Adding Capmatinib to Pembrolizumab Provides No Further Responses in PD-L1+ NSCLC

In a MET-unselected population of PD-L1–positive non–small cell lung cancer, the addition of capmatinib to pembrolizumab did not lead to more responses but increased toxicity.

Combining capmatinib (Tabrecta) with pembrolizumab (Keytruda) did not improve antitumor activity in patients with MET unselected, PD-L1–positive (≥50%) previously untreated non–small cell lung cancer (NSCLC), according to results of a phase 2 trial (NCT04139317) that were presented at the 2022 American Society of Clinical Oncology (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 MET unselected, PD-L1 ≥50% treatment-naïve NSCLC population did not improve the antitumor activity of pembrolizumab and therefore did not clinical confirm the hypothesized immunomodulatory effect of capmatinib,” the study authors who were led by Tony 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.

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 evaluable [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