FDA Approves Pembrolizumab Plus Chemotherapy for Advanced/Recurrent Endometrial Carcinoma

FDA

The FDA has approved pembrolizumab (Keytruda) in combination with carboplatin and paclitaxel, followed by single-agent pembrolizumab, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma.¹

The regulatory decision was supported by data from the phase 3 KEYNOTE-868 trial (NCT03914612), which showed that patients with mismatch repair–deficient (dMMR) disease, those treated in the pembrolizumab plus chemotherapy arm experienced a median progression-free survival (PFS) that was not reached (NR; 95% CI, 30.7-NR) compared with 6.5 months (95% CI, 6.4-8.7) in the placebo plus chemotherapy arm (HR, 0.30; 95% CI, 0.19-0.48; P < .0001).

In patients whose disease was mismatch repair proficient (pMMR), the median PFS was 11.1 months (95% CI, 8.7-13.5) for the pembrolizumab regimen vs 8.5 months (95% CI, 7.2-8.8) for the placebo regimen (HR, 0.60; 95% CI, 0.46-0.78; P < .0001).

The multicenter, randomized, double-blind, placebo-controlled trial enrolled patients at least 18 years of age with advanced-stage, metastatic, or recurrent endometrial cancer of any histologic subtype except for carcinosarcoma. Patients had either newly diagnosed stage III or IVA disease per RECIST 1.1 criteria for measurable disease or stage IVB or recurrent endometrial cancer with or without measurable disease.²

Other key inclusion criteria consisted of institutional results on MMR status per immunohistochemistry (IHC), except for sites in Japan; available biopsy specimens for central IHC assessment; and an ECOG performance-status score of 0 to 2.

The study included 2 cohorts based on MMR status, and within these cohorts, patients were randomly assigned 1:1 to receive a pembrolizumab at 200 mg once every 3 weeks plus paclitaxel at 175 mg/m² and carboplatin at area under the curve 5 mg/mL/min for 6 cycles, followed by pembrolizumab at 400 mg once every 6 weeks for up to 14 cycles; or placebo once every 3 weeks plus the same chemotherapy regimen for 6 cycles, followed by placebo every 6 weeks for up to 14 cycles.¹

Notably, patients with measurable disease who experienced stable disease or a partial response per RECIST 1.1 criteria after cycle 6 were permitted to receive paclitaxel plus carboplatin in combination with pembrolizumab or placebo for up to 10 cycles, per investigator discretion.²

Stratification factors included MMR status (dMMR vs pMMR), ECOG performance status (0 or 1 vs 2), and prior adjuvant chemotherapy (yes vs no).¹

Investigator-assessed PFS served as the trial's primary end point. Secondary end points included safety, overall survival, and health-related quality of life.²

Regarding safety, any-grade, any-cause adverse effects (AEs) were reported in 98.2% of the patients with dMMR disease in the pembrolizumab group vs 99.1% of those in the placebo group. For the pMMR cohort, those respective rates were 93.5% and 93.4%.

In the dMMR cohort, the rates of grade 3 or higher AEs were 63.3% for the pembrolizumab arm compared with 47.2% for the placebo arm. These respective rates were 55.1% and 45.3% in the pMMR group.

AEs led to death in 1.4% of all patients in the dMMR cohort, including 1 patient in the pembrolizumab group and two in the placebo group. Eight patients (1.5%) in the overall pMMR cohort experienced grade 5 AEs events, including 6 in the pembrolizumab group and 2 in the placebo group.

AEs associated with pembrolizumab plus chemotherapy were consistent with previously reported findings for the agents, with the exception of an increased rate of rash.¹

The recommended dose of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.

References

1. FDA approves pembrolizumab with chemotherapy for primary advanced or recurrent endometrial carcinoma. FDA. June 17, 2024. Accessed June 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-primary-advanced-or-recurrent-endometrial-carcinoma
2. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312