In 2 MMR Cohorts, Pembrolizumab/Chemotherapy Benefits Survival in Advanced Endometrial Cancer

Ramez N. Eskander, MD

Adding pembrolizumab (Keytruda) to standard-of-care chemotherapy, followed by maintenance pembrolizumab, led to a reduction in risk of disease progression or death in patients with advanced or recurrent endometrial cancer in 2 independent cohorts of patients, according to results of the interim analysis of the NRG GY018 trial (NCT03914612).^1,2

The phase 3 trial evaluated patients whose tumors were mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR), as established by central MMR immunohistochemistry. There was a 70% and 46% reduction in risk in the dMMR and pMMR cohorts, respectively. Findings were presented during the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer and were simultaneously published online in The New England Journal of Medicine.

To be eligible for NRG GY018, patients had to have measurable stage III/IVA, measurable/nonmeasurable stage IVB, or recurrent endometrial cancer; ECOG performance status of 0, 1, or 2; and no prior chemotherapy.

“Importantly, patients were recruited and stratified by dMMR or pMMR status,” lead author Ramez N. Eskander, MD, assistant professor of obstetrics, gynecology, and reproductive sciences at UC San Diego Health in California, said during a presentation of the data.

A total of 816 patients (dMMR = 225; pMMR = 591) were randomly assigned 1:1 to a treatment arm vs a placebo arm. In the treatment arm, patients received 200 mg of pembrolizumab, 175 mg/m² of paclitaxel, and carboplatin every 3 weeks for 6 cycles, followed by 400 mg of pembrolizumab every 6 weeks for up to 14 additional cycles. Patients in the placebo arm received 175 mg/m² of paclitaxel and carboplatin, followed by placebo maintenance on the same schedule.

The primary end point was progression-free survival (PFS) in the dMMR and pMMR populations and the secondary end points were safety, objective response rate (ORR), duration of response (DOR), and overall survival (OS) in dMMR and pMMR populations. Analyses of both populations were conducted separately and independently, Eskander said.

In the dMMR population, 112 patients received pembrolizumab plus chemotherapy treatment and 113 patients received placebo. In the pMMR population, 295 patients received pembrolizumab plus chemotherapy treatment and 296 patients received the placebo.

“The trial was designed such that in the dMMR population, 168 events would result in an 85% power to detect a reduction in the hazard of 40%, or a hazard ratio of 0.60,” Eskander said. “In the pMMR population, at approximately 394 events, [the trial] would have a 90% power to detect a reduction in the hazard of 30% or hazard ratio of 0.70,” he continued.

“These data presented today are reflective of the interim efficacy analysis, which [occurred on] December 6, 2023, for the pMMR population and December 16, 2023, for the dMMR population,” Eskander said.

Median follow-up was 12 months in the dMMR population and 7.9 months for the pMMR population for both the pembrolizumab and placebo arms, respectively. At the data cutoff, between July 2019 and December 2020, 57% of patients were off therapy, with the majority off therapy because of disease progression.

Overall, baseline characteristics between the 2 populations were balanced. Specifically, in the dMMR population, the treatment arm included 82.1% who were White, 9.8% were Black, 4.5% were Hispanic/Latino, and 2.7% were Asian. In the placebo arm, 76.1% were White, 8.0% were Black, 5.3% were Hispanic/Latino, and 3.5% were Asian.

In the pMMR population, investigators reported that in the treatment arm, 72.4 were White, 15.4% were Black, 7.2% were Hispanic/Latino, and 5.8% were Asian. A similar racial breakdown was observed in the placebo arm. This reflects a racially diverse and representative cohort, Eskander said.

Histologically, in the dMMR population treatment arm, 18.8% of patients had endometroid grade 1, 46.4% had grade 2, and 13.4% had grade 3. In the placebo arm, the endometroid grades were 31.0%, 36.3%, and 14.2%, respectively.

“We observed more diverse histologies in the pMMR population, with 26.6% of patients in the treatment arm having serous endometrial cancer and 24.4% in the placebo arm, and 5.8% in the treatment arm having clear cell endometrial cancer and 6.8% of patients in the placebo arm,” Eskander said.

In the dMMR population, patients in the treatment arm did not reach a median PFS vs 7.6 months in the placebo arm (HR, 0.30; 95% CI, 0.19-0.48; P < .00001). In the pMMR population, median PFS was 13.1 months in the treatment arm vs 8.7 months in the placebo arm (HR, 0.54; 95% CI, 0.41-0.71; P < .00001).

Subgroup analysis showed a consistent benefit with pembrolizumab in combination with chemotherapy across relevant subgroups, including patients who received prior radiation therapy, those who received prior systemic adjuvant chemotherapy, and newly diagnosed advanced stage or recurrent patients, as well as patient with more aggressive histologies such as serous and clear cell cohorts.

In terms of safety, in the dMMR population treatment arm, 63.3% of patients experienced grade 3 to 5 adverse events (AEs) vs 47.2% in the placebo arm. In the pMMR population treatment arm, 55.1% experienced grade 3 to 5 AEs and 45.3% experienced grade 3 to 5 AEs in the placebo arm.

AEs with incidence of 15% or more were similar for both populations and there were no new safety signals reported. The frequency of grade 3 or 4 AEs were also similar in both populations. AEs of interest for both cohorts, including potential immune-related etiologies, were slightly more frequent in the pembrolizumab arm for both cohorts. However, 9.4% of patients in the dMMR population who received placebo were diagnosed with hypothyroidism vs 2.6% in the pMMR population who received placebo.

The combination of pembrolizumab to chemotherapy shows clinical benefit in progression-free and overall survival, concluded Eskander.

References:

Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab versus placebo in addition to carboplatin and paclitaxel for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: the phase 3, NRG GY018 study. Presented at: 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, FL.

Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer [published online ahead of print, 2023 Mar 27]. N Engl J Med. 2023. doi:10.1056/NEJMoa2302312