Safety, Efficacy and Biomarker Analysis of Crizotinib in MET Mutated Non-Small Cell Lung Cancer - Results from the Drug Rediscovery Protocol

• Published in: Clinical cancer research pp. OF1 - OF10
• Main Authors: Verkerk, Karlijn, van der Wel, Tijmen J W T, Zeverijn, Laurien J, Geurts, Birgit S, Spiekman, Ilse A C, de Wit, Gijs F, Roepman, Paul, Jansen, Anne M L, van der Noort, Vincent, Smit, Egbert F, Hoeben, Ann, Hendriks, Lizza E L, Van den Heuvel, Michel M, Piet, Berber, Herder, Gerarda J M, Hashemi, Sayed M S, Gelderblom, Hans, Verheul, Henk M W, Voest, Emile E, de Langen, Adrianus J
• Format: Journal Article
• Language: English
• Published: United States 01-10-2024
• DOI: 10.1158/1078-0432.CCR-24-1925
• EISSN: 1557-3265
• ISSN: 1078-0432; 1557-3265

MET mutations occur in 3-4% of advanced non-small cell lung cancer (aNSCLC), correlating with poor survival. Despite known sensitivity of MET mutated (METmut) aNSCLC to c-MET-inhibition, no approved therapies existed until 2022.
In the Drug Rediscovery Protocol (NCT0295234), patients with an actionable molecular profile are treated with off-label registered drugs. Both treated and untreated patients with aNSCLC harboring MET exon 14 skipping (METex14) or other METmuts received crizotinib 250 mg BID until disease progression or intolerable toxicity. Primary endpoints were clinical benefit (CB: RECIST v1.1 confirmed partial response (PR), complete response (CR) or stable disease (SD) ≥16 weeks) and safety. Patients were enrolled using a Simon-like two-stage design, with eight patients in stage 1 and if ≥1/8 patients had CB, 24 patients in stage 2. Whole genome and RNA-sequencing were performed on baseline biopsies.
Between 09/2018 and 10/2022, 30 patients started treatment, and 24 were response-evaluable after completing ≥1 full treatment cycle. Two patients (8.3%) achieved CR, thirteen (54.2%) PR and two (8.3%) SD. The CB-rate was 70.8% (95%CI 48.9-87.4) and the objective response rate was 62.5% (95%CI 40.6-81.2). After 21.2 months median follow-up, median duration of response, progression-free and overall survival were 9.3 (95%CI 6.5-NA), 10.2 (95%CI 6.0-20.1) and 13.0 months (95%CI 9.0-NA), respectively. Twenty-three treatment-related grade ≥3 adverse events occurred in 12/30 patients (40%), causing treatment-discontinuation in three (10%). One patient (achieving CR) had a tyrosine kinase domain mutation (p.H1094Y), all other patients had METex14.
Crizotinib is a valuable treatment option in METmut aNSCLC.