Difference between revisions of "Non-small cell lung cancer, ALK-positive"

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====Biomarker Eligibility Criteria====
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*Biomarker: ALK Fusion Gene Rearrangement
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*Diagnostics: FISH or FDA-approved test
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====Chemotherapy====
 
====Chemotherapy====
 
*[[Ceritinib (Zykadia)]] 450 mg PO once per day with food
 
*[[Ceritinib (Zykadia)]] 450 mg PO once per day with food

Revision as of 23:51, 8 January 2020

Section editor
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 Travis Osterman, DO, MS
Vanderbilt University
Nashville, TN
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Note: these are regimens tested in biomarker-specific populations, please see the main NSCLC page for other regimens.

22 regimens on this page
27 variants on this page


Advanced or metastatic disease, ALK inhibitor-naive

Alectinib monotherapy

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Variant #1, 300 mg twice per day

Study Evidence Comparator Comparative Efficacy Years of study
Seto et al. 2013 (AF-001JP) Phase I/II 2010-2012
Hida et al. 2017 (J-ALEX) Phase III (E-switch-ic) Crizotinib Superior PFS 2013-2015

This is the PMDA-approved dose in Japan.

Biomarker Eligibility Criteria

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

Chemotherapy

Continued indefinitely

Variant #2, 600 mg twice per day

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy Years of study
Peters et al. 2017 (ALEX) Phase III (E-RT-switch-ic) Crizotinib Superior PFS 2014-2016
Zhou et al. 2019 (ALESIA) Phase III (E-switch-ic) Crizotinib Superior PFS 2016-2017

Biomarker Eligibility Criteria

  • Biomarker: ALK Fusion Gene Rearrangement
  • Diagnostics: IHC

Chemotherapy

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 verified protocol PubMed
    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 protocol PubMed
    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 SD 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 verified protocol PubMed
    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 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
  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 protocol PubMed

Brigatinib monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy Years of study
Camidge et al. 2018 (ALTA-1L) Phase III (E-switch-ic) Crizotinib Superior PFS 2016-2017

Biomarker Eligibility Criteria

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

Chemotherapy

  • Brigatinib (Alunbrig) as follows:
    • Lead-in: 90 mg PO once per day for 7 days
    • Subsequently: 180 mg PO once per day

Continued indefinitely

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 protocol PubMed

Carboplatin & Pemetrexed

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

Variant #1, 5/500 x 4

Study Evidence Comparator Comparative Efficacy Years of study
Soria et al. 2017 (ASCEND-4) Phase III (C) Ceritinib Inferior PFS 2013-2015

Biomarker Eligibility Criteria

  • Biomarker: ALK Fusion Gene Rearrangement
  • Diagnostics: IHC

Chemotherapy

Supportive medications

21-day cycle for up to 4 cycles

Subsequent treatment

Variant #2, 6/500 x 4

Study Evidence Comparator Comparative Efficacy Years of study
Soria et al. 2017 (ASCEND-4) Phase III (C) Ceritinib Inferior PFS 2013-2015

Biomarker Eligibility Criteria

  • Biomarker: ALK Fusion Gene Rearrangement
  • Diagnostics: IHC

Chemotherapy

Supportive medications

21-day cycle for up to 4 cycles

Subsequent treatment

References

  1. 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 protocol PubMed

Ceritinib monotherapy

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Variant #1, 450 mg/day with food

FDA-recommended dose
Study Evidence Comparator
Cho et al. 2017 (ASCEND-8) Randomized phase I (E-de-esc) Ceritinib; 750 mg/d

Biomarker Eligibility Criteria

  • Biomarker: ALK Fusion Gene Rearrangement
  • Diagnostics: IHC

Chemotherapy

Continued indefinitely

Variant #2, 750 mg/day fasting

Study Evidence Comparator Comparative Efficacy Years of study
Shaw et al. 2014 (ASCEND-1) Phase I, >20 pts in this dosing cohort (RT) NR-2012
Soria et al. 2017 (ASCEND-4) Phase III (E-RT-switch-ooc) 1. Carboplatin & Pemetrexed
2. Cisplatin & Pemetrexed 		Superior PFS 2013-2015
Cho et al. 2017 (ASCEND-8) Randomized phase I (C) Ceritinib; 450 mg/d Not reported 2015-2016

Biomarker Eligibility Criteria

  • Biomarker: ALK Fusion Gene Rearrangement
  • Diagnostics: IHC

Chemotherapy

21-day cycles

References

  1. Phase I: 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 link to PMC article PubMed
    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 protocol PubMed
  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 protocol PubMed

Cisplatin & Pemetrexed

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

Variant #2, 75/500

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy Years of study
Solomon et al. 2014 (PROFILE 1014) Phase III (C) Crizotinib Inferior PFS 2011-2013
Soria et al. 2017 (ASCEND-4) Phase III (C) Ceritinib Inferior PFS 2013-2015

Biomarker Eligibility Criteria Biomarker: ALK Fusion Gene Rearrangement Diagnostics: FISH or IHC

Chemotherapy

Supportive medications

21-day cycle for 4 to 6 cycles

Subsequent treatment

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 verified protocol PubMed
    1. Supgroup 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 protocol PubMed

Crizotinib monotherapy

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Variant #1, 250 mg/day

FDA-recommended dose

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

Chemotherapy

Continued indefinitely

Variant #2, 400 mg/day

FDA-recommended dose

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

Chemotherapy

Continued indefinitely

Variant #3, 500 mg/day

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy Years of study
Kwak et al. 2010 (PROFILE 1001) Phase I/II ORR: 57% 2008-2010
Shaw et al. 2013 (PROFILE 1007) Phase III (E-RT-switch-ooc) 1. Pemetrexed Superior PFS 2010-2012
2. Docetaxel Superior PFS
Solomon et al. 2014 (PROFILE 1014) Phase III (E-RT-switch-ooc) 1. Carboplatin & Pemetrexed
2. Cisplatin & Pemetrexed 		Superior PFS 2011-2013
Wu et al. 2018 (PROFILE 1029) Phase III (E-switch-ooc) 1. Carboplatin & Pemetrexed
2. Cisplatin & Pemetrexed 		Superior PFS 2012-2014
Hida et al. 2017 (J-ALEX) Phase III (C) Alectinib Inferior PFS 2013-2015
Peters et al. 2017 (ALEX) Phase III (C) Alectinib Inferior PFS 2014-2016
Camidge et al. 2018 (ALTA-1L) Phase III (C) Brigatinib Inferior PFS 2016-2017
Zhou et al. 2019 (ALESIA) Phase III (C) Alectinib Inferior PFS 2016-2017

Note: PROFILE 1007 used 21-day cycles, and crizotinib was similarly given 250 mg PO twice per day on all days.

Chemotherapy

28-day cycles

References

  1. PROFILE 1001: 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 link to PMC article 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 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 verified protocol PubMed
    1. 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 verified protocol PubMed
    1. Supgroup 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 protocol PubMed
    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 SD 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 verified protocol PubMed
    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 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
  7. 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 protocol PubMed
  8. 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 protocol PubMed
  9. 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 protocol PubMed

Docetaxel monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Shaw et al. 2013 (PROFILE 1007) Phase III (C) Crizotinib Inferior PFS

Biomarker Eligibility Criteria Biomarker: ALK Fusion Gene Rearrangement Diagnostics: FISH

Chemotherapy

Supportive medications

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 verified protocol PubMed
    1. 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

Pemetrexed monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Shaw et al. 2013 (PROFILE 1007) Phase III (C) Crizotinib Inferior PFS

Biomarker Eligibility Criteria

  • Biomarker: ALK Fusion Gene Rearrangement
  • Diagnostics: FISH

Chemotherapy

Supportive medications

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 verified protocol PubMed
    1. 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

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Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Ou et al. 2015 (NP28673) Phase II (RT) ORR: 50% (95% CI, 41-59)
Shaw et al. 2015 (NP28761) Phase II (RT) ORR: 48% (95% CI, 36–60)
Novello et al. 2018 (ALUR) Phase III (E-switch-ooc) Docetaxel
Pemetrexed 		Superior PFS

Biomarker Eligibility Criteria

  • Biomarker: ALK Fusion Gene Rearrangement
  • Diagnostics: FISH

Chemotherapy

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. link to original article contains verified protocol 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 protocol 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 protocol PubMed

Brigatinib monotherapy

Brigatinib (Alunbrig) for advanced or metastatic ALK-positive non-small cell lung cancer

Ceritinib monotherapy

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Variant #1, 450 mg/day with food

FDA-recommended dose
Study Evidence Comparator
Cho et al. 2017 (ASCEND-8) Randomized phase I (de-esc) Ceritinib; 750 mg/d

Biomarker Eligibility Criteria

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

Chemotherapy

Continued indefinitely

Variant #2, 750 mg/day fasting

Study Evidence Comparator Comparative Efficacy
Shaw et al. 2014 (ASCEND-1) Phase I, >20 pts in this dosing cohort (RT)
Shaw et al. 2017 (ASCEND-5) Phase III (E-switch-ooc) 1. Docetaxel
2. Pemetrexed 		Superior PFS
Cho et al. 2017 (ASCEND-8) Randomized phase I (C) Ceritinib; 450 mg/d Not reported

Chemotherapy

21-day cycles

References

  1. Phase I: 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 link to PMC article PubMed
    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 articlecontains protocolPubMed
  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 protocol PubMed

Docetaxel monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Shaw et al. 2017 (ASCEND-5) Phase III (C) Ceritinib Inferior PFS

Chemotherapy

Supportive medications

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 protocolPubMed
  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 PubMed

Lorlatinib monotherapy

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Regimen

FDA-recommended dose
Study Evidence
Shaw et al. 2017 (B7461001) Phase I, >20 pts in this subgroup (RT)

Chemotherapy

Continued indefinitely

References

  1. Phase 1: 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 protocol PubMed

Pemetrexed monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Shaw et al. 2017 (ASCEND-5) Phase III (C) Ceritinib Inferior PFS

Chemotherapy

Supportive medications

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 protocolPubMed
  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 PubMed
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