Pembrolizumab/Chemo Extends PFS In Advanced/Recurrent Endometrial Cancer

“In our trial, the efficacy curves in the two MMR cohorts separated early in the course of treatment, with a preserved separation throughout the evaluation period,” according to the study authors.

The addition of pembrolizumab (Keytruda) to standard chemotherapy significantly prolonged progression-free survival (PFS) compared with placebo among patients with advanced or recurrent endometrial cancer, according to findings from a phase 3 clinical trial (NCT03914612) published recently in The New England Journal of Medicine.

Treatment with pembrolizumab yielded a 70% difference in the relative risk of disease progression or death vs placebo among patients with mismatch repair­–deficient (dMMR) disease; Kaplan-Meier estimates of PFS rates at 12 months were 74% in the pembrolizumab cohort compared with 38% in the placebo cohort (Hazard ratio [HR], 0.30; 95% CI, 0.19-0.48; P <.001). Median PFS in this cohort was not reached (NR) with pembrolizumab (95% CI, 30.6-NR) vs 7.6 months with placebo (95% CI, 6.4-9.9).

Moreover, among patients with mismatch repair–proficient (pMMR) disease, the median PFS was 13.1 months (95% CI, 10.5-18.8) with pembrolizumab vs 8.7 months with placebo (95% CI, 8.4-10.7; HR, 0.54; 95% CI, 0.41-0.71; P < .001). Pembrolizumab thus yielded a 46% reduction in risk of progression or death.

The mediation duration of follow-up was 12 months in the dMMR cohort compared with 7.9 months in the pMMR cohort. The trial population included patients with either measurable disease (stage III or IVA), stage IVB disease, or recurrent disease.

“In our trial, the efficacy curves in the two MMR cohorts separated early in the course of treatment, with a preserved separation throughout the evaluation period,” the investigators wrote. “This benefit was observed in most subgroups, including among patients who had received previous adjuvant chemotherapy or radiation and among those with less common histologic subtypes. The question of whether pembrolizumab plus chemotherapy has greater efficacy than pembrolizumab monotherapy in patients with newly diagnosed, advanced-stage or recurrent dMMR endometrial cancer warrants additional study.”

This double-blind, randomized, phase 3 trial included 816 patients from July 2019 to December 2022, of whom 225 had dMMR disease, 591 had pMMR disease, and 588 were evaluable for the efficacy analysis. Roughly 6% of patients in the dMMR cohort had received prior adjuvant chemotherapy; the corresponding figure was 25.3% in the pMMR cohort. Approximately 43.0% and 39.6% of patients had received radiotherapy in the dMMR and pMMR cohorts, respectively.

Demographic factors were relatively similar across all treatment subgroups. Patients had a median age of 65.5 years (range, 29-93), with median subgroup ages ranging from 65 to 67 years. Patients were most commonly White (72.1%), Black (16.3%), or Asian (5.3%), and 6.3% of the population identified as Hispanic. Notably, 8.9% of patients identified as Black in the dMMR cohort, whereas 16.3% identified as Black in the pMMR cohort.

Most patients had an ECOG performance status of 0 (67%) or 1 (29.9%). The vast majority (86.1%) had received prior surgery.

The patients included in the trial were randomly assigned 1:1 to receive paclitaxel plus carboplatin along with either pembrolizumab or placebo for 6 cycles, followed by pembrolizumab or placebo maintenance every 6 weeks for up to 14 cycles. Initial treatment consisted of intravenous pembrolizumab or placebo at a dose of 200 mg via a 30-minute infusion every 3 weeks in combination with chemotherapy; maintenance therapy consisted of intravenous pembrolizumab or placebo at a dose of 400 mg via a 30-minute infusion every 6 weeks.

The chemotherapy employed consisted of intravenous paclitaxel at a dose of 175 mg/m2 in a 3-hour infusion plus intravenous carboplatin at an area under the curve of 5 mg/ml per minute administered over 30 to 60 minutes.

In the dMMR cohort, grade 3 or higher adverse events (AEs) occurred in 63.3% of patients treated with pembrolizumab and 47.2% of those treated with placebo; the corresponding figures in the pMMR cohort were 55.1% and 45.3%, respectively. The most frequent any-grade AEs across all subgroups were anemia, nausea, and constipation, whereas the most frequent grade 3 or higher AEs across all subgroups were anemia and neutropenia.

Grade 5 AEs occurred in 3 patients in the dMMR cohort, including 1 in the pembrolizumab group and 2 in the placebo group. This included 1 instance each of cardiac arrest, sepsis, and lower gastrointestinal hemorrhage.

Grade 5 AEs occurred in 8 patients in the pMMR cohort, including 6 in the pembrolizumab group and 2 in the placebo group. The AEs comprised sepsis in 4 patients, cardiac arrest in 2, small intestinal obstruction in 1, and sudden death not otherwise specified in 1. Investigators deemed 1 instance of grade 5 cardiac arrest in the pMMR cohort to be potentially related to pembrolizumab.

“A limitation of this trial is the relatively short duration of follow-up. Although protocol-specified criteria were met for the primary efficacy analysis of [PFS] in both the dMMR and pMMR cohorts, safety and efficacy monitoring are ongoing,” the investigators concluded. “[Nonetheless], our results show that pembrolizumab in combination with chemotherapy and continued as maintenance therapy led to significantly longer [PFS] than placebo in patients with dMMR and pMMR endometrial cancers.”

Reference

Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2302312