Pembrolizumab Demonstrates Sustained, Robust Clinical Activity in Advanced MSI-H/dMMR Endometrial Cancer

Patients with microsatellite instability–high and mismatch repair–deficient advanced endometrial cancer experienced a long lasting benefit following treatment with pembrolizumab.

Treatment with pembrolizumab (Keytruda) resulted in efficacious, long-lasting benefit in patients with microsatellite instability–high (MSI-H) and mismatch repair–deficient (dMMR) advanced endometrial cancer, according to findings from the phase 2 KEYNOTE-158 study (NCT02628067).1

Patients who received treatment with pembrolizumab experienced an objective response rate (ORR) of 48% (95% CI, 37%-60%) with a median duration of response (DOR) that was not reached (95% CI, 2.9-49.7+). Additionally, patients achieved a median progression-free survival (PFS) of 13.1 months (95% CI, 4.3-34.4). The median overall survival (OS) was not reached (95% CI, 27.2–not reached).

“These findings suggest a long-term benefit to patients. Even the potential for curative intent is now possible in patients with recurrent or metastatic uterine cancer,” lead author David O’Malley, MD, a gynecologic oncologist at the Ohio State University Comprehensive Cancer Center–The James, said in a press release.2

The open label trial enrolled patients with different types of solid, advanced tumors, with cohort D being comprised of patients with endometrial carcinoma. To be eligible for the study, patients needed to be 18 years or older with histologically or cytologically confirmed metastatic and/or unresectable endometrial cancer. Patient disease needed to be uncurable and patients needed to progress on or be intolerant to standard therapies. An ECOG performance status of 0 or 1 and adequate organ function were also required.

Pembrolizumab was administered intravenously at a dose of 200 mg on day 1 of every 3-week cycle, totaling 35 cycles until disease progression, unacceptable toxicities, investigator decision, or withdrawal of patient consent. Imaging via CT or MRI was performed every 9 weeks within the first year and every 12 weeks subsequently.

The study had a primary end point of ORR, with key secondary end points including DOR, PFS, OS, and safety.

Investigators enrolled 90 patients who had been diagnosed with MSI-H/dMMR endometrial cancer from February 1, 2016, to September 23, 2020. At the data cutoff of October 5, 2020, a total of 79 patients had been treated with 1 or more doses of pembrolizumab. The population had a median age of 64 years (range, 42-86) and the majority had an ECOG performance status of 1 (61%). Almost half (48%) of the patients received 2 or more previous lines of therapy, with 68% previously undergoing treatment with radiation therapy.

Patients had a median treatment duration of 8.3 months. A total of 58% of patients had discontinued treatment, 20% completed all 35 cycles of treatment, and 22% were continuing treatment at the time of data cut off. The median time from first dose to data cut off was 42.6 months. Investigators stated that 14% of patients had a complete response (CR), 34% had a partial response, and 18% had stable disease, nearly all of whom experienced a reduction in tumor size (n = 13). Among the 75 patients who were evaluable for efficacy, 75% had a reduction from baseline in lesion size. Moreover, 21 of 38 patients confirmed responders had an ongoing response at the time of data cut off, 8 of whom with a CR.

A total of 57% of the patient population had progressed or died at the data cut off, 37% of whom had died. Investigators reported that the estimated PFS rate was 51% at 1 year, 41% at 2 years, and 37% at 3 and 4 years.

Adverse effects (AEs) occurred in 76% of patients, with 12% of patients experiencing grade 3/4 AEs. Notably, investigators did not report any fatal treatment-related AEs. The most common any-grade AEs were pruritus (24%), fatigue (21%), and diarrhea (16%). Few grade 3 AEs or higher occurred during the study and included hyperglycemia (2%), decreased lymphocyte count (2%), and increased transaminases (2%). Two instances of grade 4 enterocolitis and decreased neutrophil count took place in 1 patient, with both AEs having been resolved.

Immune-mediated AEs occurred in 28% of patients, the more frequent being hypothyroidism (14%), hyperthyroidism (8%), and infusion reactions (4%). Although most immune-mediated AEs were grade 1/2, 6 patients had grade 3/4 toxicities, including severe skin reactions (n = 2), adrenal insufficiency (n = 1), colitis (n = 1), hepatitis (n = 1), and type 1 diabetes mellitus (n = 1).

“Pembrolizumab demonstrated robust and durable antitumor activity with manageable toxicity in patients with advanced MSI-H/dMMR endometrial cancer. These findings support the use of pembrolizumab as a treatment option for patients with advanced MSI-H/dMMR endometrial cancer with treatment failure on prior therapy,” the investigators concluded.


  1. O'Malley D, Bariani GM, Cassier PA, et al. Pembrolizumab in patients with microsatellite instability–high advanced endometrial cancer: results from the KEYNOTE-158 study. J Clin Oncol. Published online January 6, 2022. doi:10.1200/JCO.21.01874
  2. Immunotherapy drug shows promise in advanced endometrial cancer. News release. Ohio State University Comprehensive Cancer Center–The James. January 6, 2022. Accessed January 10, 2022.