Capmatinib Plus Pembrolizumab Does Not Provide Clinical Benefit in MET Unselected, PD-L1-high Expressing NSCLC

Tony SK Mok, MD

The addition of the MET inhibitor capmatinib (Tabrecta) to pembrolizumab (Keytruda) failed to improve clinical outcomes in patients with treatment-naïve non–small cell lung cancer (NSCLC) with PD-L1 expression of at least 50% vs pembrolizumab alone. An analysis of outcomes of patients in the MET unselected population treated in a phase 2 trial (NCT04139317) were presented in a poster at the 2022 ASCO Annual Meeting.¹

The objective response rate (ORR) in evaluable patients treated with pembrolizumab plus capmatinib (n = 51) was 15.7% (95% CI, 7.0%-28.6%) vs 28.0% (95% CI, 12.1%-49.4%) for pembrolizumab alone (n = 25). Disease control rates (DCRs) were similar between groups, at 56.9% vs 56.0%, respectively.

“Early efficacy findings of the study showed that the addition of capmatinib in the MET unselected, PD-L1 [greater than or equal to] 50%, treatment-naïve NSCLC population did not improve the antitumor activity of pembrolizumab and therefore did not clinically confirm the hypothesized immunomodulatory effect of capmatinib,” the study authors who were led by Tony SK Mok, MD, of the Department of Clinical Oncology of the Chinese University of Hong Kong, wrote in a poster presentation of the data. 

Preclinical studies have demonstrated the potential of MET inhibition to enhance T-cell–mediated antitumor immune responses when combined with anti–PD-1 therapy. Capmatinib is currently approved to treat patients with MET exon 14 skipping mutation–positive NSCLC.² Therefore, the investigators of the current analysis hypothesized combining capmatinib with pembrolizumab may result in an enhanced antitumor response in patients with NSCLC and high PD-L1 expression.

The study included 76 patients randomized in a 2:1 fashion to receive oral capmatinib at 400 mg twice daily plus intravenous pembrolizumab at 200 mg every 3 weeks (n = 64) vs pembrolizumab alone. The primary end point was investigator-assessed progression-free survival (PFS) with secondary end points of ORR, DCR, and safety.

Baseline patient characteristics were well-balanced among the investigative combination and control arms in age (66 vs 65 years, respectively), ECOG performance status of 1 (58.8% vs 64.0%), non-squamous histology (80.4% vs 84.0%), and prior radiotherapy treatment (72.5% vs 80.0%). Of note, more patients in the capmatinib/pembrolizumab arm had brain metastasis at baseline (23.5% vs 8.0%).

Investigator-assessed PFS were not mature at the data cut-off, with only 14 events (27.5%) in the combination arm and 8 (32%) in the single-agent arm. Based on the available data, the median PFS was 6.3 months (95% CI, 3.2-not estimable [NE]) vs 4.3 months (95% CI, 2.3-NE) for the experimental and control arms, respectively.

Tumor shrinkage was noted in both treatment arms, with all activity comprised of partial responses in both the capmatinib and the pembrolizumab monotherapy arms. Stable disease occurred in 21 patients (41.2%) in the capmatinib/pembrolizumab group vs 7 (28.0%) in the pembrolizumab group.

Notably, the combination therapy was associated with higher rates of adverse events (AEs) leading to dose adjustments and treatment discontinuation, which led to the decision to cut the study recruitment goal by half.

Treatment discontinuation occurred at a rate of 27.5% with the capmatinib combination vs 16% with pembrolizumab alone. Corresponding rates of dose adjustments/interruptions were 52.9% and 16%.

Treatment-related AEs (TRAEs) occurred in 78.4% of the patients treated with the combination vs 60.0% with monotherapy. Serious TRAEs occurred in 31.4% vs 4.0%, respectively. The most common any-grade suspected TRAEs in the capmatinib plus pembrolizumab vs pembrolizumab alone arms were peripheral edema (21.6% vs 0%), elevated alanine aminotransferase (ALT; 19.6% vs 8.0%), elevated aspartate aminotransferase (AST; 19.6% vs 8.0%), nausea (19.6% vs 0%), and vomiting (19.6% vs 4.0%). The most common grade 3 or greater suspected TRAEs were elevated ALT (9.8% vs 4.0%, respectively), elevated AST (7.8% vs 4.0%), rash (3.9% vs 0%), elevated g-glutamyltransferase (3.9% vs 4.0%), and elevated blood alkaline phosphatase (2.0% vs 0%).

References

1. Mok T, Cortinovis D, Majem M, et al. Efficacy and safety of capmatinib plus pembrolizumab in treatment (tx)-naïve patients with advanced non–small cell lung cancer (NSCLC) with high tumor PD-L1 expression: Results of a randomized, open-label, multicenter, phase 2 study. J Clin Oncol. 2022;40(suppl 16):9118. doi:10.1200/JCO.2022.40.16_suppl.9118
2. FDA grants accelerated approval to capmatinib for metastatic non-small cell lung cancer. FDA. May 6, 2020. Accessed June 6, 2022. https://bit.ly/3NSJYo3