Mixed Results for Adjuvant Pembro in Endometrial Cancer

BARCELONA, Spain — New phase 3 findings revealed that most patients with newly diagnosed high-risk endometrial cancer did not benefit from receiving adjuvant immunotherapy alongside chemotherapy following surgery with curative intent.

In the ENGOT-en11/GOG-3053/KEYNOTE-B21 trial, adding pembrolizumab to adjuvant chemotherapy did not improve disease-free survival in the “all-comer” intention-to-treat population. However, in prespecified subgroup analyses, patients with mismatch repair-deficient (dMMR) tumors did demonstrate a significant and clinically meaningful improvement in disease-free survival with immune checkpoint inhibitor therapy.

The study results, presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2024, were simultaneously published in Annals of Oncology.

The reason for this finding of no disease-free survival difference in most patients “is unclear,” wrote Toon Van Gorp, MD, with Leuven Cancer Institute in Leuven, Belgium, and his fellow study authors. In fact, these results contrast with the clinically meaningful improvement in progression-free survival seen in the pembrolizumab trial published last year, Gorp and colleagues added.

That 2023 trial showed that the addition of pembrolizumab to chemotherapy significantly improved outcomes in advanced or recurrent endometrial cancer, regardless of MMR status.

The ENGOT-en11/GOG-3053/KEYNOTE-B21 trial evaluated this approach in patients with newly diagnosed high-risk disease.

The study enrolled 1095 patients who had undergone surgery with curative intent and had no evidence of disease postoperatively and no prior radiotherapy or systemic therapy.

Patients were randomly allocated (1:1) to receive adjuvant pembrolizumab (200 mg) or placebo every 3 weeks for six cycles plus carboplatin-paclitaxel, followed by pembrolizumab 400 mg or placebo every 6 weeks for four or six cycles. Radiotherapy was at the investigator’s discretion.

The coprimary endpoints were investigator-assessed disease-free survival and overall survival in the intention-to-treat population. Median follow-up was 23.9 months.

In the overall intention-to-treat population, there was no difference in 2-year disease-free survival rates, which were 75% in the pembrolizumab group and 76% in the placebo group (hazard ratio [HR], 1.02).

In contrast, in the dMMR subgroup, 2-year disease-free survival rates were significantly improved in the pembrolizumab group — 92% vs 80% without (HR, 0.31).

During his talk, Van Gorp explained that the dMMR subgroup represents about 25% of the population — a population well-established to have a high tumor mutational burden and an inflamed phenotype with elevated programmed death ligand 1 (PD-L1) expression. In this population, anti-programmed cell death protein 1/PD-L1 therapies have demonstrated potent antitumor activity across treatment settings.

However, in the mismatch repair-proficient subgroup, adding adjuvant pembrolizumab did not lead to a significant disease-free survival benefit, with 2-year rates at 75% with pembrolizumab vs 69% without (HR, 1.20).

The pembrolizumab group did experience more grade 3 or higher adverse events (71% vs 63%), “which is expected when you add an additional treatment,” but the safety profile of combination therapy appeared “manageable,” Van Gorp noted.

While the overall results are “disappointing,” they are also “game-changing” and could represent a “new standard of care” for the dMMR subgroup, said study discussant Christian Marth, MD, PhD, with Medical University of Innsbruck in Innsbruck, Austria.

In Marth’s view, carboplatin, paclitaxel, and pembrolizumab should be considered as adjuvant treatments in dMMR, high-risk endometrial carcinoma.

The trial “gives us important information indicating that patients with endometrial dMMR tumors are more sensitive and reactive to immunotherapy,” Elene Mariamidze, MD, medical oncologist with Todua Clinic, Tbilisi, Georgia, who was not involved in the study, said in an ESMO press release.

Although immunotherapy is beneficial in some gynecological cancers, it is not for all patients, added Isabelle Ray-Coquard, MD, PhD, with the Cancer Research Center of Lyon, Lyon, France.

“We need to focus on which subgroups of patients with particular gynecological cancers benefit from immunotherapy,” Ray-Coquard said in the release. “Findings on the subgroup with newly diagnosed endometrial dMMR tumors offer a powerful example that identifying a good biomarker enables us to change a patient’s story definitively.”

Funding for the study was provided by Merck Sharp & Dohme. Van Gorp reported various relationships with AbbVie, AstraZeneca, Amgen, BioNTech, Eisai, GSK, ImmunoGen, Incyte, Karyopharm Therapeutics, Inc., Merck Sharp & Dohme, OncXerna Therapeutics, Inc., Seagen, Tubulis, Zentalis Pharmaceuticals, Inc., and PharmaMar. Marth has disclosed relationships with Novartis, Merck, PharmaMar, AstraZeneca, GlaxoSmithKline, Pfizer, ImmunoGen, Daiichi Sankyo, BioNTech, Novocure, AbbVie, Seagen, and Eisai.