Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial

Abstract

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.

Conflict of interest statement

Mansfield: Direct research funding: Novartis, and Verily; Honoraria to institution for participation in advisory boards: AbbVie, BeiGene, BMS, Genentech, Inc., Janssen; Travel support: Roche, and non-remunerated member of the Mesothelioma Applied Research Foundation Board of Directors. Forde: Consultant/Advisory boards: Abbvie, AstraZeneca, BMS, Janssen. Research Funding (to institution): AstraZeneca, BMS. Dr. Shaw has served as a compensated consultant or received honoraria from Achilles, Archer, Ariad/Takeda, Bayer, Blueprint Medicines, Chugai, Daiichi-Sankyo, EMD Serono, Foundation Medicine, Guardant, Ignyta, KSQ Therapeutics, Loxo Oncology, Natera, Novartis, Pfizer, Roche-Genentech, Servier, Syros, Taiho Pharmaceutical, and TP Therapeutics; received institutional research funding from Ariad, Ignyta, Novartis, Pfizer, Roche-Genentech, and TP Therapeutics; received travel support from Genentech and Pfizer, and is currently employed by and owns stock in Novartis. Drilon: Honoraria/Advisory Boards: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi; Research to Institution: Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar; Royalties: Wolters Kluwer; OTHER: Merck, Puma, Merus, Boehringer Ingelheim. Hovelson: Equity holder and employee of Strata Oncology. Tomlins: Equity holder and employee of Strata Oncology. Named as co-inventors on a patent issued to Strata Oncology related to MSI status assessment. Named as co-inventor and included in royalty streams for a patent issued to the University of Michigan regarding ETS fusions in prostate cancer that has been licensed to Hologic/Gen-Probe (sublicensed to Ventana Medical Systems) and LynxDx. Equity holder in Javelin Oncology. Previously served as a consultant to Strata Oncology and has consulted for Astellas/Medivation and Janssen. He has received research (to the University of Michigan) funding from Astellas and has received travel support from the Prostate Cancer Foundation. Hamilton: Consultant/Advisory Boards: Merck, Incyte, Bristol Myers Squibb, GSK, Loxo, Roche, Thermo Fisher Scientific, illmina, HalioDx. Research Funding to Institution: Guardant Health, CME: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences. Arteaga: reported receiving grants from Lilly, Pfizer, and Takeda; serving in an expert advisory role to Novartis, Lilly, Immunomedics, Merck, Daiichi Sankyo, Taiho Oncology, AstraZeneca, and OrigiMed outside the submitted work; holding minor stock options in Y-TRAP and Provista, and serving in the Scientific Advisory Board of the Susan G. Komen Foundation. All remaining authors have declared no conflicts of interest.

© 2022. The Author(s).

Figures

Fig. 1. Waterfall and Swimmer plot of responses and their durations.

The waterfall plot shows responses for all patients who had response assessment (An = 7). One patient on subprotocol G (ROS1) is not included as treatment was discontinued during cycle one for toxicity and response was not evaluable. The Swimmer plot shows the duration of responses for all patients (Bn = 8). CR complete responses, PD progressive disease, PR partial response.

Fig. 2. Progression-free and overall survival for both sub-protocols.

The PFS A and OS B are presented for both ALK (EAY131-F) and ROS1 (EAY131-G) sub-protocols.

Fig. 3. Fusion partners for ALK and ROS1 in the expanded molecular cohort.

The most common fusion partners are shown for ALK and ROS1 from the expanded molecular cohort.