CHMP Moves to Recommend Pembrolizumab for MSI-H/dMMR Cancers

The European Medicines Agency’s Committee for Medicinal Products for Human Use recommended pembrolizumab for the treatment of adult patients with a variety of microsatellite instability-high or mismatch repair deficient tumors.

On March 25, 2022, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended pembrolizumab (Keytruda) for the treatment of adult patients with a variety of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors.1

The committee’s positive opinion supports the use of pembrolizumab, an igG4 antibody, as a monotherapy for the treatment of patients: with unresectable or metastatic colorectal cancer after previous fluoropyrimidine-based combination therapy, who have advanced or recurrent endometrial carcinoma with disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation, and unresectable or metastatic gastric, small intestine, or biliary cancer who have disease progression on or following at least 1 prior therapy. The CHMP cited data from the phase 2 KEYNOTE-158 (NCT02628067) and the phase 2 KEYNOTE-164 trial (NCT02460198) to support the decision.

“We are committed to advancing the use of biomarkers to identify patients most likely to respond to pembrolizumab,” Scot Ebbinghaus, MD, vice president, global clinical development, Merck Research Laboratories, the manufacturer of pembrolizumab, said in a news release. “This positive CHMP opinion reinforces the predictive value of MSI-H/dMMR across many different cancer types and the importance of biomarker testing. Pembrolizumab has already become an important first-line treatment option for certain patients in Europe with MSI-H or dMMR colorectal cancer, and we are pleased the CHMP has recommended pembrolizumab as a monotherapy for additional patients with MSI-H or dMMR tumors.”

The recommendation is set to be reviewed by the European Commission for marketing authorization in the European Union. A final decision is expected to be made by the commission in the second quarter of 2022.

Results from KEYNOTE-158 showed that patients with MSI-H/dMMR solid tumors treated with pembrolizumab (n = 233) achieved an objective response rate (ORR) of 34.3% (95% CI, 28.3%-40.8%). Notably, the median duration of response (DOR) was not reached (NR; range, 2.9-31.3+).2

KEYNOTE-158 was a multicenter, nonrandomized trial that enrolled patients with a variety of MSI-H/dMMR cancers including endometrial (21.0%), gastric (10.3%), cholangiocarcinoma (9.4), pancreatic (9.4), and small intestine (8.2%). Patients received 200 mg IV pembrolizumab every 3 weeks for 35 cycles until unacceptable toxicity or disease progression.

The median age of the study population was 60.0 years (range, 20-87). Most patients were female (58.8%) and had an ECOG performance status of 1 (51.5%). Few patients had brain metastases (1.7%) and 23.6% underwent prior neoadjuvant treatment.

Patients with endometrial cancer experienced the best ORR (57.1%; 95% CI, 42.2%-71.2%) and the highest median progression-free survival (PFS; 25.7 months; 95% CI, 4.9-not reached [NR]). Patients with gastric cancer achieved an ORR of 45.8% (95% CI, 25.6%-67.2%), while patients with cholangiocarcinoma registered an ORR of 40.9% (95% CI, 20.7%-63.6%). The median PFS for these cohorts was 11.0 months (95% CI, 2.1-NR) and 4.2 months (95% CI, 2.1-NR), respectively.

The most common adverse events (AEs) of any grade included fatigue (14.6%), pruritus (12.9%), and diarrhea (12%). Investigators observed grade 3/4 AEs in 14.6% of patients. Treatment with pembrolizumab was discontinued due to AEs in 9.4% of patients and serious adverse reactions occurred in 7.7% of patients.

Investigators in KEYNOTE-164 assigned a total of 124 adult patients with MSI-H/dMMR colorectal cancer (CRC) to the same treatment regimen used in KEYNOTE-158. Patients who received 2 or more prior therapies (cohort A; n = 61) achieved an ORR of 33% (95% CI, 21%-46%) with pembrolizumab. The median DOR was NR (range, 6.2-41.2+).

In patients who received 1 or more prior therapies (cohort B; n = 63), the ORR was 33% (95% CI, 22%-46%) and the median DOR was also NR (range, 3.9+-37.1+).3

Patients in cohort A had a median age of 53 (range, 21-84) compared with 59 (range, 23-83) in cohort B. In both cohorts, men were the majority (59% and 52%, respectively) and most patients had an ECOG performance status of 1 (52% and 65%, respectively). Prior neoadjuvant therapy was given to 34% of patients in cohort A and 27% of patients in cohort B.

Sixty-two percent of patients in cohort A experienced treatment-related AEs of any grade compared with 70% in cohort B. Incidence of grade 3/4 AEs was 16% and 13%, respectively. Three percent of patients in both groups had to discontinue treatment due to AEs and no patients died because of a treatment-related AE.

Common AEs in cohort A of any grade included arthralgia, nausea (both 16%), diarrhea, asthenia, and pruritus (all 13%). AEs in cohort B included fatigue and hypothyroidism (both 17%), arthralgia, diarrhea, and hyperthyroidism (all 11%).


  1. Merck receives positive EU CHMP opinion for KEYTRUDA® (pembrolizumab) for patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in five different types of cancer. News release. Merck. March 25, 2022. Accessed March 25, 2022.
  2. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1-10. doi:10.1200/JCO.19.02105
  3. Diza LA, Kim TW, Van Cutsem E, et al. Pembrolizumab monotherapy for patients with advanced MSI-H colorectal cancer: longer-term follow-up of the phase 2, KEYNOTE-164 study. J Clin Oncol. 2020;38(suppl 15):4032. doi:10.1200/JCO.2020.38.15_suppl.4032