Pembrolizumab Monotherapy Adds Option in MSI-H/dMMR Endometrial Cancer

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Partner | Cancer Centers | <b>The Ohio State University Comprehensive Cancer Center - James Cancer Hospital & Solove Research Institute (OSUCCC - James)</b>

The FDA has approved pembrolizumab in patients with advanced endometrial cancer that is microsatellite instability-high or mismatch repair–deficient and who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.

On March 21, 2022, the FDA approved the humanized monoclonal antiPD-1 antibody pembrolizumab (Keytruda) for the treatment of patients with advanced endometrial cancer that is microsatellite instability-high (MSI-H) or mismatch repair–deficient (dMMR) and who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.1

“[This approval] gives these patients an option beyond chemotherapy,” David M. O’Malley, MD, said in an interview with OncologyLive®. “In the past, chemotherapy was quite limited in its response rate and the duration of responses was only 3 to 4 months. With [this] recent update, we see response rates of 46%. If you get a response, the chance that response lasts [at least] 3 years is approximately two-thirds. These are durable responses; we may actually be talking about curative intent in patients with recurrent uterine cancer who are MSI-H or dMMR.”

O’Malley is a professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine and the director of the Division of Gynecologic Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center in Columbus.

The approval was based on data from the phase 2, multicenter, nonrandomized KEYNOTE-158 trial (NCT02628067), which showed that the overall response rate (ORR) was 46% (95% CI, 35%-56%), including a 12% complete response (CR) rate, among 90 patients with advanced MSI-H or dMMR endometrial cancer. Notably, the median duration of response (DOR) was not reached ([NR]; range, 2.9-55.7).2

“In the past, the options were quite limited in patients with recurrent uterine cancer, and there was no differentiating MSI-H or dMMR,” O’Malley said. “This is a great step into personalized medicine [and] really using the molecular changes within tumors to help us differentiate care and treatments.” O’Malley noted that patients with mismatch repair–proficient or MSI-stable disease should not receive single-agent pembrolizumab. “Those patients have an option of pembrolizumab [plus] lenvatinib [Lenvima],” he said. “It’s very important that we prescribe the proper therapies specifically to those patients with MSI-H or dMMR [disease].”

Safety and Efficacy Outcomes in KEYNOTE-158

Cohort D of KEYNOTE-158 was open to patients with endometrial carcinoma; cohort K enrolled patients with advanced solid tumors that were MSI-H or dMMR. Eligible patients had an ECOG performance status of 1 or less, adequate organ function, and were at least age 18 years. Patients with an immunodeficiency diagnosis, active autoimmune disease requiring systemic therapy within 2 years, or who had been treated with a monoclonal antibody or investigational agents within 4 weeks of the study were not included.3

In total, 11 patients from cohort D and 79 patients from cohort K were included in the analysis. Patients were treated with intravenous pembrolizumab 200 mg every 3 weeks for approximately 2 years or until unacceptable toxicity orprogressive disease. Tumor imaging was performed every 9 weeks for the first year of the study and survival was assessed every 12 weeks. Retreatment with pembrolizumab was offered to those who achieved a CR, a partial response, or stable disease prior to discontinuation.

The primary end point was ORR per RECIST 1.1 criteria assessed by independent central radiologic review. Secondary end points consisted of DOR, progression-free survival (PFS), overall survival (OS), and safety.

The median age of patients in cohorts D and K was 64 years (range, 42-86). Most patients had an ECOG performance status of 1 (61%), had received prior radiation therapy (68%), and had prior surgery (87%). Only 1 patient was treatment-naïve, 51% had 1 prior line of therapy, 22% had 2 prior lines, and 26% had 3 or more lines of prior therapy.

Additional results from the trial showed that 68% of patients had a response that lasted at least 1 year and 44% experienced a response lasting at least 2 years.2 Investigators of the study concluded that the response rate elicited from pembrolizumab in KEYNOTE-158 was especially robust when compared with second-line cytotoxic therapies.3

In an analysis of patients who had at least 1 dose of pembrolizumab administered at least 24 weeks prior to data cutoff (n = 79), the median PFS was 13.1 months (95% CI, 4.3-34.4). The 12-month, 24-month, 36-month, and 48-month PFS rates were 51%, 41%, 37%, and 37%, respectively. The median OS was NR (95% CI, 27.2-NR) and the 12-month, 24-month, 36-month, and 48-month PFS rates were 69%, 64%, 60%, and 60%, respectively. In a subgroup analysis stratified by prior lines of therapy, the ORRs were 53% (95% CI, 36%-69%) and 44% (95% CI, 28%-60%) among patients who received 1 previous line of therapy and at least 2 lines of prior therapy, respectively.3

Regarding safety, no adverse effects (AEs) that led to death were reported. Most patients (76%) experienced a treatment-related AE (TRAE) of any grade. Grade 3/4 TRAEs occurred in 12% of patients and 7% of AEs led to treatment discontinuation.2,3

Common TRAEs of any grade included pruritus (24%), fatigue (21%), diarrhea (16%), arthralgia (14%), and nausea (14%). Immune-mediated AEs and/ or infusion reactions of any grade occurred in 28% of patients and consisted of hypothyroidism (14%) and hyperthyroidism (8%), among others. Grade 3/4 immune-mediated AEs and/or infusion reactions were less common, occurring 7% of the time.

“The next steps [in this field] are so exciting,” O’Malley concluded. “We have multiple first-line trials, [one of] which is looking at patients with early-stage disease who are at an intermediate risk of recurrence, combining pembrolizumab with radiation [NCT04214067]. Other trials [will] look at patients who are dMMR or MSI-H and treat them with pembrolizumab vs the standard therapy of carboplatin and paclitaxel. We may be replacing the cytotoxic agents with a single immune therapy. The future is bright for our patients with uterine cancer, thanks to immune therapies.”


  1. FDA approves pembrolizumab for advanced endometrial carcinoma. FDA. March 21, 2022. Accessed May 2, 2022.
  2. Keytruda. Prescribing information. Merck; 2022. Accessed May 2, 2022.
  3. 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. 2022;40(7):752-761. doi:10.1200/JCO.21.01874