021-12	Phase 3 (C)	Alectinib	Inferior DFS

Preceding treatment

• Resection

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

References

1. ALINA: Wu YL, Dziadziuszko R, Ahn JS, Barlesi F, Nishio M, Lee DH, Lee JS, Zhong W, Horinouchi H, Mao W, Hochmair M, de Marinis F, Migliorino MR, Bondarenko I, Lu S, Wang Q, Ochi Lohmann T, Xu T, Cardona A, Ruf T, Noe J, Solomon BJ; ALINA Investigators. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024 Apr 11;390(14):1265-1276. link to original article contains dosing details in manuscript PubMed NCT03456076

Carboplatin & Pemetrexed

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2024 (ALINA)	2018-08 to 2021-12	Phase 3 (C)	Alectinib	Inferior DFS

Preceding treatment

• Resection

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

21-day cycle for 4 cycles

References

1. ALINA: Wu YL, Dziadziuszko R, Ahn JS, Barlesi F, Nishio M, Lee DH, Lee JS, Zhong W, Horinouchi H, Mao W, Hochmair M, de Marinis F, Migliorino MR, Bondarenko I, Lu S, Wang Q, Ochi Lohmann T, Xu T, Cardona A, Ruf T, Noe J, Solomon BJ; ALINA Investigators. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024 Apr 11;390(14):1265-1276. link to original article contains dosing details in manuscript PubMed NCT03456076

Carboplatin & Vinorelbine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2024 (ALINA)	2018-08 to 2021-12	Phase 3 (C)	Alectinib	Inferior DFS

Preceding treatment

• Resection

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

References

1. ALINA: Wu YL, Dziadziuszko R, Ahn JS, Barlesi F, Nishio M, Lee DH, Lee JS, Zhong W, Horinouchi H, Mao W, Hochmair M, de Marinis F, Migliorino MR, Bondarenko I, Lu S, Wang Q, Ochi Lohmann T, Xu T, Cardona A, Ruf T, Noe J, Solomon BJ; ALINA Investigators. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024 Apr 11;390(14):1265-1276. link to original article contains dosing details in manuscript PubMed NCT03456076

Cisplatin & Gemcitabine (GC)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2024 (ALINA)	2018-08 to 2021-12	Phase 3 (C)	Alectinib	Inferior DFS

Preceding treatment

• Resection

Chemotherapy

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

21-day cycle for 4 cycles

References

1. ALINA: Wu YL, Dziadziuszko R, Ahn JS, Barlesi F, Nishio M, Lee DH, Lee JS, Zhong W, Horinouchi H, Mao W, Hochmair M, de Marinis F, Migliorino MR, Bondarenko I, Lu S, Wang Q, Ochi Lohmann T, Xu T, Cardona A, Ruf T, Noe J, Solomon BJ; ALINA Investigators. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024 Apr 11;390(14):1265-1276. link to original article contains dosing details in manuscript PubMed NCT03456076

Cisplatin & Pemetrexed

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2024 (ALINA)	2018-08 to 2021-12	Phase 3 (C)	Alectinib	Inferior DFS

Preceding treatment

• Resection

Chemotherapy

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

21-day cycle for 4 cycles

References

1. ALINA: Wu YL, Dziadziuszko R, Ahn JS, Barlesi F, Nishio M, Lee DH, Lee JS, Zhong W, Horinouchi H, Mao W, Hochmair M, de Marinis F, Migliorino MR, Bondarenko I, Lu S, Wang Q, Ochi Lohmann T, Xu T, Cardona A, Ruf T, Noe J, Solomon BJ; ALINA Investigators. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024 Apr 11;390(14):1265-1276. link to original article contains dosing details in manuscript PubMed NCT03456076

Cisplatin & Vinorelbine (CVb)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2024 (ALINA)	2018-08 to 2021-12	Phase 3 (C)	Alectinib	Inferior DFS

Preceding treatment

• Resection

Chemotherapy

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

21-day cycle for 4 cycles

References

1. ALINA: Wu YL, Dziadziuszko R, Ahn JS, Barlesi F, Nishio M, Lee DH, Lee JS, Zhong W, Horinouchi H, Mao W, Hochmair M, de Marinis F, Migliorino MR, Bondarenko I, Lu S, Wang Q, Ochi Lohmann T, Xu T, Cardona A, Ruf T, Noe J, Solomon BJ; ALINA Investigators. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024 Apr 11;390(14):1265-1276. link to original article contains dosing details in manuscript PubMed NCT03456076

Advanced or metastatic disease, ALK inhibitor-naive

Alectinib monotherapy

Regimen variant #1, 300 mg twice per day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Seto et al. 2013 (AF-001JP)	2010-2012	Phase 1/2
Hida et al. 2017 (J-ALEX)	2013-2015	Phase 3 (E-switch-ic)	Crizotinib	Superior PFS (primary endpoint) Median PFS: NYR vs 10.2 mo (HR 0.34, 99.7% CI 0.17-0.71)

This is the PMDA-approved dose in Japan.

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: FISH or RT-PCR

Targeted therapy

• Alectinib (Alecensa) 300 mg PO twice per day

Continued indefinitely

Regimen variant #2, 600 mg twice per day

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Peters et al. 2017 (ALEX)	2014-2016	Phase 3 (E-RT-switch-ic)	Crizotinib	Superior PFS1 (primary endpoint) Median PFS: 34.8 vs 10.9 mo (HR 0.43, 95% CI 0.32-0.58) Seems to have superior OS1 (secondary endpoint) Median OS: NYR vs 57.4 mo (HR 0.67, 95% CI 0.46-0.98)
Zhou et al. 2019 (ALESIA)	2016-08-03 to 2017-05-16	Phase 3 (E-switch-ic)	Crizotinib	Superior PFS (primary endpoint) Median PFS: NYR vs 11.1 mo (HR 0.22, 95% CI 0.13-0.38)

¹Reported efficacy for ALEX is based on the 2020 update; the authors mention that OS results are immature.

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: IHC

Targeted therapy

• Alectinib (Alecensa) 600 mg PO twice per day

Continued indefinitely

References

1. AF-001JP: Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, Hida T, Yamamoto N, Yoshioka H, Harada M, Ohe Y, Nogami N, Takeuchi K, Shimada T, Tanaka T, Tamura T. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol. 2013 Jun;14(7):590-8. Epub 2013 Apr 30. link to original article contains dosing details in manuscript PubMed JapicCTI-101264
   1. Update: Tamura T, Kiura K, Seto T, Nakagawa K, Maemondo M, Inoue A, Hida T, Yoshioka H, Harada M, Ohe Y, Nogami N, Murakami H, Kuriki H, Shimada T, Tanaka T, Takeuchi K, Nishio M. Three-year follow-up of an alectinib phase I/II study in ALK-positive non-small-cell lung cancer: AF-001JP. J Clin Oncol. 2017 May 10;35(14):1515-1521. Epub 2017 Mar 15. link to original article link to PMC article PubMed
2. J-ALEX: Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, Takiguchi Y, Nishio M, Yoshioka H, Imamura F, Hotta K, Watanabe S, Goto K, Satouchi M, Kozuki T, Shukuya T, Nakagawa K, Mitsudomi T, Yamamoto N, Asakawa T, Asabe R, Tanaka T, Tamura T. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017 Jul 1;390(10089):29-39. Epub 2017 May 10. link to original article contains dosing details in abstract PubMed JapicCTI-132316
   1. Subgroup analysis: Nishio M, Nakagawa K, Mitsudomi T, Yamamoto N, Tanaka T, Kuriki H, Zeaiter A, Tamura T. Analysis of central nervous system efficacy in the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. Lung Cancer. 2018 Jul;121:37-40. Epub 2018 Apr 17. link to original article PubMed
3. ALEX: Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Pérol M, Dziadziuszko R, Rosell R, Zeaiter A, Mitry E, Golding S, Balas B, Noe J, Morcos PN, Mok T; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017 Aug 31;377(9):829-838. Epub 2017 Jun 6. link to original article contains dosing details in manuscript PubMed NCT02075840
   1. Subgroup analysis: Gadgeel S, Peters S, Mok T, Shaw AT, Kim DW, Ou SI, Pérol M, Wrona A, Novello S, Rosell R, Zeaiter A, Liu T, Nüesch E, Balas B, Camidge DR. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018 Nov 1;29(11):2214-2222. link to original article link to PMC article PubMed
   2. Update: Camidge DR, Dziadziuszko R, Peters S, Mok T, Noe J, Nowicka M, Gadgeel SM, Cheema P, Pavlakis N, de Marinis F, Cho BC, Zhang L, Moro-Sibilot D, Liu T, Bordogna W, Balas B, Müller B, Shaw AT. Updated efficacy and safety data and impact of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non-small cell lung cancer in the global phase III ALEX study. J Thorac Oncol. 2019 Jul;14(7):1233-1243. Epub 2019 Mar 20. link to original article PubMed
   3. Update: Mok T, Camidge DR, Gadgeel SM, Rosell R, Dziadziuszko R, Kim DW, Pérol M, Ou SI, Ahn JS, Shaw AT, Bordogna W, Smoljanović V, Hilton M, Ruf T, Noé J, Peters S. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020 Aug;31(8):1056-1064. Epub 2020 May 11. link to original article PubMed
4. ALESIA: Zhou C, Kim SW, Reungwetwattana T, Zhou J, Zhang Y, He J, Yang JJ, Cheng Y, Lee SH, Bu L, Xu T, Yang L, Wang C, Liu T, Morcos PN, Lu Y, Zhang L. Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALESIA): a randomised phase 3 study. Lancet Respir Med. 2019 May;7(5):437-446. Epub 2019 Apr 10. link to original article contains dosing details in abstract PubMed NCT02838420

Brigatinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Camidge et al. 2018 (ALTA-1L)	2016-04 to 2017-08	Phase 3 (E-RT-switch-ic)	Crizotinib	Superior PFS1 (primary endpoint) Median PFS: 24 vs 11.1 mo (HR 0.48, 95% CI 0.35-0.66)

¹Reported efficacy is based on the 2021 update.

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: FISH or FDA-approved test

Targeted therapy

• Brigatinib (Alunbrig) as follows:
  • Cycle 0: 90 mg PO once per day on days 1 to 7
  • Cycle 1 onwards: 180 mg PO once per day on days 1 to 28

7-day course, then 28-day cycles

References

1. ALTA-1L: Camidge DR, Kim HR, Ahn MJ, Yang JC, Han JY, Lee JS, Hochmair MJ, Li JY, Chang GC, Lee KH, Gridelli C, Delmonte A, Garcia Campelo R, Kim DW, Bearz A, Griesinger F, Morabito A, Felip E, Califano R, Ghosh S, Spira A, Gettinger SN, Tiseo M, Gupta N, Haney J, Kerstein D, Popat S. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2027-2039. Epub 2018 Sep 25. link to original article contains dosing details in manuscript PubMed NCT02737501
   1. Update: Camidge DR, Kim HR, Ahn MJ, Yang JCH, Han JY, Hochmair MJ, Lee KH, Delmonte A, García Campelo MR, Kim DW, Griesinger F, Felip E, Califano R, Spira A, Gettinger SN, Tiseo M, Lin HM, Gupta N, Hanley MJ, Ni Q, Zhang P, Popat S. Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial. J Clin Oncol. 2020 Nov 1;38(31):3592-3603. Epub 2020 Aug 11. link to original article link to PMC article PubMed
   2. HRQoL analysis: Garcia Campelo MR, Lin HM, Zhu Y, Pérol M, Jahanzeb M, Popat S, Zhang P, Camidge DR. Health-related quality of life in the randomized phase III trial of brigatinib vs crizotinib in advanced ALK inhibitor-naive ALK + non-small cell lung cancer (ALTA-1L). Lung Cancer. 2021 May;155:68-77. Epub 2021 Mar 9. link to original article PubMed
   3. Update: Camidge DR, Kim HR, Ahn MJ, Yang JCH, Han JY, Hochmair MJ, Lee KH, Delmonte A, Garcia Campelo MR, Kim DW, Griesinger F, Felip E, Califano R, Spira AI, Gettinger SN, Tiseo M, Lin HM, Liu Y, Vranceanu F, Niu H, Zhang P, Popat S. Brigatinib Versus Crizotinib in ALK Inhibitor-Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial. J Thorac Oncol. 2021 Dec;16(12):2091-2108. Epub 2021 Sep 16. link to original article PubMed

Carboplatin & Pemetrexed

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

Regimen variant #1, 5/500 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Solomon et al. 2014 (PROFILE 1014)	2011-2013	Phase 3 (C)	Crizotinib	Inferior PFS
Wu et al. 2018 (PROFILE 1029)	2012-2014	Phase 3 (C)	Crizotinib	Inferior PFS
Soria et al. 2017 (ASCEND-4)	2013-2015	Phase 3 (C)	Ceritinib	Inferior PFS

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: IHC

Chemotherapy

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

Supportive therapy

• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
• Folic acid (Folate) 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 (ASCEND-4) or 6 cycles (PROFILE 1014 & PROFILE 1029)

Subsequent treatment

• ASCEND-4: Pemetrexed maintenance

Regimen variant #2, 6/500 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Solomon et al. 2014 (PROFILE 1014)	2011-2013	Phase 3 (C)	Crizotinib	Inferior PFS
Wu et al. 2018 (PROFILE 1029)	2012-2014	Phase 3 (C)	Crizotinib	Inferior PFS
Soria et al. 2017 (ASCEND-4)	2013-2015	Phase 3 (C)	Ceritinib	Inferior PFS

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: IHC

Chemotherapy

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

Supportive therapy

• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
• Folic acid (Folate) 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 (ASCEND-4) or 6 cycles (PROFILE 1014 & PROFILE 1029)

Subsequent treatment

• ASCEND-4: Pemetrexed maintenance

References

1. PROFILE 1014: Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4;371(23):2167-77. Erratum in: N Engl J Med. 2015 Oct 15;373(16):1582. link to original article contains dosing details in manuscript PubMed NCT01154140
   1. Subgroup analysis: Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, Nakagawa K, Wu YL, Mekhail T, Paolini J, Tursi J, Usari T, Wilner KD, Selaru P, Mok TS. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol. 2016 Aug 20;34(24):2858-65. Epub 2016 Mar 28. link to original article PubMed
   2. Pooled subgroup analysis: Nishio M, Kim DW, Wu YL, Nakagawa K, Solomon BJ, Shaw AT, Hashigaki S, Ohki E, Usari T, Paolini J, Polli A, Wilner KD, Mok T. Crizotinib versus chemotherapy in Asian patients with ALK-positive advanced non-small cell lung cancer. Cancer Res Treat. 2018 Jul;50(3):691-700. Epub 2017 Jul 6. link to original article link to PMC article PubMed
   3. Update: Solomon BJ, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Tang Y, Wilner KD, Blackhall F, Mok TS. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol. 2018 Aug 1;36(22):2251-2258. Epub 2018 May 16. link to original article PubMed
2. ASCEND-4: Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, Geater SL, Orlov S, Cortinovis D, Yu CJ, Hochmair M, Cortot AB, Tsai CM, Moro-Sibilot D, Campelo RG, McCulloch T, Sen P, Dugan M, Pantano S, Branle F, Massacesi C, de Castro G Jr. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017 Mar 4;389(10072):917-929. Epub 2017 Jan 24. link to original article contains dosing details in abstract PubMed NCT01828099
3. PROFILE 1029: Wu YL, Lu S, Lu Y, Zhou J, Shi YK, Sriuranpong V, Ho JCM, Ong CK, Tsai CM, Chung CH, Wilner KD, Tang Y, Masters ET, Selaru P, Mok TS. Results of PROFILE 1029, a phase III comparison of first-line crizotinib versus chemotherapy in East Asian patients with ALK-positive advanced non-small cell lung cancer. J Thorac Oncol. 2018 Oct;13(10):1539-1548. Epub 2018 Aug 14. link to original article contains dosing details in manuscript PubMed NCT01639001

Ceritinib monotherapy

Regimen variant #1, 450 mg/day with food

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cho et al. 2017 (ASCEND-8)	2015-2016	Randomized phase 1 (E-de-esc)	Ceritinib; 750 mg/d	Not reported

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: IHC

Targeted therapy

• Ceritinib (Zykadia) 450 mg PO once per day, taken with food

Continued indefinitely

Regimen variant #2, 750 mg/day fasting

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shaw et al. 2014 (ASCEND-1)	2011-2013	Phase 1, >20 pts in this dosing cohort (RT)
Soria et al. 2017 (ASCEND-4)	2013-2015	Phase 3 (E-RT-switch-ooc)	1a. Carboplatin & Pemetrexed 1b. Cisplatin & Pemetrexed	Superior PFS (primary endpoint) Median PFS: 16.6 vs 8.1 mo (HR 0.55, 95% CI 0.42-0.73)
Cho et al. 2017 (ASCEND-8)	2015-2016	Randomized phase 1 (C)	Ceritinib; 450 mg/d	Not reported

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: IHC

Targeted therapy

• Ceritinib (Zykadia) 750 mg PO once per day on days 1 to 21, taken on an empty stomach

21-day cycles

References

1. ASCEND-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 dosing details in manuscript link to PMC article PubMed NCT01283516
   1. Update: Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Sutradhar S, Li S, Szczudlo T, Yovine A, Shaw AT. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016 Apr;17(4):452-463. Epub 2016 Mar 11. link to original article link to PMC article PubMed
2. ASCEND-4: Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, Geater SL, Orlov S, Cortinovis D, Yu CJ, Hochmair M, Cortot AB, Tsai CM, Moro-Sibilot D, Campelo RG, McCulloch T, Sen P, Dugan M, Pantano S, Branle F, Massacesi C, de Castro G Jr. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017 Mar 4;389(10072):917-929. Epub 2017 Jan 24. link to original article contains dosing details in abstract PubMed NCT01828099
3. ASCEND-8: Cho BC, Kim DW, Bearz A, Laurie SA, McKeage M, Borra G, Park K, Kim SW, Ghosn M, Ardizzoni A, Maiello E, Greystoke A, Yu R, Osborne K, Gu W, Scott JW, Passos VQ, Lau YY, Wrona A. ASCEND-8: a randomized phase 1 study of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg in fasted state in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC). J Thorac Oncol. 2017 Sep;12(9):1357-1367. Epub 2017 Jul 17. link to original article contains dosing details in abstract PubMed NCT02299505

Cisplatin & Pemetrexed

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

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Solomon et al. 2014 (PROFILE 1014)	2011-2013	Phase 3 (C)	Crizotinib	Inferior PFS
Wu et al. 2018 (PROFILE 1029)	2012-2014	Phase 3 (C)	Crizotinib	Inferior PFS
Soria et al. 2017 (ASCEND-4)	2013-2015	Phase 3 (C)	Ceritinib	Inferior PFS

Biomarker eligibility criteria

Biomarker: ALK Fusion Gene Rearrangement Diagnostics: FISH or IHC

Chemotherapy

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

Supportive therapy

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

21-day cycle for up to 4 cycles (ASCEND-4) or 6 cycles (PROFILE 1014 & PROFILE 1029)

Subsequent treatment

• ASCEND-4: Pemetrexed maintenance

References

1. PROFILE 1014: Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4;371(23):2167-77. Erratum in: N Engl J Med. 2015 Oct 15;373(16):1582. link to original article contains dosing details in manuscript PubMed NCT01154140
   1. Subgroup analysis: Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, Nakagawa K, Wu YL, Mekhail T, Paolini J, Tursi J, Usari T, Wilner KD, Selaru P, Mok TS. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol. 2016 Aug 20;34(24):2858-65. Epub 2016 Mar 28. link to original article PubMed
   2. Pooled subgroup analysis: Nishio M, Kim DW, Wu YL, Nakagawa K, Solomon BJ, Shaw AT, Hashigaki S, Ohki E, Usari T, Paolini J, Polli A, Wilner KD, Mok T. Crizotinib versus chemotherapy in Asian patients with ALK-positive advanced non-small cell lung cancer. Cancer Res Treat. 2018 Jul;50(3):691-700. Epub 2017 Jul 6. link to original article link to PMC article PubMed
   3. Update: Solomon BJ, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Tang Y, Wilner KD, Blackhall F, Mok TS. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol. 2018 Aug 1;36(22):2251-2258. Epub 2018 May 16. link to original article PubMed
2. ASCEND-4: Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, Geater SL, Orlov S, Cortinovis D, Yu CJ, Hochmair M, Cortot AB, Tsai CM, Moro-Sibilot D, Campelo RG, McCulloch T, Sen P, Dugan M, Pantano S, Branle F, Massacesi C, de Castro G Jr. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017 Mar 4;389(10072):917-929. Epub 2017 Jan 24. link to original article contains dosing details in abstract PubMed NCT01828099
3. PROFILE 1029: Wu YL, Lu S, Lu Y, Zhou J, Shi YK, Sriuranpong V, Ho JCM, Ong CK, Tsai CM, Chung CH, Wilner KD, Tang Y, Masters ET, Selaru P, Mok TS. Results of PROFILE 1029, a phase III comparison of first-line crizotinib versus chemotherapy in East Asian patients with ALK-positive advanced non-small cell lung cancer. J Thorac Oncol. 2018 Oct;13(10):1539-1548. Epub 2018 Aug 14. link to original article contains dosing details in manuscript PubMed NCT01639001

Crizotinib monotherapy

Regimen variant #1, 250 mg/day

FDA-recommended dose

Note: this is the FDA-recommended dosing for "severe" hepatic or renal impairment.

Targeted therapy

• Crizotinib (Xalkori) 250 mg PO once per day

Continued indefinitely

Regimen variant #2, 400 mg/day

FDA-recommended dose

Note: this is the FDA-recommended dosing for "moderate" hepatic impairment.

Targeted therapy

• Crizotinib (Xalkori) 200 mg PO twice per day

Continued indefinitely

Regimen variant #3, 500 mg/day

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kwak et al. 2010 (PROFILE 1001 ALK)	2008-2011	Phase 1 (RT)		ORR: 61%
Shaw et al. 2013 (PROFILE 1007)	2010-2012	Phase 3 (E-RT-switch-ooc)	1a. Pemetrexed 1b. Docetaxel	Superior PFS (primary endpoint) Median PFS: 7.7 vs 3 mo (HR 0.49, 95% CI 0.37-0.64)
Blackhall et al. 2017 (PROFILE 1005)	2010-2014	Phase 2 (RT)
Solomon et al. 2014 (PROFILE 1014)	2011-2013	Phase 3 (E-RT-switch-ooc)	1a. Carboplatin & Pemetrexed 1b. Cisplatin & Pemetrexed	Superior PFS (primary endpoint) Median PFS: 10.9 vs 7 mo (HR 0.45, 95% CI 0.35-0.60) Might have superior OS1 (secondary endpoint) Median OS: NYR vs 47.5 mo (HR 0.76, 95% CI 0.55-1.05)
Wu et al. 2018 (PROFILE 1029)	2012-2014	Phase 3 (E-switch-ooc)	1a. Carboplatin & Pemetrexed 1b. Cisplatin & Pemetrexed	Superior PFS (primary endpoint) Median PFS: 11.1 vs 6.8 mo (HR 0.40, 95% CI 0.29-0.565)
Hida et al. 2017 (J-ALEX)	2013-2015	Phase 3 (C)	Alectinib	Inferior PFS
Peters et al. 2017 (ALEX)	2014-2016	Phase 3 (C)	Alectinib	Seems to have inferior OS2
Camidge et al. 2018 (ALTA-1L)	2016-04 to 2017-08	Phase 3 (C)	Brigatinib	Inferior PFS
Zhou et al. 2019 (ALESIA)	2016-08-03 to 2017-05-16	Phase 3 (C)	Alectinib	Inferior PFS
Horn et al. 2021 (eXalt3)	2016-2018	Phase 3 (C)	Ensartinib	Inferior PFS
Shaw et al. 2020 (CROWN)	2017-2019	Phase 3 (C)	Lorlatinib	Inferior PFS
Yang et al. 2023 (TQ-B3139-III-01)	2019-08-21 to 2020-07-13	Phase 3 (C)	Envonalkib	Inferior PFS (primary endpoint)

¹Reported efficacy for OS endpoint in PROFILE 1014 is based on the 2018 update.
²Reported efficacy for ALEX is based on the 2020 update; the authors mention that OS results are immature.
Note: PROFILE 1007 used 21-day cycles, and crizotinib was similarly given 250 mg PO twice per day on all days.

Targeted therapy

• Crizotinib (Xalkori) 250 mg PO twice per day on days 1 to 28

28-day cycles

References

1. PROFILE 1001 ALK: 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 dosing details in manuscript link to PMC article PubMed NCT00585195
   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 dosing details in manuscript link to PMC article 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 link to PMC article PubMed
3. PROFILE 1007: 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 dosing details in manuscript PubMed NCT00932893
   1. PRO analysis: Blackhall F, Kim DW, Besse B, Nokihara H, Han JY, Wilner KD, Reisman A, Iyer S, Hirsh V, Shaw AT. Patient-reported outcomes and quality of life in PROFILE 1007: a randomized trial of crizotinib compared with chemotherapy in previously treated patients with ALK-positive advanced non-small-cell lung cancer. J Thorac Oncol. 2014 Nov;9(11):1625-33. Erratum in: J Thorac Oncol. 2015 Nov;10(11):1657. link to original article PubMed
   2. Pooled subgroup analysis: Nishio M, Kim DW, Wu YL, Nakagawa K, Solomon BJ, Shaw AT, Hashigaki S, Ohki E, Usari T, Paolini J, Polli A, Wilner KD, Mok T. Crizotinib versus chemotherapy in Asian patients with ALK-positive advanced non-small cell lung cancer. Cancer Res Treat. 2018 Jul;50(3):691-700. Epub 2017 Jul 6. link to original article link to PMC article PubMed
4. PROFILE 1014: Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4;371(23):2167-77. Erratum in: N Engl J Med. 2015 Oct 15;373(16):1582. link to original article contains dosing details in manuscript PubMed NCT01154140
   1. Subgroup analysis: Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, Nakagawa K, Wu YL, Mekhail T, Paolini J, Tursi J, Usari T, Wilner KD, Selaru P, Mok TS. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol. 2016 Aug 20;34(24):2858-65. Epub 2016 Mar 28. link to original article PubMed
   2. Pooled subgroup analysis: Nishio M, Kim DW, Wu YL, Nakagawa K, Solomon BJ, Shaw AT, Hashigaki S, Ohki E, Usari T, Paolini J, Polli A, Wilner KD, Mok T. Crizotinib versus chemotherapy in Asian patients with ALK-positive advanced non-small cell lung cancer. Cancer Res Treat. 2018 Jul;50(3):691-700. Epub 2017 Jul 6. link to original article link to PMC article PubMed
   3. Update: Solomon BJ, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Tang Y, Wilner KD, Blackhall F, Mok TS. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol. 2018 Aug 1;36(22):2251-2258. Epub 2018 May 16. link to original article PubMed
5. J-ALEX: Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, Takiguchi Y, Nishio M, Yoshioka H, Imamura F, Hotta K, Watanabe S, Goto K, Satouchi M, Kozuki T, Shukuya T, Nakagawa K, Mitsudomi T, Yamamoto N, Asakawa T, Asabe R, Tanaka T, Tamura T. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017 Jul 1;390(10089):29-39. Epub 2017 May 10. link to original article contains dosing details in abstract PubMed JapicCTI-132316
   1. Subgroup analysis: Nishio M, Nakagawa K, Mitsudomi T, Yamamoto N, Tanaka T, Kuriki H, Zeaiter A, Tamura T. Analysis of central nervous system efficacy in the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. Lung Cancer. 2018 Jul;121:37-40. Epub 2018 Apr 17. link to original article PubMed
6. ALEX: Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Pérol M, Dziadziuszko R, Rosell R, Zeaiter A, Mitry E, Golding S, Balas B, Noe J, Morcos PN, Mok T; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017 Aug 31;377(9):829-838. Epub 2017 Jun 6. link to original article contains dosing details in manuscript PubMed NCT02075840
   1. Subgroup analysis: Gadgeel S, Peters S, Mok T, Shaw AT, Kim DW, Ou SI, Pérol M, Wrona A, Novello S, Rosell R, Zeaiter A, Liu T, Nüesch E, Balas B, Camidge DR. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018 Nov 1;29(11):2214-2222. link to original article link to PMC article PubMed
   2. Update: Camidge DR, Dziadziuszko R, Peters S, Mok T, Noe J, Nowicka M, Gadgeel SM, Cheema P, Pavlakis N, de Marinis F, Cho BC, Zhang L, Moro-Sibilot D, Liu T, Bordogna W, Balas B, Müller B, Shaw AT. Updated efficacy and safety data and impact of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non-small cell lung cancer in the global phase III ALEX study. J Thorac Oncol. 2019 Jul;14(7):1233-1243. Epub 2019 Mar 20. link to original article PubMed
   3. Update: Mok T, Camidge DR, Gadgeel SM, Rosell R, Dziadziuszko R, Kim DW, Pérol M, Ou SI, Ahn JS, Shaw AT, Bordogna W, Smoljanović V, Hilton M, Ruf T, Noé J, Peters S. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020 Aug;31(8):1056-1064. Epub 2020 May 11. link to original article PubMed
7. PROFILE 1005: Blackhall F, Camidge DR, Shaw AT, Soria JC, Solomon BJ, Mok T, Hirsh V, Jänne PA, Shi Y, Yang PC, Pas T, Hida T, Carpeño JC, Lanzalone S, Polli A, Iyer S, Reisman A, Wilner KD, Kim DW. Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer. ESMO Open. 2017 Aug 17;2(3):e000219. eCollection 2017. link to original article link to PMC article contains dosing details in abstract PubMed NCT00932451
8. PROFILE 1029: Wu YL, Lu S, Lu Y, Zhou J, Shi YK, Sriuranpong V, Ho JCM, Ong CK, Tsai CM, Chung CH, Wilner KD, Tang Y, Masters ET, Selaru P, Mok TS. Results of PROFILE 1029, a phase III comparison of first-line crizotinib versus chemotherapy in East Asian patients with ALK-positive advanced non-small cell lung cancer. J Thorac Oncol. 2018 Oct;13(10):1539-1548. Epub 2018 Aug 14. link to original article contains dosing details in manuscript PubMed NCT01639001
9. ALTA-1L: Camidge DR, Kim HR, Ahn MJ, Yang JC, Han JY, Lee JS, Hochmair MJ, Li JY, Chang GC, Lee KH, Gridelli C, Delmonte A, Garcia Campelo R, Kim DW, Bearz A, Griesinger F, Morabito A, Felip E, Califano R, Ghosh S, Spira A, Gettinger SN, Tiseo M, Gupta N, Haney J, Kerstein D, Popat S. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2027-2039. Epub 2018 Sep 25. link to original article contains dosing details in abstract PubMed NCT02737501
   1. Update: Camidge DR, Kim HR, Ahn MJ, Yang JCH, Han JY, Hochmair MJ, Lee KH, Delmonte A, García Campelo MR, Kim DW, Griesinger F, Felip E, Califano R, Spira A, Gettinger SN, Tiseo M, Lin HM, Gupta N, Hanley MJ, Ni Q, Zhang P, Popat S. Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial. J Clin Oncol. 2020 Nov 1;38(31):3592-3603. Epub 2020 Aug 11. link to original article link to PMC article PubMed
   2. HRQoL analysis: Garcia Campelo MR, Lin HM, Zhu Y, Pérol M, Jahanzeb M, Popat S, Zhang P, Camidge DR. Health-related quality of life in the randomized phase III trial of brigatinib vs crizotinib in advanced ALK inhibitor-naive ALK + non-small cell lung cancer (ALTA-1L). Lung Cancer. 2021 May;155:68-77. Epub 2021 Mar 9. link to original article PubMed
   3. Update: Camidge DR, Kim HR, Ahn MJ, Yang JCH, Han JY, Hochmair MJ, Lee KH, Delmonte A, Garcia Campelo MR, Kim DW, Griesinger F, Felip E, Califano R, Spira AI, Gettinger SN, Tiseo M, Lin HM, Liu Y, Vranceanu F, Niu H, Zhang P, Popat S. Brigatinib Versus Crizotinib in ALK Inhibitor-Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial. J Thorac Oncol. 2021 Dec;16(12):2091-2108. Epub 2021 Sep 16. link to original article PubMed
10. ALESIA: Zhou C, Kim SW, Reungwetwattana T, Zhou J, Zhang Y, He J, Yang JJ, Cheng Y, Lee SH, Bu L, Xu T, Yang L, Wang C, Liu T, Morcos PN, Lu Y, Zhang L. Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALESIA): a randomised phase 3 study. Lancet Respir Med. 2019 May;7(5):437-446. Epub 2019 Apr 10. link to original article contains dosing details in abstract PubMed NCT02838420
11. CROWN: Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, Mazieres J, Kim DW, Mok T, Polli A, Thurm H, Calella AM, Peltz G, Solomon BJ; CROWN Trial Investigators. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2020 Nov 19;383(21):2018-2029. link to original article contains dosing details in manuscript PubMed NCT03052608
    1. PRO analysis: Mazieres J, Iadeluca L, Shaw AT, Solomon BJ, Bauer TM, de Marinis F, Felip E, Goto Y, Kim DW, Mok T, Reisman A, Thurm H, Polli AM, Liu G. Patient-reported outcomes from the randomized phase 3 CROWN study of first-line lorlatinib versus crizotinib in advanced ALK-positive non-small cell lung cancer. Lung Cancer. 2022 Dec;174:146-156. Epub 2022 Nov 7. link to original article PubMed
12. eXalt3: Horn L, Wang Z, Wu G, Poddubskaya E, Mok T, Reck M, Wakelee H, Chiappori AA, Lee DH, Breder V, Orlov S, Cicin I, Cheng Y, Liu Y, Fan Y, Whisenant JG, Zhou Y, Oertel V, Harrow K, Liang C, Mao L, Selvaggi G, Wu YL. Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Randomized Clinical Trial. JAMA Oncol. 2021 Nov 1;7(11):1617-1625. link to original article link to PMC article PubMed NCT02767804
13. TQ-B3139-III-01: Yang Y, Min J, Yang N, Yu Q, Cheng Y, Zhao Y, Li M, Chen H, Ren S, Zhou J, Zhuang W, Qin X, Cao L, Yu Y, Zhang J, He J, Feng J, Yu H, Zhang L, Fang W. Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trial. Signal Transduct Target Ther. 2023 Aug 14;8(1):301. link to original article link to PMC article contains dosing details in manuscript PubMed NCT04009317

Docetaxel monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shaw et al. 2013 (PROFILE 1007)	2010-2012	Phase 3 (C)	Crizotinib	Inferior PFS

Biomarker eligibility criteria

Biomarker: ALK Fusion Gene Rearrangement Diagnostics: FISH

Chemotherapy

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

Supportive therapy

• Per JMEI: Dexamethasone (Decadron) 8 mg PO twice per day on days -1 to 2 (3 days)

21-day cycles

References

1. PROFILE 1007: 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 dosing details in manuscript PubMed NCT00932893
   1. PRO analysis: Blackhall F, Kim DW, Besse B, Nokihara H, Han JY, Wilner KD, Reisman A, Iyer S, Hirsh V, Shaw AT. Patient-reported outcomes and quality of life in PROFILE 1007: a randomized trial of crizotinib compared with chemotherapy in previously treated patients with ALK-positive advanced non-small-cell lung cancer. J Thorac Oncol. 2014 Nov;9(11):1625-33. Erratum in: J Thorac Oncol. 2015 Nov;10(11):1657. link to original article PubMed
   2. Pooled subgroup analysis: Nishio M, Kim DW, Wu YL, Nakagawa K, Solomon BJ, Shaw AT, Hashigaki S, Ohki E, Usari T, Paolini J, Polli A, Wilner KD, Mok T. Crizotinib versus chemotherapy in Asian patients with ALK-positive advanced non-small cell lung cancer. Cancer Res Treat. 2018 Jul;50(3):691-700. Epub 2017 Jul 6. link to original article link to PMC article PubMed

Ensartinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Horn et al. 2021 (eXalt3)	2016-2018	Phase 3 (E-switch-ic)	Crizotinib	Superior PFS (primary endpoint) Median PFS: 25.8 vs 12.7 mo (HR 0.51, 95% CI 0.35-0.72)

Targeted therapy

• Ensartinib (Ensacove) 225 mg PO once per day

Continued indefinitely

References

1. eXalt3: Horn L, Wang Z, Wu G, Poddubskaya E, Mok T, Reck M, Wakelee H, Chiappori AA, Lee DH, Breder V, Orlov S, Cicin I, Cheng Y, Liu Y, Fan Y, Whisenant JG, Zhou Y, Oertel V, Harrow K, Liang C, Mao L, Selvaggi G, Wu YL. Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Randomized Clinical Trial. JAMA Oncol. 2021 Nov 1;7(11):1617-1625. link to original article link to PMC article contains dosing details in abstract PubMed NCT02767804

Lorlatinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shaw et al. 2020 (CROWN)	2017-2019	Phase 3 (E-RT-switch-ic)	Crizotinib	Superior PFS (primary endpoint) PFS12: 78% vs 39% (HR 0.28, 95% CI 0.19-0.41)

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: Ventana ALK (D5F3) CDx immunohistochemical assay

Targeted therapy

• Lorlatinib (Lorbrena) 100 mg PO once per day on days 1 to 28

28-day cycles

References

1. CROWN: Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, Mazieres J, Kim DW, Mok T, Polli A, Thurm H, Calella AM, Peltz G, Solomon BJ; CROWN Trial Investigators. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2020 Nov 19;383(21):2018-2029. link to original article contains dosing details in manuscript PubMed NCT03052608
   1. PRO analysis: Mazieres J, Iadeluca L, Shaw AT, Solomon BJ, Bauer TM, de Marinis F, Felip E, Goto Y, Kim DW, Mok T, Reisman A, Thurm H, Polli AM, Liu G. Patient-reported outcomes from the randomized phase 3 CROWN study of first-line lorlatinib versus crizotinib in advanced ALK-positive non-small cell lung cancer. Lung Cancer. 2022 Dec;174:146-156. Epub 2022 Nov 7. link to original article PubMed

Pemetrexed monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shaw et al. 2013 (PROFILE 1007)	2010-2012	Phase 3 (C)	Crizotinib	Inferior PFS

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: FISH

Chemotherapy

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

Supportive therapy

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

21-day cycles

References

1. PROFILE 1007: 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 dosing details in manuscript PubMed NCT00932893
   1. PRO analysis: Blackhall F, Kim DW, Besse B, Nokihara H, Han JY, Wilner KD, Reisman A, Iyer S, Hirsh V, Shaw AT. Patient-reported outcomes and quality of life in PROFILE 1007: a randomized trial of crizotinib compared with chemotherapy in previously treated patients with ALK-positive advanced non-small-cell lung cancer. J Thorac Oncol. 2014 Nov;9(11):1625-33. Erratum in: J Thorac Oncol. 2015 Nov;10(11):1657. link to original article PubMed
   2. Pooled subgroup analysis: Nishio M, Kim DW, Wu YL, Nakagawa K, Solomon BJ, Shaw AT, Hashigaki S, Ohki E, Usari T, Paolini J, Polli A, Wilner KD, Mok T. Crizotinib versus chemotherapy in Asian patients with ALK-positive advanced non-small cell lung cancer. Cancer Res Treat. 2018 Jul;50(3):691-700. Epub 2017 Jul 6. link to original article link to PMC article PubMed

Advanced or metastatic disease, ALK inhibitor-exposed

Alectinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ou et al. 2015 (NP28673)	2013-2014	Phase 2 (RT)		ORR: 50% (95% CI, 41-59)
Shaw et al. 2015 (NP28761)	2013-2014	Phase 2 (RT)		ORR: 48% (95% CI, 36–60)
Novello et al. 2018 (ALUR)	2015-2018	Phase 3 (E-switch-ooc)	1a. Docetaxel 1b. Pemetrexed	Superior PFS1 (primary endpoint) Median PFS: 10.9 vs 1.4 mo (HR 0.20, 95% CI 0.12-0.33)

¹Reported efficacy for ALUR is based on the 2022 update.

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: FISH

Targeted therapy

• Alectinib (Alecensa) 600 mg PO twice per day, taken within 30 minutes of eating

Continued indefinitely

References

1. NP28673: 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. Epub 2015 Nov 23. link to original article contains dosing details in manuscript PubMed NCT01801111
   1. Pooled update: Ou SI, Gadgeel SM, Barlesi F, Yang JC, De Petris L, Kim DW, Govindan R, Dingemans AM, Crino L, Léna H, Popat S, Ahn JS, Dansin E, Mitry E, Müller B, Bordogna W, Balas B, Morcos PN, Shaw AT. Pooled overall survival and safety data from the pivotal phase II studies (NP28673 and NP28761) of alectinib in ALK-positive non-small-cell lung cancer. Lung Cancer. 2020 Jan;139:22-27. Epub 2019 Oct 14. link to original article PubMed
2. NP28761: Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, Camidge DR, Socinski MA, Chiappori A, Mekhail T, Chao BH, Borghaei H, Gold KA, Zeaiter A, Bordogna W, Balas B, Puig O, Henschel V, Ou SI; study investigators. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 2016 Feb;17(2):234-242. Epub 2015 Dec 19. link to original article link to PMC article contains dosing details in abstract PubMed NCT01871805
   1. Pooled update: Ou SI, Gadgeel SM, Barlesi F, Yang JC, De Petris L, Kim DW, Govindan R, Dingemans AM, Crino L, Léna H, Popat S, Ahn JS, Dansin E, Mitry E, Müller B, Bordogna W, Balas B, Morcos PN, Shaw AT. Pooled overall survival and safety data from the pivotal phase II studies (NP28673 and NP28761) of alectinib in ALK-positive non-small-cell lung cancer. Lung Cancer. 2020 Jan;139:22-27. Epub 2019 Oct 14. link to original article PubMed
3. ALUR: Novello S, Mazières J, Oh IJ, de Castro J, Migliorino MR, Helland Å, Dziadziuszko R, Griesinger F, Kotb A, Zeaiter A, Cardona A, Balas B, Johannsdottir HK, Das-Gupta A, Wolf J. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol. 2018 Jun 1;29(6):1409-1416. link to original article link to PMC article contains dosing details in abstract PubMed NCT02604342
   1. Update: Wolf J, Helland Å, Oh IJ, Migliorino MR, Dziadziuszko R, Wrona A, de Castro J, Mazieres J, Griesinger F, Chlistalla M, Cardona A, Ruf T, Trunzer K, Smoljanovic V, Novello S. Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer. ESMO Open. 2022 Feb;7(1):100333. Epub 2022 Jan 15. link to original article link to PMC article PubMed
4. ALTA-3: NCT03596866

Brigatinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kim et al. 2017 (ALTA)	2014-2015	Randomized Phase 2 (E-RT-esc)	Brigatinib; 90 mg/day	Did not meet primary endpoint of ORR1

¹A chi-square analysis of the ORR (not reported in the manuscript; our analysis) gives a non-significant ORR increase, 54% versus 45% (p=0.18).

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement

Targeted therapy

• Brigatinib (Alunbrig) 90 mg PO once per day on days 1 to 7, then 180 mg PO once per day

Continued indefinitely

References

1. ALTA: Kim DW, Tiseo M, Ahn MJ, Reckamp KL, Hansen KH, Kim SW, Huber RM, West HL, Groen HJM, Hochmair MJ, Leighl NB, Gettinger SN, Langer CJ, Paz-Ares Rodríguez LG, Smit EF, Kim ES, Reichmann W, Haluska FG, Kerstein D, Camidge DR. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol. 2017 Aug 1;35(22):2490-2498. Epub 2017 May 5. link to original article contains dosing details in manuscript PubMed NCT02094573
   1. Subgroup analysis: Camidge DR, Kim DW, Tiseo M, Langer CJ, Ahn MJ, Shaw AT, Huber RM, Hochmair MJ, Lee DH, Bazhenova LA, Gold KA, Ou SI, West HL, Reichmann W, Haney J, Clackson T, Kerstein D, Gettinger SN. Exploratory analysis of brigatinib activity in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer and brain metastases in two clinical trials. J Clin Oncol. 2018 Sep 10;36(26):2693-2701. Epub 2018 May 16. link to original article PubMed
   2. PRO analysis: Lenderking WR, Lin H, Speck RM, Zhu Y, Huang H, Huang J, Kerstein D, Langer CJ. Patient-reported outcomes and quality of life in advanced ALK+ non-small-cell lung cancer trial of brigatinib (ALTA). Future Oncol. 2019 Aug;15(24):2841-2855. Epub 2019 Jul 31. link to original article PubMed
   3. Update: Huber RM, Hansen KH, Paz-Ares Rodríguez L, West HL, Reckamp KL, Leighl NB, Tiseo M, Smit EF, Kim DW, Gettinger SN, Hochmair MJ, Kim SW, Langer CJ, Ahn MJ, Kim ES, Kerstein D, Groen HJM, Camidge DR. Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial. J Thorac Oncol. 2020 Mar;15(3):404-415. Epub 2019 Nov 19. link to original article PubMed
2. ALTA-3: NCT03596866

Ceritinib monotherapy

Regimen variant #1, 450 mg/day with food

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cho et al. 2017 (ASCEND-8)	2015-2016	Randomized phase 1 (de-esc)	Ceritinib; 750 mg/d	Not reported

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: FISH or IHC

Targeted therapy

• Ceritinib (Zykadia) 450 mg PO once per day, taken with food

Continued indefinitely

Regimen variant #2, 750 mg/day fasting

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shaw et al. 2014 (ASCEND-1)	2011-2013	Phase 1, >20 pts in this dosing cohort (RT)
Shaw et al. 2017 (ASCEND-5)	2013-2015	Phase 3 (E-switch-ooc)	1a. Docetaxel 1b. Pemetrexed	Superior PFS (primary endpoint) Median PFS: 5.4 vs 1.6 mo (HR 0.49, 95% CI 0.36-0.67)
Cho et al. 2017 (ASCEND-8)	2015-2016	Randomized phase 1 (C)	Ceritinib; 450 mg/d	Not reported

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: FISH or IHC

Targeted therapy

• Ceritinib (Zykadia) 750 mg PO once per day on days 1 to 21, taken on an empty stomach

21-day cycles

References

1. ASCEND-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 dosing details in manuscript link to PMC article PubMed NCT01283516
   1. Update: Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Sutradhar S, Li S, Szczudlo T, Yovine A, Shaw AT. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016 Apr;17(4):452-463. Epub 2016 Mar 11. link to original article link to PMC article PubMed
2. ASCEND-5: Shaw AT, Kim TM, Crinò L, Gridelli C, Kiura K, Liu G, Novello S, Bearz A, Gautschi O, Mok T, Nishio M, Scagliotti G, Spigel DR, Deudon S, Zheng C, Pantano S, Urban P, Massacesi C, Viraswami-Appanna K, Felip E. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):874-886. Epub 2017 Jun 9. link to original article contains dosing details in abstract PubMed NCT01828112
3. ASCEND-8: Cho BC, Kim DW, Bearz A, Laurie SA, McKeage M, Borra G, Park K, Kim SW, Ghosn M, Ardizzoni A, Maiello E, Greystoke A, Yu R, Osborne K, Gu W, Scott JW, Passos VQ, Lau YY, Wrona A. ASCEND-8: a randomized phase 1 study of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg in fasted state in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC). J Thorac Oncol. 2017 Sep;12(9):1357-1367. Epub 2017 Jul 17. link to original article contains dosing details in abstract PubMed NCT02299505

Docetaxel monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shaw et al. 2017 (ASCEND-5)	2013-2015	Phase 3 (C)	Ceritinib	Inferior PFS
Novello et al. 2018 (ALUR)	2015-2018	Phase 3 (C)	Alectinib	Inferior PFS1

¹Reported efficacy for ALUR is based on the 2022 update.

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: FISH or IHC

Chemotherapy

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

Supportive therapy

• Per JMEI: Dexamethasone (Decadron) 8 mg PO twice per day on days -1 to 2 (3 days)

21-day cycles

References

1. ASCEND-5: Shaw AT, Kim TM, Crinò L, Gridelli C, Kiura K, Liu G, Novello S, Bearz A, Gautschi O, Mok T, Nishio M, Scagliotti G, Spigel DR, Deudon S, Zheng C, Pantano S, Urban P, Massacesi C, Viraswami-Appanna K, Felip E. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):874-886. Epub 2017 Jun 9. link to original articlecontains dosing details in abstractPubMed NCT01828112
2. ALUR: Novello S, Mazières J, Oh IJ, de Castro J, Migliorino MR, Helland Å, Dziadziuszko R, Griesinger F, Kotb A, Zeaiter A, Cardona A, Balas B, Johannsdottir HK, Das-Gupta A, Wolf J. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol. 2018 Jun 1;29(6):1409-1416. link to original article link to PMC article contains dosing details in abstract PubMed NCT02604342
   1. Update: Wolf J, Helland Å, Oh IJ, Migliorino MR, Dziadziuszko R, Wrona A, de Castro J, Mazieres J, Griesinger F, Chlistalla M, Cardona A, Ruf T, Trunzer K, Smoljanovic V, Novello S. Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer. ESMO Open. 2022 Feb;7(1):100333. Epub 2022 Jan 15. link to original article link to PMC article PubMed

Ensartinib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Horn et al. 2018 (X396-CLI-101)	NR	Phase 1/2 (RT)

Note: this is the dose used in the dose expansion phase.

Targeted therapy

• Ensartinib (Ensacove) 225 mg PO once per day

Continued indefinitely

References

1. X396-CLI-101: Horn L, Infante JR, Reckamp KL, Blumenshein GR, Leal TA, Waqar SN, Gitlitz BJ, Sanborn RE, Whisenant JG, Du L, Neal JW, Gockerman JP, Dukart G, Harrow K, Liang C, Gibbons JJ, Holzhausen A, Lovly CM, Wakelee HA. Ensartinib (X-396) in ALK-positive non-small cell lung cancer: results from a first-in-human phase I/II, multicenter study. Clin Cancer Res. 2018 Jun 15;24(12):2771-2779. Epub 2018 Mar 21. link to original article link to PMC article PubMed NCT01625234

Lorlatinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence
Shaw et al. 2017 (B7461001)	2014-2016	Phase 1/2 (RT)

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: FISH or IHC

Targeted therapy

• Lorlatinib (Lorbrena) 100 mg PO once per day on days 1 to 28

28-day cycles

References

1. B7461001: Shaw AT, Felip E, Bauer TM, Besse B, Navarro A, Postel-Vinay S, Gainor JF, Johnson M, Dietrich J, James LP, Clancy JS, Chen J, Martini JF, Abbattista A, Solomon BJ. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017 Dec;18(12):1590-1599. Epub 2017 Oct 23. link to original article contains dosing details in abstract link to PMC article PubMed NCT01970865
   1. Update: Solomon BJ, Besse B, Bauer TM, Felip E, Soo RA, Camidge DR, Chiari R, Bearz A, Lin CC, Gadgeel SM, Riely GJ, Tan EH, Seto T, James LP, Clancy JS, Abbattista A, Martini JF, Chen J, Peltz G, Thurm H, Ou SI, Shaw AT. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018 Dec;19(12):1654-1667. Epub 2018 Nov 6. Erratum in: Lancet Oncol. 2019 Jan;20(1):e10. link to original article PubMed
   2. PRO analysis: Peters S, Shaw AT, Besse B, Felip E, Solomon BJ, Soo RA, Bearz A, Gadgeel SM, Lin CC, Kao S, Seto T, Masters ET, Abbattista A, Clancy JS, Thurm H, Reisman A, Peltz G, Ross Camidge D. Impact of lorlatinib on patient-reported outcomes in patients with advanced ALK-positive or ROS1-positive non-small cell lung cancer. Lung Cancer. 2020 Jun;144:10-19. Epub 2020 Mar 10. link to original article PubMed

Pemetrexed monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shaw et al. 2017 (ASCEND-5)	2013-2015	Phase 3 (C)	Ceritinib	Inferior PFS
Novello et al. 2018 (ALUR)	2015-2018	Phase 3 (C)	Alectinib	Inferior PFS1

¹Reported efficacy for ALUR is based on the 2022 update.

Biomarker eligibility criteria

• Biomarker: ALK Fusion Gene Rearrangement
• Diagnostics: FISH or IHC

Chemotherapy

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

Supportive therapy

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

21-day cycles

References

1. ASCEND-5: Shaw AT, Kim TM, Crinò L, Gridelli C, Kiura K, Liu G, Novello S, Bearz A, Gautschi O, Mok T, Nishio M, Scagliotti G, Spigel DR, Deudon S, Zheng C, Pantano S, Urban P, Massacesi C, Viraswami-Appanna K, Felip E. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):874-886. Epub 2017 Jun 9. link to original articlecontains dosing details in abstractPubMed NCT01828112
2. ALUR: Novello S, Mazières J, Oh IJ, de Castro J, Migliorino MR, Helland Å, Dziadziuszko R, Griesinger F, Kotb A, Zeaiter A, Cardona A, Balas B, Johannsdottir HK, Das-Gupta A, Wolf J. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol. 2018 Jun 1;29(6):1409-1416. link to original article link to PMC article contains dosing details in abstract PubMed NCT02604342
   1. Update: Wolf J, Helland Å, Oh IJ, Migliorino MR, Dziadziuszko R, Wrona A, de Castro J, Mazieres J, Griesinger F, Chlistalla M, Cardona A, Ruf T, Trunzer K, Smoljanovic V, Novello S. Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer. ESMO Open. 2022 Feb;7(1):100333. Epub 2022 Jan 15. link to original article link to PMC article PubMed