KEYTRUDA® (pembrolizumab) Plus LENVIMA® (lenvatinib) Shows Durable 5-Year Survival Benefit Over Chemotherapy in Advanced Endometrial Carcinoma
Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced updated five-year follow-up data from the pivotal Phase 3 KEYNOTE-775/Study 309 trial. The results confirm that the combination of KEYTRUDA® (pembrolizumab), Merck’s anti–PD-1 therapy, and LENVIMA® (lenvatinib), Eisai’s orally available multiple receptor tyrosine kinase inhibitor (TKI), continues to deliver durable survival benefits compared with chemotherapy in patients with advanced endometrial carcinoma previously treated with at least one platinum-based regimen.
The long-term findings, presented at the European Society for Medical Oncology (ESMO) Congress 2025 in Berlin (Poster #1119P), represent the longest follow-up reported for an immunotherapy and TKI combination in this setting.
Study Overview and Patient Population
The trial enrolled 827 patients with advanced endometrial carcinoma, including 697 with mismatch repair–proficient (pMMR) and 130 with mismatch repair–deficient (dMMR) tumors. Participants were randomized 1:1 to receive either KEYTRUDA (200 mg IV every three weeks) plus LENVIMA (20 mg orally once daily) or the physician’s choice of chemotherapy (doxorubicin or paclitaxel).
Primary endpoints were overall survival (OS) and progression-free survival (PFS) in the pMMR and overall (all-comers) populations. Secondary endpoints included objective response rate (ORR) and safety outcomes.
Durable Five-Year Survival Benefi
After a median follow-up of nearly 69 months, the combination therapy demonstrated a clear, long-term survival advantage across key subgroups.
In the pMMR population, the five-year OS rate was 16.7% with KEYTRUDA plus LENVIMA compared to 7.3% with chemotherapy. Median OS reached 18.0 months (95% CI, 14.9–20.5) versus 12.2 months (95% CI, 11.0–14.1) for chemotherapy, representing a 30% reduction in the risk of death (HR 0.70; 95% CI, 0.60–0.83).
In the all-comers population (including both pMMR and dMMR patients), results were similarly favorable. The five-year OS rate was 19.9% for KEYTRUDA plus LENVIMA versus 7.7% for chemotherapy, with a median OS of 18.7 months (95% CI, 15.6–21.3) compared with 11.9 months (95% CI, 10.6–13.3) for chemotherapy (HR 0.66; 95% CI, 0.57–0.77).
These outcomes align closely with earlier findings reported at the Society of Gynecologic Oncology (SGO) 2021 Annual Meeting and published in the New England Journal of Medicine. Importantly, no new safety signals were observed with longer follow-up, and the combination’s safety profile remained consistent with prior analyses.
Expert Perspectives
“Endometrial carcinoma in the advanced or recurrent setting remains particularly challenging, especially for patients with mismatch repair–proficient disease that typically shows limited response to immunotherapy alone,” said Dr. Vicky Makker, Principal Investigator and Gynecologic Oncologist at Memorial Sloan Kettering Cancer Center. “These five-year results reinforce that pembrolizumab plus lenvatinib provides meaningful, sustained survival benefit for these patients following prior platinum-based therapy.”
Dr. Gregory Lubiniecki, Vice President, Global Clinical Development at Merck Research Laboratories, emphasized the broader significance of these findings: “The durability of response observed with KEYTRUDA plus LENVIMA reflects our continued commitment to advancing therapies that extend survival and improve quality of life for patients facing difficult-to-treat cancers.”
Dr. Corina Dutcus, Senior Vice President and Oncology Global Clinical Development Lead at Eisai Inc., added: “This represents the longest follow-up for any trial evaluating an immunotherapy and TKI combination in advanced endometrial carcinoma. We are deeply grateful to the patients, their families, and the investigators who made this milestone possible.”
Safety and Adverse Events
Treatment-related adverse events (TRAEs) occurred in 97.3% of patients receiving KEYTRUDA plus LENVIMA compared with 93.8% of those receiving chemotherapy. Discontinuation of one or both study drugs due to adverse events occurred in 40.1% of patients in the combination arm (16.0% discontinued both agents) versus 8.0% with chemotherapy.
The most frequent TRAEs (≥20%) for KEYTRUDA plus LENVIMA were hypertension (61.8%), hypothyroidism (55.7%), diarrhea (43.3%), nausea (40.1%), decreased appetite (37.9%), fatigue (28.8%), proteinuria (27.6%), vomiting (24.4%), arthralgia (23.9%), weight loss (22.7%), and hand-foot syndrome (20.7%). No unexpected toxicities emerged during long-term treatment.
Progression-Free Survival and Response Rates
The combination also demonstrated sustained improvements in progression-free survival and response rates over chemotherapy.
- In the pMMR subgroup, five-year PFS was 6.3% with KEYTRUDA plus LENVIMA vs 2.1% with chemotherapy. Median PFS was 6.7 months vs 3.8 months, and the five-year ORR was 32.4% vs 14.8%.
- In the all-comers population, five-year PFS was 9.8% vs 3.2%, median PFS 7.3 months vs 3.8 months, and ORR 33.8% vs 14.4% for chemotherapy.
Among dMMR patients, who represented a smaller cohort, outcomes were even more favorable. The five-year OS rate was 36.5% for KEYTRUDA plus LENVIMA compared with 9.8% for chemotherapy, and median OS was 31.9 months versus 8.6 months. PFS at five years reached 26.4% versus 10.8%, and the ORR was 41.5% versus 12.3%, respectively.
Regulatory Approvals and Ongoing Impact
Based on the 2021 primary analysis of KEYNOTE-775/Study 309, the combination therapy is already approved in the U.S., European Union, and Japan for the treatment of advanced or recurrent endometrial carcinoma following prior systemic therapy, regardless of mismatch repair status.
Lenvatinib is also marketed as KISPLYX® in the EU for advanced renal cell carcinoma.
The five-year findings presented at ESMO 2025 provide robust, long-term evidence supporting the continued use of pembrolizumab plus lenvatinib as a standard of care for patients with previously treated advanced endometrial carcinoma.
About KEYNOTE-775/Study 309:
This Phase 3, multicenter, randomized, open-label study (ClinicalTrials.gov: NCT03517449) compared KEYTRUDA plus LENVIMA against physician’s choice of chemotherapy. Treatment continued until disease progression, unacceptable toxicity, or a maximum of 35 cycles for pembrolizumab. The study’s design, rigorous oversight, and independent review confirm the reliability and clinical significance of these durable survival results.
