Capmatinib Generates Clinically Meaningful Activity in MET Exon 14-Mutated NSCLC

Edward B. Garon, MD

Capmatinib (INC280) induced antitumor efficacy, as well as deep and durable responses, in 97 patients with advanced non–small cell lung cancer (NSCLC) harboring a MET exon 14 mutation, according to GEOMETRY mono-1 study (NCT0241413), presented at the 2020 American Association for Cancer Research Annual Meeting.

The study stratified patients into 7 cohorts, but only patients in cohorts 4 (n = 69) and 5b (n = 28) were analyzed in this presentation.

“Cohorts 4 and 5b were comprised of patients with MET exon 14 mutations,” Edward B. Garon, MD, said. “In cohort 4, patients had received at least 1 prior line of therapy for advanced disease, whereas patients in cohort 5b were treatment naïve.”

The primary end point of objective response rate (ORR) as reported by blinded independent review committee (BIRC) for cohort 4 was 40.6% (95% CI, 28.9-53.1); in cohort 5b, the ORR was 67.9% (95% CI, 47.6-84.1). Median duration of response (mDOR) was 9.72 months (95% CI, 5.55-12.98) in cohort 4 and 11.14 months (95% CI, 5.55-not evaluable) in cohort 5b. Median progression-free survival (mPFS) was 5.42 months (95% CI, 4.17-6.97) and 9.69 months (95% CI, 5.52-13.86), respectively.

The investigators also observed preliminary intracranial response in 54% (7 of 13) of patients with brain metastases. Garon, an associate professor in the Department of Medicine, Division of Hematology/Oncology at the Geffen School of Medicine of the University of California Los Angeles, presented findings during the 2020 American Association for Cancer Research Virtual Annual Meeting I, held from April 27 to 28, 2020.¹

Patients with stage IIIB or IV NSCLC were enrolled in the phase II, multicohort study. Inclusion criteria included patients with an ECOG performance status less than or equal to 1 and tumors that were EGFR wild type, ALK negative, and had METdysregulation.

All patients were treated with a twice-daily dose of 400 mg of capmatinib, a small ATP competitive, reversible inhibitor of the MET receptor tyrosine kinase, which has been shown to have in vitro and in vivo effects against preclinical cancer models with MET activation.²

Notably, both cohorts included patients who exhibited neurologically stable or asymptomatic BM, even if the patient had not received local therapy, such as radiation.

The key secondary end point was DOR. Other secondary end points were PFS, overall survival, and safety. Garon said that cohorts 4 and 5b were analyzed separately and had independent statistical hypotheses.

The investigators reported that baseline characteristics were similar in both cohorts, but median age was higher than usually observed in driver-mutation positive NSCLC in clinical trials. However, the median patients age in both cohorts of 71 years was in line with the age of patients with lung cancer in general. Adenocarcinoma was the most common histology.

“Of note, over 10% of patients in both cohorts had BMs. Specifically, 15.9% of patients in cohort 4 and 10.7% of patients in cohort 5b had BMs at the time of enrollment,” Garon said.

For patients in cohort 4, the ORR by investigator assessment was 42.0% (95% CI, 30.2%-54.5%). The disease control rate (DCR) was 78.3% (95% CI, 66.7%-87.3%) by BIRC and 76.8% (95% CI, 65.1%-86.1%) by investigator assessment.

Findings from cohort 5b were even more impressive, according to Garon. The investigator-assessed ORR was 60.7% (95% CI, 40.6%-78.5%). DCR was 96.4% (95% CI, 81.7%-99.9%) by BIRC and 96.4% (95% CI, 81.7%-99.9%) by investigator assessment.

Evaluation of waterfall plots demonstrated deep responses in a majority of patients across both cohorts, Garon said. He observed that results were higher when assessed by the trial investigators rather than central review.

Swimmer plots for responders suggest rapid and long-lasting responses across both cohorts, with the majority of patients having an onset of response within the first 7 weeks of treatment. “Responses tended to occur early, exceeded 1 year, and many remain ongoing,” Garon said.

Of the 13 evaluable patients with BMs at baseline, 4 patients had complete resolution of all brain lesions, whereas the other 3 responding patients had complete resolution in 3 lesions with stabilization in 4; complete resolution in 2 lesions with stabilization in 1; and compete resolution in 1 lesion, with stabilization in 3.

Garon highlighted the results in 1 patient, a 73-year-old woman with multiple BMs who had been previously treated with whole brain radiotherapy and pembrolizumab (Keytruda) and who had 85% PD-L1 expression. Systemic and intracranial progression was observed after 3 cycles. She was started on capmatinib in February 2018.

“At her last follow-up in March 2020, the patient continues to be doing well in both the body and the brain,” Garon said. “All brain lesions have completely resolved from the start of therapy 12 weeks ago.”

The GEOMETRY study has collected the largest safety dataset of patients with NSCLC who harbor MET mutations (N = 334).

Investigators reported 35.6% of patients experienced grade 3/4 adverse events (AEs) and 12.9% of patients experiencing serious treatment-related AEs. The most common AE reported was peripheral edema (all-grade, 41.6%; grade 3/4, 7.5%). No treatment-related deaths have been reported.

Garon said 21.9% of patients underwent dose reduction because of treatment-related AEs (TRAEs) and 11.1% of patients stopped therapy because of TRAEs. The most frequent (≥1%) causes for treatment discontinuation were peripheral edema (1.8%), pneumonitis (1.5%), and fatigue (1.5%).

“Among patients with MET exon 14 mutations, with typically poor outcomes and poor responses to standard therapies, clinical meaningful activity has been shown with capmatinib,” Garon said. “Results were rapid and deep, leading to impressive duration of response in both treatment-naïve and previously treated patients.”

Garon emphasized that because of the higher ORR observed in treatment-naïve patients with MET exon 14, the importance of early molecular testing is recommended. Further study is needed to validate the intracranial efficacy of the agent.

_References

1. _{Garon EB, Heist RS, Seto T, et al. Capmatinib in METex14-mutated (mut) advanced non-small cell lung cancer (NSCLC): Results from the phase II GEOMETRY mono-1 study, including efficacy in patients (pts) with brain metastases (BM). Presented at: 2020 American Association for Cancer Research Virtual Annual Meeting I: Virtual; April 27-28, 2020. Abstract CT082. bit.ly/2W9rtTc}
2. _{Baltschukat S, Engstler BS, Huang A, et al. Capmatinib (INC280) is active against models of non-small cell lung cancer and other cancer types with defined mechanisms of MET activation. Clin Cancer Res. 2019;25(10):3164-3175. doi: 10.1158/1078-0432.CCR-18-2814}