Merck's Keytruda Receives Positive CHMP Opinion for First-Line Treatment of MSI-H/dMMR Metastatic Colorectal Cancer in the EU

Compiled by Hemingway

On December 11, Merck Sharp & Dohme (MSD) announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) had adopted a positive opinion regarding a new indication for Keytruda (pembrolizumab), recommending the approval of Keytruda as a monotherapy first-line treatment for adult patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer.

This recommendation is based on the results of the pivotal Phase III clinical KEYNOTE-177 (NCT02563002) trial. In this Phase III, open-label trial, 307 patients with previously untreated metastatic MSI-H/dMMR colorectal cancer were randomized in a 1:1 ratio to receive either pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (a 5-fluorouracil-based regimen, with or without bevacizumab or cetuximab) every 2 weeks. Patients in the chemotherapy arm were permitted to cross over to receive pembrolizumab upon disease progression. The two primary endpoints were progression-free survival and overall survival.

At the second interim analysis, after a median follow-up of 32.4 months (range, 24.0–48.3) from randomization to the data cutoff date, pembrolizumab demonstrated superior progression-free survival compared with chemotherapy (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI]; P=0.0002). The estimated restricted mean survival times at 24 months of follow-up were 13.7 months (range, 12.0–15.4) and 10.8 months (range, 9.4–12.2), respectively. As of the data cutoff date, 56 patients in the pembrolizumab group and 69 patients in the chemotherapy group had died. Overall survival data continue to accumulate (with 66% of the required number of events reached), and blinding will be maintained until the final analysis.

According to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the overall response rates (complete or partial response) were 43.8% in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients who achieved an overall response, 83% in the pembrolizumab group and 35% in the chemotherapy group maintained their response at 24 months. Treatment-related grade 3 or higher adverse events occurred in 22% of patients in the pembrolizumab group and 66% of patients in the chemotherapy group (including one death).

Progression-Free Survival in Patients with MSI-H/dMMR Metastatic Colorectal Cancer

Therefore, Keytruda as monotherapy significantly prolonged progression-free survival in patients compared with chemotherapy, with fewer treatment-related adverse events.

Anticancer Activity of Keytruda in the Intent-to-Treat Population

Colorectal cancer, as the third most common malignancy worldwide, is considered a heterogeneous disease from a genetic perspective. Although there is significant genetic heterogeneity in colorectal cancer, its chemotherapy regimens remain largely standardized. Mismatch repair-deficient (dMMR) colorectal cancer, a well-characterized genetic subset, accounts for approximately 15% of all colorectal cancers. This deficiency impairs the cell’s ability to recognize and repair spontaneous mutations, leading to a high tumor mutational burden and alterations in microsatellite sequences, thereby classifying these tumors as microsatellite instability-high (MSI-H) colorectal cancer. Accumulating evidence suggests that conventional chemotherapy has limited efficacy in MSI-H/dMMR colorectal cancer; however, as the literature remains inconclusive, chemotherapy continues to be the standard treatment for patients with MSI-H/dMMR colorectal cancer.

The regimen of PD-1 inhibitors combined with chemotherapy for refractory MSI-H/dMMR metastatic colorectal cancer patients has also previously received approval from the U.S. FDA, with pembrolizumab/nivolumab indicated for the treatment of patients with MSI-H/dMMR metastatic colorectal cancer who have progressed after treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

Keytruda’s positive recommendation from the CHMP will facilitate a faster review and marketing authorization by the European Commission, with the final approval expected to be completed in the first quarter of 2021.

References:

1.Merck Receives Positive EU CHMP Opinion for KEYTRUDA® (pembrolizumab) as First-Line Treatment in Adult Patients With Metastatic Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Colorectal Cancer

Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer