Non-small cell lung cancer, ROS1-positive

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Note: these are regimens tested in biomarker-specific populations, please see the main NSCLC page for other regimens.
There are several related dedicated pages:
*Histology-specific:
**NSCLC, Nonsquamous
**NSCLC, Squamous
*Site-specific:
**NSCLC, CNS metastases
Last updated on 2024-07-23:6 regimens on this page
8 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 EuroPMC
==ESMO==
*2024: Lee et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with oncogene-addicted metastatic non-small-cell lung cancer EuroPMC
*2023: Hendriks et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Non-Small Cell Lung Cancer.
=Advanced or metastatic disease, ROS1 inhibitor-naive=
==Ceritinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence	Efficacy
Lim et al. 2017	2013-06-07 to 2016-02-01	Phase 2 	ORR: 67% (95% CI, 48-81)
====Targeted therapy====
*Ceritinib (Zykadia) 750 mg PO once per day on days 1 to 28, taken on an empty stomach
28-day cycles
===References===
# Lim SM, Kim HR, Lee JS, Lee KH, Lee YG, Min YJ, Cho EK, Lee SS, Kim BS, Choi MY, Shim HS, Chung JH, La Choi Y, Lee MJ, Kim M, Kim JH, Ali SM, Ahn MJ, Cho BC. Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol. 2017 Aug 10;35(23):2613-2618. Epub 2017 May 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01964157
==Crizotinib monotherapy==
===Regimen variant #1, standard-dose===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Efficacy
Shaw et al. 2014 (PROFILE 1001 ROS1)	2010-2013 	Phase 1 (RT)	ORR: 72% (95% CI, 58-84)
Note: this was an expansion cohort of a phase 1 study.
====Targeted therapy====
*Crizotinib (Xalkori) 250 mg PO twice per day on days 1 to 28
28-day cycles
===Regimen variant #2, 200 mg twice per 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, 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
===References===
# PROFILE 1001 ROS1: Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, Iafrate AJ. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Nov 20;371(21):1963-71. Epub 2014 Sep 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00585195
##Update: Shaw AT, Riely GJ, Bang YJ, Kim DW, Camidge DR, Solomon BJ, Varella-Garcia M, Iafrate AJ, Shapiro GI, Usari T, Wang SC, Wilner KD, Clark JW, Ou SI. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol. 2019 Jul 1;30(7):1121-1126. link to original article link to PMC article EuroPMC
==Entrectinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Drilon et al. 2017 (ALKA-372-001)	2012-2018 	Phase 1 (RT)
Drilon et al. 2017 (STARTRK-1) 	2012-2018 	Phase 1 (RT)
Note: this is the MTD used in the phase 2 portion; it is also the FDA-recommended dose for adults.
====Targeted therapy====
*Entrectinib (Rozlytrek) 600 mg PO once per day on days 1 to 28
28-day cycles
===References===
# ALKA-372-001: Drilon A, Siena S, Ou SI, Patel M, Ahn MJ, Lee J, Bauer TM, Farago AF, Wheler JJ, Liu SV, Doebele R, Giannetta L, Cerea G, Marrapese G, Schirru M, Amatu A, Bencardino K, Palmeri L, Sartore-Bianchi A, Vanzulli A, Cresta S, Damian S, Duca M, Ardini E, Li G, Christiansen J, Kowalski K, Johnson AD, Patel R, Luo D, Chow-Maneval E, Hornby Z, Multani PS, Shaw AT, De Braud FG. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017 Apr;7(4):400-409. Epub 2017 Feb 9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2012-000148-88
##Pooled update: Drilon A, Siena S, Dziadziuszko R, Barlesi F, Krebs MG, Shaw AT, de Braud F, Rolfo C, Ahn MJ, Wolf J, Seto T, Cho BC, Patel MR, Chiu CH, John T, Goto K, Karapetis CS, Arkenau HT, Kim SW, Ohe Y, Li YC, Chae YK, Chung CH, Otterson GA, Murakami H, Lin CC, Tan DSW, Prenen H, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Doebele RC; trial investigators. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb;21(2):261-270. Epub 2019 Dec 11. Erratum in: Lancet Oncol. 2020 Feb;21(2):e70. Erratum in: Lancet Oncol. 2020 Jul;21(7):e341. link to original article link to PMC article EuroPMC
##Pooled update: Dziadziuszko R, Krebs MG, De Braud F, Siena S, Drilon A, Doebele RC, Patel MR, Cho BC, Liu SV, Ahn MJ, Chiu CH, Farago AF, Lin CC, Karapetis CS, Li YC, Day BM, Chen D, Wilson TR, Barlesi F. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2021 Apr 10;39(11):1253-1263. Epub 2021 Mar 1. link to original article link to PMC article EuroPMC
# STARTRK-1: Drilon A, Siena S, Ou SI, Patel M, Ahn MJ, Lee J, Bauer TM, Farago AF, Wheler JJ, Liu SV, Doebele R, Giannetta L, Cerea G, Marrapese G, Schirru M, Amatu A, Bencardino K, Palmeri L, Sartore-Bianchi A, Vanzulli A, Cresta S, Damian S, Duca M, Ardini E, Li G, Christiansen J, Kowalski K, Johnson AD, Patel R, Luo D, Chow-Maneval E, Hornby Z, Multani PS, Shaw AT, De Braud FG. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017 Apr;7(4):400-409. Epub 2017 Feb 9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02097810
##Pooled update: Drilon A, Siena S, Dziadziuszko R, Barlesi F, Krebs MG, Shaw AT, de Braud F, Rolfo C, Ahn MJ, Wolf J, Seto T, Cho BC, Patel MR, Chiu CH, John T, Goto K, Karapetis CS, Arkenau HT, Kim SW, Ohe Y, Li YC, Chae YK, Chung CH, Otterson GA, Murakami H, Lin CC, Tan DSW, Prenen H, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Doebele RC; trial investigators. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb;21(2):261-270. Epub 2019 Dec 11. Erratum in: Lancet Oncol. 2020 Feb;21(2):e70. Erratum in: Lancet Oncol. 2020 Jul;21(7):e341. link to original article link to PMC article EuroPMC
##Pooled update: Dziadziuszko R, Krebs MG, De Braud F, Siena S, Drilon A, Doebele RC, Patel MR, Cho BC, Liu SV, Ahn MJ, Chiu CH, Farago AF, Lin CC, Karapetis CS, Li YC, Day BM, Chen D, Wilson TR, Barlesi F. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2021 Apr 10;39(11):1253-1263. Epub 2021 Mar 1. link to original article link to PMC article EuroPMC
==Repotrectinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence
Drilon et al. 2024 (TRIDENT-1)	2017-02-27 to 2022-12-19	Phase 1/2 (RT)
====Targeted therapy====
*Repotrectinib (Augtyro) as follows:
**Cycle 1: 160 mg PO once per day on days 1 to 14, then 160 mg PO twice per day on days 15 to 28
**Cycle 2 onwards: 160 mg PO twice per day on days 1 to 28
28-day cycles
===References===
#TRIDENT-1: Drilon A, Camidge DR, Lin JJ, Kim SW, Solomon BJ, Dziadziuszko R, Besse B, Goto K, de Langen AJ, Wolf J, Lee KH, Popat S, Springfeld C, Nagasaka M, Felip E, Yang N, Velcheti V, Lu S, Kao S, Dooms C, Krebs MG, Yao W, Beg MS, Hu X, Moro-Sibilot D, Cheema P, Stopatschinskaja S, Mehta M, Trone D, Graber A, Sims G, Yuan Y, Cho BC; TRIDENT-1 Investigators. Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024 Jan 11;390(2):118-131. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03093116
=Advanced or metastatic disease, ROS1 inhibitor-exposed=
==Lorlatinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Shaw et al. 2017 (B7461001)	2014-2016 	Phase 1/2
====Targeted therapy====
*Lorlatinib (Lorbrena) 100 mg PO once per day on days 1 to 28
28-day cycles
===References===
# 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 dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT01970865
##Update: Shaw AT, Solomon BJ, Chiari R, Riely GJ, Besse B, Soo RA, Kao S, Lin CC, Bauer TM, Clancy JS, Thurm H, Martini JF, Peltz G, Abbattista A, Li S, Ou SI. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2019 Dec;20(12):1691-1701. Epub 2019 Oct 25. link to original article EuroPMC
==Repotrectinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence
Drilon et al. 2024 (TRIDENT-1)	2017-02-27 to 2022-12-19	Phase 1/2 (RT)
====Targeted therapy====
*Repotrectinib (Augtyro) as follows:
**Cycle 1: 160 mg PO once per day on days 1 to 14, then 160 mg PO twice per day on days 15 to 28
**Cycle 2 onwards: 160 mg PO twice per day on days 1 to 28
28-day cycles
===References===
#TRIDENT-1: Drilon A, Camidge DR, Lin JJ, Kim SW, Solomon BJ, Dziadziuszko R, Besse B, Goto K, de Langen AJ, Wolf J, Lee KH, Popat S, Springfeld C, Nagasaka M, Felip E, Yang N, Velcheti V, Lu S, Kao S, Dooms C, Krebs MG, Yao W, Beg MS, Hu X, Moro-Sibilot D, Cheema P, Stopatschinskaja S, Mehta M, Trone D, Graber A, Sims G, Yuan Y, Cho BC; TRIDENT-1 Investigators. Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024 Jan 11;390(2):118-131. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03093116
=Additional resources=
*The ROS1ders
Category:Non-small cell lung cancer regimens
Category:Biomarker-specific pages
Category:Non-small cell lung cancers