Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2
Authors: F. Barlesi, A. Drilon, F. De Braud, B.C. Cho, M.J. Ahn, S. Siena, M.G. Krebs, C.C. Lin, T. John, D.S.W. Tan, T. Seto, R. Dziadziuszko, H.-T. Arkenau, C. Rolfo, J. Wolf, C. Ye, T. Riehl, S. Eng, R.C. Doebele
Journal: Annals of Oncology (2019)

Background: Entrectinib is a potent ROS1 inhibitor (as well as TRKA/B/C), designed to effectively penetrate the central nervous system (CNS); brain metastases are common in patients (pts) with advanced ROS1 fusion-positive NSCLC. Entrectinib achieves therapeutic levels in the CNS with antitumour activity in multiple intracranial tumour models. We present updated integrated safety and efficacy data from three Phase 1/2 entrectinib studies (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]) in pts with locally advanced/metastatic ROS1 fusion-positive NSCLC. Methods: The analysis included pts with ROS1 inhibitor-naïve NSCLC harbouring a ROS1 fusion identified via nucleic acid-based diagnostic platforms. The ROS1 safety-evaluable population included pts who received ≥1 dose of entrectinib; the integrated efficacy analysis included pts with at least 6 months of follow-up. Tumour assessments were done at wk 4 and then every 8 wks by blinded independent central review (BICR), using RECIST v1.1. Primary endpoints by BICR: overall response rate (ORR), duration of response (DOR). Key secondary endpoints: progression-free survival (PFS), safety. Additional endpoints: intracranial ORR (complete/partial response), DOR in pts with intracranial response, PFS in pts with or without baseline CNS disease. Results: In the ROS1 safety-evaluable population (n = 134), at least one treatment-related AE (TRAE) of any grade was seen in 93% of pts. Pts with at least one TRAE by highest grade were: grade 1/2, 59%; grade 3, 31%; grade 4, 4%. There were no grade 5 TRAEs. TRAEs led to dose reduction or discontinuation in 34% and 5% of pts, respectively. Efficacy outcomes are summarised in the table.Table109OBaseline characteristicsPts with treatment-naïve, ROS1-positive NSCLC (n = 53)Median age range53 years 27–73 yearsGender male female36% 64%Smoking status never smoked former/current smoker59% 42%Efficacy outcomesORR (BICR)77% (95% CI 64–88) 3 CR 38 PRMedian DOR (BICR)25 months (95% CI 11–35)Median PFS (BICR)APts with measurable CNS disease at baseline per Investigator, without CNS disease (n = 30) with CNS disease (n = 23)26 months (95% CI 16–37) 14 months (95% CI 5–NR)Intracranial ORR (n = 20)BPts with measurable CNS disease at baseline per BICR,55% (95% CI 32–77) 4 CR 7 PRMedian intracranial DOR (n = 11)CIn pts with an intracranial response13 months (95% CI 6–NR)BICR, blinded independent central review; CNS, central nervous system; CR, complete response, DOR, duration of response; NR, not reached; ORR, overall response rate; PFS, progression-free survival; PR, partial responseA Pts with measurable CNS disease at baseline per Investigator,B Pts with measurable CNS disease at baseline per BICR,C In pts with an intracranial response Open table in a new tab BICR, blinded independent central review; CNS, central nervous system; CR, complete response, DOR, duration of response; NR, not reached; ORR, overall response rate; PFS, progression-free survival; PR, partial response Conclusions: Entrectinib is highly active in pts with ROS1 fusion-positive NSCLC, including pts with CNS disease. Entrectinib is well tolerated with a manageable safety profile. Clinical trial identification: ALKA-372-001 = EudraCT 2012-000148-88 – start date: 2015, trials ongoing STARTRK-1= NCT02097810 – start date: 2014, active, not recruiting (last update 2018) STARTRK-2 = NCT02568267 – start date: 2015, recruiting (last update 2018). Editorial acknowledgement: Medical writing and editorial support provided by Charlotte Kennerley PhD of Gardiner-Caldwell Communications, Ashfield Healthcare Communications and was sponsored by Roche in accordance with Good Publication Practice guidelines. Legal entity responsible for the study: F. Hoffmann-La Roche. Funding: Ignyta, Inc., a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. Disclosure: F. Barlesi: Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Clovis Oncology, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, Takeda. A. Drilon: Advisory boards: Bayer, Ignyta, Loxo Oncology, Pfizer, Roche/Genentech, TP Therapeutics; Research funding: Loxo Oncology. F. De Braud: Advisory boards: Novartis, Roche/Genetech, Merk Serono, Bristol-Myers Squibb, GlaxoSmithKline, BMS, Celgene, Servier, Ignyta, Pfizer, MSD, Philogen, AstraZeneca, Boehringer Ingelheim, Sanofi Aventis, Giscad, Italfarmaco, Eli Lilly, Amgen, Nadirex. S. Siena: Advisory boards: Amgen, Bayer, BMS, CheckmAb, Celgene, Incyte, Merck, Novartis, Roche and Seattle Genetics. M.G. Krebs: Honoraria for Advisory boards: Roche, Janssen, Octimet, Achilles therapeutics; Travel grants: AstraZeneca. C.C. Lin: Honoraria: AstraZeneca, BeiGene, Daiichi Sankyo, Novartis, Roche; Advisory boards: Blueprint, Boehringer Ingelheim, Novartis. T. John: Advisory boards: BMS, AstraZeneca, Boehringer, Takeda, Pfizer, Novartis, Merck, Ignyta, Roche. D.S.W. Tan: Grants and honoraria for Advisory boards: Novartis, Bayer, Boehringer Ingelheim, Merck, AstraZeneca, BMS, Roche, Pfizer and grants from GSK, Novartis, AstraZeneca. T. Seto: Honoraria/research: Astellas, AZ, Bayer, BMS, Chugai, Daiichi Sankyo, Eisai, EliLilly, Kissei, Kyowa HakkoKirin, MerckSerono, Mochida, MSD, Nippon, Novartis, BI, NipponKayakuOno, Pfizer, Roche, Sanofi, ShowaYakuhinKako, Taiho, Takeda, YakultHonsha, Verastem. R. Dziadziuszko: Honoraria, consulting fees: Roche, Pfizer, Boehringer Ingelheim, Clovis Oncology, Novartis, AstraZeneca, Tesaro. H-T. Arkenau: Employee: HCA; Advisory boards: Beigene, Guardant Health, Bicycle. C. Rolfo: Honoraria, Advisory boards: Mylan, Novartis, MSD, GuardantHealth, AstraZeneca. J. Wolf: Corporate sponsored research: BMS, MSD, Novartis, Pfizer; Advisory boards: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Ignyta, Lilly MSD, Novartis, Pfizer, Roche. C. Ye, T. Riehl, S. Eng: Employee: Genentech. R.C. Doebele: Research: Ignyta; Advisory boards; Roche, Ignyta, Takeda, AstraZeneca, Bayer; Stock ownership: Rain Therapeutics; Patent or biological material licensing fees: Ignyta, Abbott Molecular, Rain Therapeutics. All other authors have declared no conflicts of interest.