FDA Approves Pembrolizumab for Select MSI-H/dMMR Advanced Endometrial Cancer


The FDA has approved pembrolizumab for use as a single agent in the treatment of patients with advanced endometrial carcinoma that is microsatellite instability–high or mismatch repair deficient, and who experienced disease progression following previous systemic therapy in any setting and are not candidates for curative surgery or radiation.



The FDA has approved pembrolizumab (Keytruda) for use as a single agent in the treatment of patients with advanced endometrial carcinoma that is microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR), and who experienced disease progression following previous systemic therapy in any setting and are not candidates for curative surgery or radiation.1

The regulatory decision is based on findings from cohorts D and K of the phase 2 KEYNOTE-158 trial (NCT02628067). At a median follow-up of 16.0 months (range, 0.5-62.1), the immunotherapy was found to elicit an objective response rate of 46% (95% CI, 35%-56%), with a complete response (CR) rate of 12% and a partial response (PR) rate of 33%.

Notably, among the 41 responders, 68% experienced responses that persisted for 12 months or longer, and 44% experienced responses that lasted for 24 months or longer. Moreover, the median duration of response (DOR) with pembrolizumab in these patients had not yet been reached (range, 2.9-55.7+).

“New data from the KEYNOTE-158 trial showed an objective response rate of 46% for certain patients with advanced endometrial carcinoma that is MSI-H or dMMR treated with [pembrolizumab],” David M. O’Malley, MD, of the Division of Gynecologic Oncology at The Ohio State University Wexner Medical Center and The James Comprehensive Cancer Center, stated in a press release. “The objective response rate and duration of response observed in this trial solidify the role of KEYTRUDA as a treatment option for these patients.”

The open-label, multicohort KEYNOTE-158 trial enrolled patients with several types of advanced solid tumors.2 Cohort D of the trial was comprised of those with endometrial carcinoma, and cohort K included those with any advanced solid tumor except for CRC that was MSI-H/dMMR, including endometrial cancer.

To be eligible for enrollment, patients needed to be at least 18 years of age with histologically or cytologically documented advanced metastatic and/or unresectable disease that was incurable. Patients had to have experienced disease progression on, or have intolerance to, standard therapies. Patients also needed to have radiologically measurable disease per RECIST v. 1.1 criteria and ICR review, an ECOG performance status of 0 or 1, and adequate organ function.

If patients had a diagnosis of immunodeficiency, received systemic steroid therapy or immunosuppressive therapy within 7 days of first dose, had active autoimmune disease requiring systemic therapy within 2 years, or received treatment with a monoclonal antibody or an investigational agent within 4 weeks, they were excluded.

Other key exclusion criteria included use of chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks; known active central nervous system metastases and/or carcinomatous meningitis; current pneumonitis or history of pneumonitis that required steroids; and an active infection requiring systemic therapy.

Participants were given pembrolizumab intravenously at a dose of 200 mg on day 1 of each 3-week treatment cycle for 35 cycles, which equated to approximately 2 years. Treatment was administered until documented disease progression, unacceptable adverse effects (AEs), intercurrent illness preventing further treatment, investigator decision, or patient withdrawal of consent

Notably, patients who achieved CR, PR, or stable disease with pembrolizumab were eligible to receive up to 17 cycles of retreatment with the immunotherapy after disease progression, if safety criteria were met.

The primary end point of the trial was ORR, which was defined as the proportion of patients achieving CR or partial response per RECIST v1.1 criteria and ICR review, for patients with an enrolled tumor type and a positive tumor sample for 1 of the prespecified biomarkers, including MSI-H and dMMR. Secondary end points included DOR, progression-free survival (PFS), and overall survival (OS).

Data from the trial were recently published in the Journal of Clinical Oncology. A total of 90 patients with MSI-H and dMMR endometrial cancer were enrolled to cohorts D (n = 11) and K (n = 79) between February 1, 2016, and September 23, 2020. As of the data cutoff, 79 patients were eligible for efficacy analysis after having received at least 1 dose of pembrolizumab and having been enrolled to the trial for at least 26 weeks before cutoff.

The median age of these participants was 64 years (range, 42-86), and 61% had an ECOG performance status of 1. Moreover, 48% had received at least 2 lines of prior therapy, and 68% had previously received radiation treatment. The median duration of treatment was 8.3 months (range, 1 day to 26.9 months).

Findings showed that pembrolizumab produced an ORR of 48% (95% CI, 37%-60%) per independent central radiologic (ICR) review in 79 patients who comprised the efficacy analysis population. Of those who responded, 14% achieved a CR, and 34% experienced a PR.

Notably, 21 of the 38 patients who achieved a CR, including 8 of 11 who had a confirmed CR, had ongoing responses at the time of data cutoff, which was October 5, 2020. Eighteen percent of patients had stable disease, and 13 of those 14 patients experienced a reduction in tumor size from baseline.

Additionally, patients who received less than 2 lines of prior therapy (n = 38) experienced an ORR of 53% (95% CI, 36%-69%) vs an ORR of 44% (95% CI, 28%-60%) in those who received at least 2 prior lines (n = 41). Those who were administered prior radiation therapy (n = 56) experienced an ORR of 52% (95% CI, 38%-65%) with single-agent pembrolizumab vs an ORR of 39% (95% CI, 20%-61%) in those who did not receive prior radiation therapy (n = 23).

The median PFS with pembrolizumab was 13.1 months (95% CI, 4.3-34.4). The estimated 1- and 2-year PFS rates were 51% and 41%, respectively; at 3 and 4 years, this rate was 37%. Moreover, the median OS was not reached in these patients. The Kaplan-Meier estimated 1-year, 2-year, and 3- and 4-year OS rates were 69%, 64%, and 60%, respectively. Fifty-seven percent of patients experienced disease progression or died.

Immune-mediated adverse reactions that can be experienced with the immunotherapy include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications associated with allogeneic hematopoietic stem cell transplantation.

“This FDA approval is great news for women facing advanced endometrial cancer,” Scot W. Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, added in the press release. “We have seen substantial progress in delivering treatment options for patients with advanced endometrial cancer with [pembrolizumab], as monotherapy and in combination, with two approved indications in this area. We remain committed to pursuing meaningful advances in gynecologic and breast cancers through our portfolio of medicines.”


  1. FDA approves Merck's KEYTRUDA (pembrolizumab) for patients with MSI-H/dMMR advanced endometrial carcinoma, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. News release. Merck; March 21, 2022. Accessed March 21, 2022. https://bit.ly/3udt37j
  2. O’Malley DM, 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
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