FDA Approves Frontline Pembrolizumab for MSI-H/dMMR CRC

"Patients with unresectable or metastatic MSI-H colorectal cancer have historically faced poor outcomes, and until today, chemotherapy-containing regimens were the only FDA-approved first-line treatment options."

The FDA has approved pembrolizumab (Keytruda) monotherapy for the frontline treatment of patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC).1

Approval for this indication for pembrolizumab was based on findings from the phase 3 KEYNOTE-177 trial, in which pembrolizumab more than doubled the progression-free survival (PFS) over chemotherapy in patients with MSI-H/dMMR CRC.

The median PFS with pembrolizumab was 16.5 months (95% CI, 5.4-32.4) compared with 8.2 months (95% CI, 6.1-10.2) with chemotherapy, resulting in a 40% reduction in the risk of disease progression or death (HR, 0.60; 95% CI, 0.45-0.80; P = .0004).

“Patients with unresectable or metastatic MSI-H colorectal cancer have historically faced poor outcomes, and until today, chemotherapy-containing regimens were the only FDA-approved first-line treatment options,” said Luis A. Diaz, MD, head of the division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, in a statement. “In patients who were treated with Keytruda and responded (n = 67) in the KEYNOTE-177 trial, 43% of patients experienced a duration of response lasting 2 years or longer. This approval helps address the unmet need to provide a new monotherapy treatment option for patients.”

KEYNOTE-177 was a multicenter, randomized, open-label, active-controlled trial that enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR CRC, as determined by polymerase chain reaction for MSI and immunohistochemistry for dMMR status.

Patients were randomized 1:1 to receive 200 mg intravenous pembrolizumab every 3 weeks of investigators choice of: mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil [5-FU]), mFOLFOX6 plus cetuximab, mFOLFOX6 plus bevacizumab, FOLFIRI (leucovorin, 5-FU, and irinotecan); FOLFIRI plus bevacizumab, or FOLFIRI plus cetuximab.

Treatment in the pembrolizumab arm was continued for up to 35 cycles or until progressive disease, unacceptable toxicity, or patient/physician decision to withdraw. Patients in the chemotherapy arm who progressed were allowed to cross over to the pembrolizumab arm.

According to findings from KEYNOTE-177 presented during the 2020 American Society of Clinical Oncology Virtual Scientific Program, the 1-year PFS rate was 55% with pembrolizumab and 37% with chemotherapy; at 2 years, the PFS rates were 48.3% and 18.6%, respectively.2

The objective response rate was 43.8% in the pembrolizumab arm and 33.1% in the chemotherapy arm. Objective responses in the pembrolizumab arm consisted of complete responses in 11.1%, partial responses in 32.7%, and stable disease in 20.9%. In the chemotherapy arm, complete responses were seen in 3.9%, partial responses in 29.2%, and stable disease in 42.2%. About 30% of patients in the immunotherapy arm progressed compared with 12.3% in the chemotherapy arm.

The median duration of response was not reached in the immunotherapy arm compared with 10.6 months with chemotherapy. Responses lasted more than 2 years for 83% of responders in the pembrolizumab arm and for 35% of responders in the chemotherapy arm.

Frequent adverse events (AEs) in the pembrolizumab arm compared with the chemotherapy arm included diarrhea (25% vs 52%, respectively), fatigue (21% vs 44%), nausea (12% vs 55%), decreased appetite (8% vs 34%), stomatitis (5% vs 30%), alopecia (3% vs 20%), vomiting (3% vs 28%), decreased neutrophil count (1% vs 23%), neutropenia (0% vs 21%), and peripheral sensory neuropathy (0% vs 20%).

Grade ≥3 treatment-related AEs, however, were less common in the pembrolizumab arm compared with the chemotherapy arm (22% vs 66%).

“Today’s approval has the potential to change the treatment paradigm for the first-line treatment of patients with MSI-H colorectal cancer, based on the important findings from KEYNOTE-177 that showed Keytruda monotherapy demonstrated superior progression-free survival compared to standard of care chemotherapy,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, in a statement. “Our commitment to pursuing biomarker research continues to help us bring new treatments to patients, particularly for those who have few available options.”

The supplemental Biologics License Application for pembrolizumab in this indication was reviewed under the FDA’s Real-Time Oncology Review pilot program within 1 month of submission. The application was also reviewed through the FDA’s Project Orbis in collaboration with the Australian Therapeutic Goods Administration, Health Canada, and Swissmedic.

Pembrolizumab was granted FDA approval for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H/dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H/dMMR CRC following progression on fluoropyrimidine, oxaliplatin, and irinotecan in 2017.


1. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for First-Line Treatment of Patients With Unresectable or Metastatic MSI-H or dMMR Colorectal Cancer. News release. Merck. June 29, 2020. Accessed June 29, 2020. https://bwnews.pr/31sIJa7

2. Andre T. Shiu Kai-Keen, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. J Clin Oncol. 2020;38(suppl 15):LBA4. doi:10.1200/JCO.2020.38.15_suppl.LBA4