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


Pembrolizumab has been approved by the FDA for the use in advanced microsatellite instability–high/mismatch repair–deficient endometrial cancer following prior systemic therapy.

The FDA has approved pembrolizumab (Keytruda) for advanced microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) advanced endometrial cancer following prior systemic therapy in any setting, according to a press release from the FDA.1 

For this indication, MSI-H/dMMR status must be determined by an FDA-approved test.

The approval was supported results from cohorts D and K of the phase 2 KEYNOTE-158 trial (NCT02628067) in which patients with previously treated advanced MSI-H or dMMR endometrial cancer were given 200 mg of pembrolizumab once every 3 weeks for 35 cycles.2 

The overall response rate via independent central review was 46% (95% CI, 35%-56%) and the median duration of response was not reached, with 68% of patients having responses lasting at least 12 months and 44% lasting at least 24 months.

A total of 90 patients with MSI-H/dMMR endometrial cancer were evaluated from either trial cohort D (n = 11), comprised of patients with endometrial cancer regardless of MSI-H/dMMR status, or cohort K (n = 79), which assessed those with any MSI-H/dMMR solid tumor. At data cutoff of October 2020, 79 patients had received 1 or more doses of pembrolizumab and were enrolled 26 weeks or more before the cutoff, comprising the efficacy analysis population. Patients had a median age of 64 years and 61% had an ECOG score of 1. Additionally, 48% of patients received 2 or more lines of prior therapy, and 68% had previously undergone treatment with radiation therapy.

Patients received 200 mg of pembrolizumab intravenously every 3 weeks until disease progression or unacceptable toxicity. Those who did not have disease progression could be treated up to 24 months.

The median duration of treatment was 8.3 months, and 52 patients had discontinued treatment by cutoff. Eighteen patients completed 35 cycles of treatment, and 20 remained on treatment. Additionally, 2 patients received second course pembrolizumab. The median time from first dose to data cutoff was 42.6 months.

The treatment yielded an objective response rate (ORR) of 48% (95% CI, 37%-60%) by independent central radiologic review, which included 11 complete responses (CR), 27 partial responses, and 14 cases of stable disease. Thirteen patients experienced a reduction in tumor size from baseline.

Additionally, 21 of 38 patients with a confirmed response had an ongoing response at data cutoff, including 8 patients with CR. The median duration of response was not reached. The proportion of patients with a response for 1 year or more was 88%, 73% for 2 years or more, and 68% for 3 years or more.

For patients who received less than 2 lines of therapy (n = 38), the ORR was 53% (95% CI, 36%-69%), and 44% (95% CI, 28%-60%) for those who had 2 or more lines of therapy (n = 41). In 56 patients who underwent prior radiation therapy, the overall response rate was 52% (95% CI, 38%-65%) and 39% (95% CI, 20%-61%) for those with no prior radiation therapy.

Disease progression or death was observed in 45 patients at data cutoff, with 29 patients dying. The median progression-free survival (PFS) was 13.1 months (95% CI, 4.3-34.4). The estimated 1-year PFS rate was 51%, 41% at 2 years, and 37% at 3 and 4 years. The estimated overall survival rate at 1 year was 69%, 64% at 2 years, and a plateau of 60% at 3 and 4 years.

Of the 90 patients in the safety analysis, adverse effects (AEs) occurred in 68 patients, with grade 3/4 AEs occurring in 11. No patients experienced fatal treatment-related AEs (TRAEs).

Grade 3 or higher TRAEs included hyperglycemia and decreased lymphocyte count which occurred in 2 patients. Grade 4 AEs occurred in 1 patient, which included enterocolitis and decreased neutrophil count. Treatment discontinuation was required in 6 patients because of TRAEs such as increased transaminases (n = 2), arthritis (n = 1), drug-induced liver injury (n = 1), enterocolitis (n = 1), and rash (n = 1).

Immune-mediated AEs and infusion reactions were observed in 25 patients. Although the most common events were grade 1/2, grade 3/4 immune-related AEs were observed in 6 patients and included severe skin reaction (n = 2), adrenal insufficiency (n = 1), colitis (n = 1), hepatitis (n = 1), and type 1 diabetes mellitus (n = 1).

No grade 4/5 infusion reactions or grade 5 immune-meditated AEs were observed. Additionally, 2 patients discontinued treatment due to colitis or hepatitis related to treatment, both of which were resolved or being resolved.


1. FDA Approves pembrolizumab for advanced endometrial carcinoma. News Release. FDA. March 21, 2022. Accessed March 21, 2022. https://bit.ly/3IuSE0O

2. 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

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