Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer

Abstract

Purpose: Genetic rearrangements of the tyrosine receptor kinase ROS proto-oncogene 1 (ROS1) are oncogenic drivers in non-small-cell lung cancer (NSCLC). We report the results of an updated integrated analysis of three phase I or II clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2) of the ROS1 tyrosine kinase inhibitor, entrectinib, in ROS1 fusion-positive NSCLC.

Methods: The efficacy-evaluable population included adults with locally advanced or metastatic ROS1 fusion-positive NSCLC with or without CNS metastases who received entrectinib ≥ 600 mg orally once per day. Co-primary end points were objective response rate (ORR) assessed by blinded independent central review and duration of response (DoR). Secondary end points included progression-free survival (PFS), overall survival (OS), intracranial ORR, intracranial DoR, intracranial PFS, and safety.

Results: In total, 161 patients with a follow-up of ≥ 6 months were evaluable. The median treatment duration was 10.7 months (IQR, 6.4-17.7). The ORR was 67.1% (n = 108, 95% CI, 59.3 to 74.3), and responses were durable (12-month DoR rate, 63%, median DoR 15.7 months). The 12-month PFS rate was 55% (median PFS 15.7 months), and the 12-month OS rate was 81% (median OS not estimable). In 24 patients with measurable baseline CNS metastases by blinded independent central review, the intracranial ORR was 79.2% (n = 19; 95% CI, 57.9 to 92.9), the median intracranial PFS was 12.0 months (95% CI, 6.2 to 19.3), and the median intracranial DoR was 12.9 months (12-month rate, 55%). The safety profile in this updated analysis was similar to that reported in the primary analysis, and no new safety signals were found.

Conclusion: Entrectinib continued to demonstrate a high level of clinical benefit for patients with ROS1 fusion-positive NSCLC, including patients with CNS metastases.

Trial registration: ClinicalTrials.gov NCT02097810 NCT02568267.

Conflict of interest statement

Rafal DziadziuszkoHonoraria: Roche/Genentech, Novartis, Pfizer, Bristol-Myers Squibb, Takeda, AstraZeneca, MSD Oncology, Boehringer Ingelheim, Seattle GeneticsTravel, Accommodations, Expenses: Roche, AstraZeneca Matthew G. KrebsHonoraria: RocheConsulting or Advisory Role: Roche, Achilles Therapeutics, Janssen, Seattle Genetics, OM Pharmaceutical Industries, BayerSpeakers' Bureau: RocheResearch Funding: RocheTravel, Accommodations, Expenses: AstraZeneca, BerGenBio, Immutep Filippo De BraudHonoraria: Roche, Pfizer, Bristol-Myers Squibb, Merck, MSD, Servier, Sanofi, RocheConsulting or Advisory Role: Incyte, Teofarma, EMD Serono, Bristol-Myers Squibb, Nerviano Medical Sciences, Sanofi, Novartis ItalyResearch Funding: Novartis, Roche, Merck Serono, Pfizer, Servier, Philogen, Loxo, Tesaro, Nerviano Medical Sciences, Kymab Salvatore SienaStock and Other Ownership Interests: Guardant Health, Myriad GeneticsConsulting or Advisory Role: Amgen, Roche/Genentech, Bayer, Bristol-Myers Squibb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Seattle Genetics, CheckmAbPatents, Royalties, Other Intellectual Property: AmgenTravel, Accommodations, Expenses: Amgen, Bayer, Roche Alexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicans' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerviewConsulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, Abbvie, 14ner/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare TherapeuticsResearch Funding: Foundation MedicinePatents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology)Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology Robert C. DoebeleEmployment: Rain TherapeuticsLeadership: Rain TherapeuticsStock and Other Ownership Interests: Rain TherapeuticsConsulting or Advisory Role: GreenPeptide, AstraZeneca, Roche/Genentech, Bayer, Takeda, Rain Therapeutics, Anchiano, Blueprint Medicines, Foundation MedicinePatents, Royalties, Other Intellectual Property: Licensing Fees from Abbott Molecular for Patent PCT/US2013/057495, Licensing fees for biologic materials from Genentech, Licensing fees for patent from Rain Therapeutics, Licensing fees for biologic materials from Foundation Medicine, Licensing fees for biologic materials from Black Diamond, Licensing fees for biologic materials from Pearl River, licensing fees for biologic materials from VoronoiTravel, Accommodations, Expenses: Rain Therapeutics, Roche/Genentech Manish R. PatelConsulting or Advisory Role: NektarResearch Funding: Merck KGaA, AstraZeneca, Fate Therapeutics, Vyriad Byoung Chul ChoLeadership: Gencurix, Interpark BioStock and Other Ownership Interests: Theravance, Gencurix, Bridgebio, Kanaph Therapeutics, Cyrus Therapeutics, Interpark BioConsulting or Advisory Role: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Yuhan, Pfizer, Janssen, Takeda, MSD, Ono Pharmaceutical, Lilly, Medpacto, Blueprint Medicines, Kanaph Therapeutics, Bridgebio, Cyrus Therapeutics, Guardant Health, Joseah BIOResearch Funding: Novartis, Bayer, AstraZeneca, Mogam Biotechnology Research Institue, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Abbvie, Medpacto, GI Innovation, Lilly, Blueprint Medicines, Interpark BioPatents, Royalties, Other Intellectual Property: Champions OncologyOther Relationship: DAAN Biotherapeutics Stephen V. LiuConsulting or Advisory Role: Genentech, Pfizer, Lilly, Bristol-Myers Squibb, AstraZeneca, Takeda, Regeneron, Apollomics, G1 Therapeutics, Guardant Health, Janssen Oncology, Roche, MSD Oncology, Jazz Pharmaceuticals, Blueprint Medicines, Inivata, PharmaMar, Daiichi Sankyo/UCB Japan, BeiGeneResearch Funding: Genentech/Roche, Pfizer, Corvus Pharmaceuticals, Bayer, Merck, Lycera, AstraZeneca, Molecular Partners, Blueprint Medicines, Lilly, Rain Therapeutics, Alkermes, Bristol-Myers Squibb, Turning Point Therapeutics, RAPT, Spectrum PharmaceuticalsTravel, Accommodations, Expenses: AstraZeneca, Roche/Genentech, MSD Oncology Myung-Ju AhnHonoraria: AstraZeneca, Lilly, MSD, TakedaConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Lilly, Takeda, Alpha Pharmaceutical Chao-Hua ChiuHonoraria: AstraZeneca/MedImmune, Boehringer Ingelheim, Roche, Novartis, Chugai Pharma, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Lilly, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono PharmaceuticalConsulting or Advisory Role: AstraZeneca/MedImmune, MSD, Novartis, Chugai Pharma, LillySpeakers' Bureau: AstraZeneca, Boehringer Ingelheimm, Roche, Novartis, Chugai Pharma, Bristol-Myers Squibb, MSD Anna F. FaragoEmployment: NovartisHonoraria: Clinical Care Options, Medscape, Peerview, Research to PracticeConsulting or Advisory Role: Abbvie, Loxo, Genentech/Roche, Bayer, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Pfizer, H3 BiomedicineResearch Funding: PharmaMar, Abbvie, AstraZeneca, Bristol-Myers Squibb, Merck, Loxo, Ignyta, Amgen, Genentech/Roche, Bayer, LillyTravel, Accommodations, Expenses: Abbvie, Bayer, Loxo, Genentech/Roche, AstraZeneca, Boehringer Ingelheim, Merck, Bristol-Myers Squibb, Peerview, Medscape Chia-Chi LinHonoraria: Novartis, Roche, Daiichi Sankyo, LillyConsulting or Advisory Role: Novartis, Boehringer Ingelheim, Blueprint Medicines, Daiichi SankyoTravel, Accommodations, Expenses: Lilly, Daiichi Sankyo, BeiGene, Novartis, Daiichi Sankyo Christos S. KarapetisHonoraria: Roche, ServierConsulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb, Roche, EisaiTravel, Accommodations, Expenses: AstraZeneca Yu-Chung LiHonoraria: Bayer, AstraZeneca, Takeda, Novartis, Lilly, MSD, RocheResearch Funding: RocheTravel, Accommodations, Expenses: MundiPharma, Taiho Pharmaceutical, MSD, Roche, Eisai, Boehringer Ingelheim, Sanomics Limited Bann-mo DayEmployment: GenentechStock and Other Ownership Interests: GenentechResearch Funding: GenentechTravel, Accommodations, Expenses: Genentech David ChenEmployment: Genentech, AmgenStock and Other Ownership Interests: Genentech, AmgenTravel, Accommodations, Expenses: Genentech, Amgen Timothy R. WilsonEmployment: GenentechStock and Other Ownership Interests: RochePatents, Royalties, Other Intellectual Property: Methods of treatment with Taselisib Fabrice BarlesiHonoraria: Genentech/Roche, Pfizer, Pierre Fabre, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Novartis, Pierre Fabre, Merck Serono, MSD Oncology, Takeda, BayerConsulting or Advisory Role: Roche/Genentech, Pfizer, Novartis, Pierre Fabre, Bristol-Myers Squibb, AstraZeneca/MedImmune, Boehringer Ingelheim, Lilly, Merck Serono, MSD Oncology, Takeda, BayerResearch Funding: Roche/Genentech, AstraZeneca/MedImmune, Bristol-Myers Squibb, Pierre Fabre, Abbvie, Amgen, Bayer, Boehringer Ingelheim, Eisai, Lilly, Ipsen, Innate Pharma, Novartis, Merck Serono, MSD Oncology, Pfizer, Sanofi/Aventis, TakedaPatents, Royalties, Other Intellectual Property: Roche/Genentech, Bristol-Myers Squibb, AstraZeneca/MedImmune, MSD OncologyNo other potential conflicts of interest were reported.

Figures

FIG 1.

Waterfall plots of best response to entrectinib in patients with ROS proto-oncogene 1 (ROS1) fusion–positive lung cancers, shown as the maximum percent improvement in the sum of longest diameters of identified target lesions compared with baseline, as assessed by BICR: (A) the efficacy-evaluable population (patients without measurable disease were excluded); (B) patients with and without CNS metastases at baseline (investigator assessed); and (C) best intracranial responses in patients with measurable CNS metastases at baseline (BICR assessed). BICR, blinded independent central review; CR, complete response; ND, not determined; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease; SLD, sum of longest diameter.

FIG 2.

Time-to-event analyses for (A) duration of response; (B) progression-free survival; (C) time to CNS progression (deaths censored) in all patients (blue) and in patients with (gray) or without (red) baseline CNS metastases by investigator assessment; and (D) overall survival, in patients with ROS1 fusion–positive non–small-cell lung cancer (N = 161). For patients without CNS metastases at baseline, CNS progressive disease was detected either through scans triggered by symptoms suggestive of CNS disease or scans performed routinely at the investigator's discretion, since brain scans were not mandated by the protocol.