First-line pembrolizumab improves PFS vs chemo in MSI-H/dMMR mCRC

Pembrolizumab as first-line therapy significantly improves progression-free survival (PFS) vs chemotherapy in patients with microsatellite instability-high (MSI-H)/mismatch-repair deficient (dMMR) metastatic colorectal cancer (mCRC), according to results of the KEYNOTE-177 study reported at the American Society of Clinical Oncology 2020 (ASCO20) Virtual Scientific Programme.

PFS, one of the dual primary endpoints, reached a median of 16.4 months in the pembrolizumab arm vs 8.2 months with investigator-choice chemotherapy (hazard ratio [HR], 0.60; 95 percent confidence interval [CI], 0.45 to 0.80; p=0.0002). [Andre T, et al, ASCO20 Virtual, abstract LBA4]

“PFS rate at 24 months was 48 percent in the pembrolizumab arm vs 19 percent in the chemotherapy arm,” reported investigator Dr Thierry Andre of the Sorbonne University and Saint-Antoine Hospital, Paris, France.

Improvement in PFS was consistently observed with pembrolizumab vs chemotherapy across key prespecified subgroups, except in patients with KRAS or NRAS mutant tumours (HR, 1.19; 95 percent CI, 0.68 to 2.07).

“The potential benefit [of pembrolizumab] in patients with RAS wild-type MSI-H mCRC is a new finding, which was not seen in the KEYNOTE-165 and CheckMate-142 trials,” commented discussant Professor Michael J. Overman of the University of Texas MD Anderson Cancer Center, Houston, Texas, US. “Validation in other data sets is needed.”

Overall response rate was likewise significantly improved with pembrolizumab vs chemotherapy (43.8 percent vs 33.1 percent; p=0.0275), with complete response rate being nearly 3 times as high with pembrolizumab (11.1 percent vs 3.9 percent with chemotherapy).

“Reduction in size of target lesions was more frequent and deeper with pembrolizumab. The median duration of response was not reached in the pembrolizumab arm vs 10.6 months in the chemotherapy arm, with 83 percent vs 35 percent of patients having a response duration of ≥24 months,” said Andre.

“However, we also saw a higher rate of progressive disease [PD] in the pembrolizumab vs chemotherapy arm [29.4 percent vs 12.3 percent],” he noted.

“These [29.4 percent of] patients are demonstrating intrinsic or innate resistance to anti–PD-1 therapy,” suggested Overman. “Biomarkers of resistance need to be identified. The MSI-ness or level of insertion or deletion mutations should be evaluated, and results of planned immune or genomic analyses of KEYNOTE-177 are awaited.”

The KEYNOTE-177 study included 307 patients with stage IV CRC who had MSI-H/dMMR tumours and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The patients were randomized (1:1) to receive pembrolizumab (200 mg Q3W for up to 35 cycles) or investigator-choice chemotherapy (mFOLFOX or FOLFIRI, with or without bevacizumab or cetuximab). Crossover to the pembrolizumab arm was allowed in patients with confirmed PD.

“Fifty-six patients [36 percent] in the chemotherapy arm crossed over to receive pembrolizumab after confirmed PD. Thirty-five additional patients received anti–PD-1/PD-L1 therapy outside of the study, for an effective crossover rate of 59 percent in the intent-to-treat population,” said Andre. “The study will remain blinded for the other dual primary endpoint of overall survival [OS]. OS results will be reported at final analysis.”

In the trial, the safety profile of pembrolizumab was consistent with that observed across various tumour types. Grade ≥3 adverse events (AEs) were reported in 22 percent of patients in the pembrolizumab arm vs 66 percent of those in the chemotherapy arm, while grade ≥3 immune-mediated AEs and infusion reactions occurred in 9 percent vs 2 percent of patients.

“The clinically meaningful and statistically significant improvement in PFS with pembrolizumab vs chemotherapy, together with the higher ORR, more durable responses and improved safety profile, suggest that pembrolizumab should be the new standard of care as first-line therapy in patients with MSI-H mCRC,” concluded Andre.