Pembrolizumab Doubles Progression-Free Survival as First-Line Monotherapy in MSI-H/dMMR Metastatic Colorectal Cancer, NEJM Publishes KEYNOTE-177 Results

In June this year, the U.S. FDA approved an expanded indication for Keytruda (pembrolizumab), a blockbuster PD-1 inhibitor developed by MSD, as first-line treatment for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer. This marks the first immunotherapy approved for first-line use in this patient population without requiring combination with chemotherapy.

Recently, the key clinical trial results supporting the approval of this indication were officially published in The New England Journal of Medicine. Compared to chemotherapy, pembrolizumab as first-line treatment for patients with MSI-H-dMMR colorectal cancer significantly prolongs progression-free survival, while the impact on overall survival still requires longer-term data accumulation for evaluation.

Screenshot source: New England Journal of Medicine

Approximately 5% of patients with metastatic colorectal cancer harbor MSI-H or dMMR tumors, which are more sensitive to immune checkpoint inhibitors due to their high mutational burden. Previously, Keytruda was approved as a second-line therapy for the treatment of patients with MSI-H or dMMR solid tumors, regardless of tumor type.

This was a Phase 3, open-label trial enrolling 307 patients with previously untreated metastatic MSI-H/dMMR colorectal cancer. Participants were randomized 1:1 to receive pembrolizumab (200 mg every three weeks) or chemotherapy (every two weeks). Patients in the chemotherapy group were permitted to cross over to pembrolizumab upon disease progression.

The median follow-up period was 32.4 months. In the second interim analysis, the median progression-free survival (PFS) was 16.5 months in the pembrolizumab group and 8.2 months in the chemotherapy group, representing a 40% reduction in the risk of progression or death in the pembrolizumab group. After 24 months of follow-up, the estimated restricted mean survival times were 13.7 months and 10.8 months, respectively. As of the data cutoff date, there were 56 deaths in the pembrolizumab group and 69 deaths in the chemotherapy group. Overall survival data continue to be updated.

In the pembrolizumab and chemotherapy groups, 43.8% and 33.1% of patients, respectively, achieved a response. Among all responders, 83% and 35% of patients in the two groups, respectively, maintained a durable response at 24 months.

The pembrolizumab group had fewer treatment-related adverse events, with 22% of patients experiencing grade 3 or higher treatment-related adverse events, compared to 66% in the chemotherapy group (including one fatal case).

The research team stated, “These data represent another advance in biomarker-driven research for MSI-H/dMMR colorectal cancer. For patients with metastatic MSI-H/dMMR colorectal cancer, pembrolizumab should be considered as a first-line treatment option.”

References

[1] Thierry André, et al., (2020). Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer. N Engl J Med, DOI: 10.1056/NEJMoa2017699

[2] Pembrolizumab slows MSI-H-dMMR metastatic CRC. Retrieved December 4, 2020, from https://medicalxpress.com/news/2020-12-pembrolizumab-msi-h-dmmr-metastatic-crc.html