Phase 1b/2 study of capmatinib plus gefitinib in patients with EGFR-mutated, MET-dysregulated non-small cell lung cancer who received prior therapy: Final overall survival and safety.
Authors: Wu Yi-Long , Zhang Li , Kim Dong-Wan , Liu Xiaoqing , Lee Dae Ho , Yang James Chih-Hsin , Ahn Myung-Ju , Vansteenkiste Johan F. , Su Wu-Chou , Felip Enriqueta , Carbini Mariana , Glaser Sabine , Tanriverdi Oezlem , Chassot-Agostinho Andrea , Tan Daniel Shao-Weng 
Published: June 2021

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Background: Primary findings from the phase 1b/2 study (NCT01610336) demonstrated clinical activity of combination therapy with capmatinib, a potent and selective MET inhibitor, and gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in heavily pre-treated patients with EGFR-mutated and MET dysregulated non-small cell lung cancer (NSCLC). The objective response rate (ORR) was 27% in patients across phase 1b/2 of the study. At the recommended phase 2 dose (R2PD) of capmatinib 400 mg twice-daily (bid) and gefitinib 250 mg once-daily (qd), the ORR was 47% in patients with high MET-amplified tumors ( MET gene copy number ≥6). Here, we report the updated data on the efficacy and safety from the NCT01610336 study. Methods: Patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletion or L858R mutation with a recorded clinical benefit on prior single-agent EGFR-TKI before progression and confirmed dysregulated MET pathway after progression on EGFR TKIs were included. Patients in phase 1b received capmatinib 100 to 800-mg capsules qd or 200 to 600-mg capsules or tablets bid, plus gefitinib 250 mg qd. Patients in phase 2 received the R2PD dose. Data on the overall survival (OS) and cumulative safety endpoints are reported in this final analysis. Results: Overall, 161 patients received the combination treatment in this study; phase 1b (n = 61) and phase 2 (n = 100). The median age of patients was 60.0 years, mostly Asian (67.1%) with an Eastern Cooperative Oncology Group performance status of 0/1: 18.0%/78.3%. At data cut-off on May 27, 2020, all patients had discontinued the study; 82 out of the 100 patients in phase 2 had died and 18 were censored (mostly lost to follow-up [n = 15]). One patient was still on treatment with a partial response and rolled over to another study. The median (range) follow-up time for OS was 12.2 (0.9-70.2) months. The median OS was 13.9 months (95% confidence interval, 11.6-15.7 months). The median (range) duration of exposure for capmatinib plus gefitinib was 16 weeks (0.4-209.7 weeks) during phase 1b and 18.5 weeks (0.4-268.0 weeks) during phase 2. Majority of the patients (98.8%) experienced ≥1 adverse event (AE); 87% of the patients had treatment-related AEs. Most common treatment-related AEs (reported in ≥20%) were nausea (28.0%), peripheral edema (23%), rash (21.7%), and decreased appetite (21.1%). Grade 3 or 4 treatment-related AEs occurred in 51 patients (31.7%) across both phases, of which, the most frequent (reported in ≥5%) were increased amylase and increased lipase (6.2% each) and peripheral edema (5%). Conclusions: Capmatinib 400 mg bid in combination with gefitinib 250 mg qd was well-tolerated and showed encouraging clinical activity in patients with EGFR-mutant and MET-dysregulated NSCLC. Clinical trial information: NCT01610336.