On March 21, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) as a single agent for patients with advanced endometrial carcinoma that is microsatellite instability–high or mismatch repair–deficient (as determined by an FDA-approved test). Eligible patients have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
The FDA also approved the VENTANA MMR RxDx Panel (Ventana Medical Systems/Roche Tissue Diagnostics) as a companion diagnostic device to select patients with dMMR in solid tumors that are eligible for treatment with pembrolizumab. The FDA previously approved the FoundationOne CDx (F1CDx, Foundation Medicine, Inc.) as a companion diagnostic device to select patients with MSI-H in solid tumors that are eligible for treatment with pembrolizumab.
Efficacy was evaluated in KEYNOTE-158 (ClinicalTrials.gov identifier NCT02628067), a multicenter, nonrandomized, open-label, multicohort trial in 90 patients with unresectable or metastatic MSI-H or dMMR endometrial carcinoma in cohorts D and K. MSI or MMR tumor status was determined using polymerase chain reaction or immunohistochemistry, respectively. Patients received pembrolizumab at 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients treated with pembrolizumab without disease progression could be treated for up to 24 months.
The major efficacy outcome measures were objective response rate and duration of response as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Objective response rate was 46% (95% confidence interval = 35%–56%). Median duration of response was not reached, with 68% of patients having response durations of at least 12 months and 44% having response durations of at least 24 months.
The most common adverse reactions (≥ 20%) occurring in patients treated with pembrolizumab were fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritis, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism. Immune-mediated side effects are also associated with pembrolizumab; these included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions.
The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.