1384P - Phase II study of cabozantinib in patients with MET-altered lung cancers

Background

MET alterations occur in about 5% of lung cancers and define a subgroup associated with sensitivity to MET tyrosine kinase inhibitors (TKIs). Only type I MET TKIs have been approved for these patients. In contrast, cabozantinib is a type II multikinase inhibitor with activity against MET.

Methods

In this single-arm phase 2 trial, patients (pts) with stage IV MET-altered lung cancers received cabozantinib 60 mg daily until progressive disease or intolerable toxicity. A Simon two-stage minimax design was used. If at least 2 responses were observed among 16 evaluable pts, the trial would proceed to the 25-patient second stage. The primary endpoint was objective response rate (ORR).

Results

The target of 25 pts was met. Among pts evaluable to date, 19 pts (79%; 19/24) had a MET exon 14 alteration only (skipping mutation, n=17; MET fusion with exon 14 exclusion, n=2), 2 pts (8%) had MET amplification only, and 3 pts (12%) had a concurrent MET exon 14 alteration and MET amplification. In cases with available tissue, FACETS confirmed MET amplification (≥6 copies), and MET immunohistochemistry was diffusely positive (>50%) in all cases. Most pts (84%, 20/24) received a prior MET TKI (crizotinib, n=15; capmatinib, n=4; tepotinib, n=1); 16 pts (67%) and 13 pts (54%) received one or more prior lines of chemotherapy and immunotherapy, respectively. The ORR was 17% (4/24; 95% CI 6.8-35.8%; MET skipping mutation, n=3; concurrent MET skipping mutation and MET amplification, n=1) and the disease control rate was 71% (95% CI 50.8-85.1%; partial response, n=4; stable disease, n=13, one with MET D1228N). Of the 4 pts with a partial response, 2 had received crizotinib and 1 capmatinib. The median progression-free survival was 6 months (95% CI 3.9-8.8 months), and the median overall survival was 9 months (95% CI 4.0-13.5 months). The most frequent treatment-related adverse events were grade 1 and 2 palmar-plantar erythrodysesthesia (42%), fatigue (38%), and diarrhea (38%).

Conclusions

Cabozantinib was active in MET-dependent cancers. Due to its alternative type II binding mode, cabozantinib can be useful in the treatment of type I TKI resistance. As proof of concept, 3 of 4 responses were observed in patients with type I MET TKI progression.

Clinical trial identification

NCT01639508.

Editorial acknowledgement

Legal entity responsible for the study

Memorial Sloan Kettering Cancer Center.

Funding

Exelixis.

Disclosure

G. Harada: Financial Interests, Advisory Board: AstraZeneca, MSD, Lilly; Financial Interests, Speaker’s Bureau: Bayer, Merck. F.C. Santini: Financial Interests, Steering Committee Member: Lilly. M.G. Kris: Financial Interests, Other: BerGenBio, Merus, Pfizer, Daiichi Sankyo, AstraZeneca. A. Drilon: Financial Interests, Personal, Advisory Board: 14ner/Elevation Oncology, AbbVie, Amgen, ArcherDX, AstraZeneca, BeiGene, BerGenBio, Blueprint Medicines, EcoR1, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Liberum, Loxo/Bayer/Lilly, Melendi, Monopteros, Monte Rosa, Novartis, Pfizer, Remedica Ltd., TP Therapeutics, Takeda/Ariad/Millennium, Tyra Biosciences, Verastem Oncology; Financial Interests, Personal, Other, CME: AiCME, Clinical Care Options, MJH Life Sciences, Med Learning, Medscape, Medscape, Onclive, Paradigm Medical Communications, PeerView Institute, PeerVoice, Physicians Education Resources, Targeted Oncology, WebMD; Financial Interests, Personal, Other, Consulting: Applied Pharmaceutical Science, Inc, EPG Health, Entos, Harborside Nexus, Merus, Nuvalent, Ology, Prelude, TouchIME, Treeline Bio, mBrace; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, RV More, Remedica Ltd; Financial Interests, Personal, Other, stocks: mBrace; Financial Interests, Personal, Stocks/Shares: Treeline Biosciences; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, PharmaMar, GSK, Teva, Taiho; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Member: ASCO, AACR, IASLC; Other, Food/Beverage: Merck, Puma, Merus; Other: Boehringer Ingelheim. All other authors have declared no conflicts of interest.