FDA Approves First-Line Pembrolizumab for MSI-H/dMMR Metastatic Colorectal Cancer


The FDA has approved pembrolizumab (Keytruda) for the first-line treatment of patients with unresectable or metastatic microsatellite instability–high or mismatch repair deficient colorectal cancer.

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

The regulatory decision is based on data from the phase 3 KEYNOTE-177 trial which showed that treatment with pembrolizumab significantly reduced the risk of disease progression or death by 40% (HR, 0.60; 95% CI, 0.45-0.80; P =.0004) versus standard-of-care chemotherapy.2 Additionally, the PD-1 inhibitor was found to more than double progression-free survival (PFS) versus chemotherapy, at 16.5 months (95% CI, 5.4-32.4) versus 8.2 months (95% CI, 6.1-10.2), respectively.

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

A total of 307 patients with treatment-naïve MSI-H/dMMR metastatic CRC were enrolled on KEYNOTE-177. In order to be eligible to participate, patients had to have MSI-H/dMMR stage IV disease, an ECOG performance status of 0 or 1, and measurable disease.

These patients were then randomized 1:1 to either 200 mg of pembrolizumab every 3 weeks for up to 2 years or investigator’s choice of standard chemotherapy, including intravenous mFOLFOX6 (5-fluorouracil [5-FU], leucovorin, and oxaliplatin) every 2 weeks; mFOLFOX6 plus bevacizumab (Avastin; 5 mg/kg IV on day 1 of each 2-week cycle); mFOLFOX6 plus cetuximab (Erbitux; 400 mg/m2 IV, then 250 mg/m2 weekly in each 2-week cycle); FOLFIRI (leucovorin, 5-FU, and irinotecan); FOLFIRI plus bevacizumab (5 mg/kg IV on day 1 of each 2-week cycle); or FOLFIRI plus cetuximab (400 mg/m2 IV, then 250 mg/m2 weekly in each 2-week cycle).

Notably, patients in the chemotherapy arm were permitted to cross over to the pembrolizumab arm upon disease progression. In the pembrolizumab arm, treatment was continued for up to 35 cycles, until disease progression, unacceptable toxicity, or the patient/physician’s choice to withdraw.

Additional results presented during the 2020 ASCO Virtual Scientific Program showed that the 12-month PFS rate was 55% in the pembrolizumab arm and 37% in the chemotherapy arm; the 24-month PFS rates were 48.3% and 18.6%, respectively. The overall response rate (ORR) was 43.8% with pembrolizumab, which included a 11.1% complete response (CR) rate, 32.7% partial response (PR) rate, and 20.9% stable disease (SD) rate. The ORR was 33.1% with chemotherapy, which was comprised of a 3.9% CR rate, a 29.2% PR rate, and a 42.2% SD rate.

Thirty percent of patients of patients on the pembrolizumab arm went on to develop progressive disease compared with 12.3% of those on the chemotherapy arm.

Additionally, responses proved to be more durable with the PD-1 inhibitor versus chemotherapy. The median duration of response had not been reached in the pembrolizumab arm compared with 10.6 months in the chemotherapy arm. The majority of patients, or 83%, on the pembrolizumab arm experienced a response lasting at least 2 years compared with 35% of those on the chemotherapy arm.

With regard to safety, the PD-1 inhibitor demonstrated an improved toxicity profile compared with chemotherapy. The most commonly reported all-grade adverse events (AEs) occurred in at least 20% of patients in the pembrolizumab and chemotherapy arms and included diarrhea (25% vs 52%, respectively), fatigue (21% vs 44%), nausea (12% vs 55%), reduced appetite (8% vs 34%), stomatitis (5% vs 30%), alopecia (3% vs 20%), vomiting (3% vs 28%), reduced neutrophil count (1% vs 23%), neutropenia (0% vs 21%), and peripheral sensory neuropathy (0% vs 20%).

Grade 3 or higher treatment-related AEs were less commonly reported with pembrolizumab than they were with chemotherapy, at 22% versus 66%, respectively. The most common immune-related events with the PD-1 inhibitor included colitis and hepatitis.

The approval of pembrolizumab was granted just less than 1 month after the submission of a new supplemental biologics license application, which had been reviewed as part of the FDA’s Real-Time Oncology Review pilot program. The review was also done under Project Orbis.

“Patients with unresectable or metastatic MSI-H colorectal cancer have historically faced poor outcomes, and until today, chemotherapy-containing regimens were only FDA-approved first-line treatment options,” said Luis A. Diaz, MD, head of the division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center. “In patients who were treated with [pembrolizumab] and responded 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.”

In May 2017, the FDA granted an accelerated approval to the PD-1 inhibitor for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-H/dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, and for patients with MSI-H/dMMR CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

The decision was was based on findings from 149 patients with MSI-H/dMMR cancers who were enrolled across 5 single-arm clinical trials, in which pembrolizumab induced durable responses and prolonged survival.3


  1. FDA approves Merck’s Keytruda (pembrolizumab) 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. bwnews.pr/3ePxyfu.
  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; abstr LBA4). doi:10.1200/JCO.2020.38.15_suppl.LBA4
  3. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. News release. FDA. May 23, 2017. Accessed June 29, 2020. bit.ly/3bI0DHK.
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