FDA Approves Keytruda as First-Line Monotherapy for MSI-H/dMMR Metastatic Colorectal Cancer

Today, the U.S. FDA announced the approval of an expanded indication for Keytruda (pembrolizumab), a blockbuster PD-1 inhibitor developed by Merck Sharp & Dohme (MSD), for the first-line treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer. The press release noted that this is the first immunotherapy approved for first-line treatment in this patient population without requiring combination with chemotherapy. It is also the first first-line immunotherapy approved based on the MSI-H or dMMR biomarkers, marking another breakthrough in the use of molecular biomarkers for patient selection.

Approximately 5% of patients with metastatic colorectal cancer harbor MSI-H or dMMR tumors. Due to abnormalities in DNA repair mechanisms within cells, MSI-H and dMMR tumors accumulate a high burden of genomic mutations, rendering these tumors more sensitive to immune checkpoint inhibitors.

Keytruda enhances the body’s immune cell response against cancer by blocking the PD-1/PD-L1 signaling pathway. Previously, it was approved as a second-line therapy for patients with MSI-H or dMMR solid tumors, regardless of tumor type. Recently, it also received FDA approval as a second-line, tumor-agnostic therapy for patients with high tumor mutational burden (TMB-H) solid tumors.

The FDA approval of this indication was based on the results of a multicenter, open-label, active-controlled randomized trial that compared the efficacy and safety of Keytruda versus chemotherapy in 307 patients with MSI-H or dMMR metastatic colorectal cancer. The study demonstrated a statistically significant improvement in progression-free survival (PFS) among patients treated with Keytruda, as assessed by blinded independent review. The median PFS was 16.5 months in the Keytruda group compared to 8.2 months in the standard-of-care group. Longer-term follow-up is required to assess the impact on overall survival. Compared with chemotherapy, Keytruda reduced the risk of disease progression or death by 40%.

“Metastatic colorectal cancer is a serious and life-threatening disease with a poor prognosis, and existing combination therapies comprising chemotherapy and other biologics are associated with significant toxicity,” said Dr. Richard Pazdur, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and Director of the FDA’s Oncology Center of Excellence. “Providing a non-chemotherapy option for certain patients represents a notable shift in the treatment paradigm.”

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