Pembrolizumab Plus Chemotherapy Shows Long-Term OS Benefit in Advanced/Recurrent Endometrial Cancer

With approximately 4 years of extended follow-up, pembrolizumab (Keytruda) plus carboplatin and paclitaxel continued to demonstrate an overall survival (OS) benefit over chemotherapy alone in both mismatch repair–deficient (dMMR) and mismatch repair–proficient (pMMR) advanced or recurrent endometrial cancer, according to updated results from the phase 3 NRG-GY018 trial (KEYNOTE-868; NCT03914612) presented at the 2026 ASCO Annual Meeting.¹

In the dMMR cohort (n = 223), at a median follow-up of 49 months across both treatment arms, pembrolizumab plus chemotherapy reduced the risk of death by 44% compared with placebo plus chemotherapy (HR, 0.56; 95% CI, 0.34-0.92; log-rank P = .0124). In the pMMR cohort (n = 586), at a median follow-up of 44 months, OS was directionally favorable for pembrolizumab plus chemotherapy, with an HR of 0.86 (95% CI, 0.69-1.08; log-rank P = .1072). This corresponded to a median OS of 44.4 months (95% CI, 37.8-52.1) vs 35.1 months (95% CI, 30.2-43.8) with placebo.

Subgroup analyses of OS in both the dMMR and pMMR cohorts were generally consistent with the overall findings.

"Importantly, this OS benefit persisted despite substantial post-study immune checkpoint inhibitor [ICI] utilization in the placebo arms of both of these populations. This is the largest proportion of the placebo-treated patients who went on to receive a subsequent ICI strategy amongst all of the contemporary phase 3 trials in this clinical setting. Taken together, these data add great confidence to the established United States and international approvals of this regimen.” -Ramez Eskander, MD, presenter, gynecologic oncologist and professor of Obstetrics, Gynecology, and Reproductive Sciences at UC San Diego Health.

What prior data have been reported from NRG-GY018?

NRG-GY018 previously met its primary end point of progression-free survival (PFS), demonstrating statistically significant improvements with the addition of pembrolizumab to chemotherapy followed by pembrolizumab maintenance in patients with advanced or recurrent endometrial cancer, regardless of MMR status.¹

In the dMMR cohort (n = 225), pembrolizumab plus chemotherapy reduced the risk of disease progression or death by 70% compared with placebo plus CP (HR, 0.30; 95% CI, 0.19-0.48; P < .001), and in the pMMR cohort (n = 591), it reduced the risk by 46% (HR, 0.54; 95% CI, 0.41-0.71; P < .001).² Adverse effects were consistent with the known profiles of the individual agents. Of note, at the time of the primary analysis, OS data were immature but directionally favored pembrolizumab plus chemotherapy.¹

Based on these results, on June 17, 2024, the FDA approved pembrolizumab with carboplatin and paclitaxel, followed by single-agent pembrolizumab, for adult patients with primary advanced or recurrent endometrial carcinoma.³ The regimen was simultaneously included in treatment guidelines for endometrial cancer in the United States and Europe.¹

How was NRG-GY018 designed?

NRG-GY018 was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Eligible patients had measurable stage III or IVA disease, measurable or nonmeasurable stage IVB disease, or recurrent EC, with a pathology report confirming institutional MMR immunohistochemistry results.¹ Additional eligibility criteria included an ECOG performance-status score of 0 to 2 and no prior chemotherapy except prior adjuvant chemotherapy completed at least 12 months before study entry.

A total of 810 patients (pMMR, n = 588; dMMR, n = 222) were randomly assigned 1:1 to either:

• Arm 1: Intravenous (IV) placebo plus 175 mg/m² of IV paclitaxel and IV carboplatin at AUC 5 every 3 weeks for 6 cycles, followed by IV placebo every 6 weeks for up to 14 additional cycles
• Arm 2: IV pembrolizumab at 200 mg plus paclitaxel and carboplatin at the above dosages every 3 weeks for 6 cycles, followed by 400 mg of IV pembrolizumab every 6 weeks for up to 14 additional cycles

Patients were stratified by MMR status (dMMR vs pMMR), ECOG performance status (0 or 1 vs 2), and prior adjuvant chemotherapy (yes vs no). The study’s primary end point was PFS per RECIST 1.1 criteria by investigator assessment in both the pMMR and dMMR cohorts. The focus of this long-term follow-up analysis was updated OS and post-study ICI therapy in both cohorts.

Regarding the trial's statistical design, Eskander noted that OS was a predefined secondary end point without a hierarchical strategy or alpha allocation. "This trial was essentially 2 clinical trials in 1," he explained. "The dMMR and the pMMR populations had a separate statistical analysis plan, separate assumptions, and separate alpha allocations because we understood the biologic strength of checkpoint inhibition in a biomarker-directed dMMR population and wanted to have great confidence [in] the benefit if it existed in the pMMR cohort."

He further noted that unblinding was planned at disease progression because available therapies during the trial's conduct—including ubiquitous availability of single-agent pembrolizumab in pretreated recurrent dMMR patients and lenvatinib (Lenvima) plus pembrolizumab in the pretreated pMMR population—made PFS the appropriate primary end point. Following unblinding, which also occurred for safety concerns related to COVID-19 and at the interim analysis data presentation, there was near-ubiquitous availability of pembrolizumab and lenvatinib plus pembrolizumab for all participants.

What were the updated OS outcomes in the dMMR vs pMMR cohorts?

In the dMMR cohort, the median OS was not reached in both the pembrolizumab plus chemotherapy arm (n = 111) and placebo plus chemotherapy (n = 112) arm (HR, 0.56; 95% CI, 0.34-0.92; log-rank P = .0124). The information fraction was 43.3%. Landmark OS rates in the pembrolizumab vs placebo arms, respectively, were as follows:

• 24 months: 83.5% (95% CI, 75.2%-89.3%) vs 72.1% (95% CI, 62.4%-79.7%)
• 36 months: 79.7% (95% CI, 70.9%-86.2%) vs 68.0% (95% CI, 58.0%-76.1%)
• 48 months: 78.6% (95% CI, 69.6%-85.2%) vs 60.4% (95% CI, 50.0%-69.2%)

In the pMMR cohort, the median OS was 44.4 months (95% CI, 37.8-52.1) with pembrolizumab plus chemotherapy (n = 291) vs 35.1 months (95% CI, 30.2-43.8) with placebo plus chemotherapy (n = 295; HR, 0.86; 95% CI, 0.69-1.08; log-rank P = .1072). The information fraction was 82.1%. Landmark OS rates in the pembrolizumab vs placebo arms were as follows:

• 24 months: 67.0% (95% CI, 61.1%-72.3%) vs 63.4% (95% CI, 57.4%-68.8%)
• 36 months: 57.1% (95% CI, 50.9%-62.7%) vs 49.7% (95% CI, 43.6%-55.5%)
• 48 months: 46.7% (95% CI, 40.0%-53.1%) vs 39.5% (95% CI, 33.0%-46.0%)

How did the utilization of post-study ICI therapy affect OS outcomes?

Among patients who received post-study therapy in the dMMR cohort, 93.2% of patients in the placebo arm received a subsequent ICI, compared with 34.2% in the pembrolizumab arm. In the pMMR cohort, corresponding rates were 81.1% vs 42.9%.

Beyond the overall rates of post-study ICI use reported in each cohort, additional detail on the type of ICI received and the duration of benefit was reported.

In the dMMR cohort, 34.1% of patients in the pembrolizumab arm who received any post-study therapy (n = 41) received post-study ICIs. This included 14.6% who received ICI monotherapy, 14.6% who received lenvatinib plus pembrolizumab, 2.4% who received chemotherapy plus ICI, and 1 (2.4%) who received other ICI-containing therapy. Of the patients in the placebo arm who received any post-study therapy (n = 74), 93.2% received a subsequent ICI. This included 63.5% who received ICI monotherapy, 17.6% who received lenvatinib plus pembrolizumab, 6.8% who received chemotherapy plus ICI, and 9.5% who received other therapy.

"We also looked to understand the clinical benefit of subsequent checkpoint inhibition in the pMMR population, irrespective of whether they were randomized to pembrolizumab or to placebo, to get an understanding of what that might be," Eskander explained. "What we saw was actually quite interesting; the magnitude of benefit was similar in both the pembrolizumab[-treated patients]—the majority of which utilized lenvatinib plus pembrolizumab—and the placebo-treated patients.”

In the pMMR cohort, 48 patients in the pembrolizumab arm and 136 patients in the placebo arm received lenvatinib plus pembrolizumab as post-study therapy. The median time on first post-progression ICI therapy was 6.0 months (95% CI, 4.8-8.1) in the placebo arm and 5.5 months (95% CI, 4.1-5.7) in the pembrolizumab arm (log-rank P = .6462).

The comparable time on post-study post-progression ICI therapy between arms in the pMMR cohort further supports the interpretation that the OS signal reflects frontline pembrolizumab benefit rather than differential post-progression salvage efficacy, Eskander concluded.

Disclosures: Eskander reported serving in a consulting or advisory role for AbbVie; AstraZeneca/MedImmune; BioNTech SE; Daiichi Sankyo/Lilly; Eisai; Gilead Sciences; GlaxoSmithKline; Immunogen; Merck; Myriad Genetics; Pfizer; PMV Pharma; Regeneron; Seagen; receiving research funding from Acrivon Therapeutics (Inst); AstraZeneca (Inst); Corcept Therapeutics (Inst); Daiichi Sankyo/Astra Zeneca (Inst); GlaxoSmithKline (Inst); Merck (Inst); Nivectis (Inst); receiving travel, accommodations, expenses from AstraZeneca/MedImmune; Eisai; Merck; and other relationships with the GOG Foundation.

References

1. Eskander RN, Sill MW, Beffa L, et al. Updated overall survival analysis and examination of subsequent therapy in endometrial cancer participants treated with pembrolizumab plus carboplatin/paclitaxel as compared to CP plus placebo in the NRG-GY018 trial. J Clin Oncol. 2026;44(suppl 16):5002. doi:10.1200/JCO.2026.44.16_suppl.5502
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
3. FDA approves pembrolizumab with chemotherapy for primary advanced or recurrent endometrial carcinoma. FDA. June 17, 2024. Accessed May 29, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-primary-advanced-or-recurrent-endometrial-carcinoma