Merck and Eisai announced long-term follow-up data from the Phase 3 KEYNOTE-775/Study 309 trial showing sustained survival benefits of KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) compared to chemotherapy in patients with advanced endometrial carcinoma following at least one prior platinum-based regimen. The findings were presented at the European Society for Medical Oncology (ESMO) Congress 2025 in Berlin, Germany.
Five-Year Survival Results
The trial randomized 827 patients (697 with mismatch repair proficient [pMMR] disease and 130 with mismatch repair deficient [dMMR] disease) to receive either KEYTRUDA plus LENVIMA (n=411) or chemotherapy (n=416). After a median follow-up of 68.8 months, the five-year overall survival (OS) rate in the pMMR subgroup was 16.7% for the combination therapy versus 7.3% for chemotherapy alone.
Median OS was 18.0 months (95% CI, 14.9-20.5) for KEYTRUDA plus LENVIMA versus 12.2 months (95% CI, 11.0-14.1) for chemotherapy alone (HR 0.70; 95% CI, 0.60-0.83). The results in the pMMR subgroup were consistent with the all-comers population, which demonstrated an OS rate of 19.9% for the combination versus 7.7% for chemotherapy, with median OS of 18.7 months versus 11.9 months respectively (HR 0.66; 95% CI, 0.57-0.77).
Progression-Free Survival and Response Rates
In the pMMR subgroup, KEYTRUDA plus LENVIMA demonstrated a five-year progression-free survival (PFS) rate of 6.3% versus 2.1% for chemotherapy alone. Median PFS was 6.7 months (95% CI, 5.6-7.4) for the combination versus 3.8 months (95% CI, 3.6-5.0) for chemotherapy alone. The objective response rate (ORR) at five years was 32.4% (95% CI, 27.5-37.6) for KEYTRUDA plus LENVIMA compared with 14.8% (95% CI, 11.3-19.0) for chemotherapy.
Similar benefits were observed in the all-comers population, with a five-year PFS rate of 9.8% versus 3.2% for chemotherapy alone, and an ORR of 33.8% versus 14.4% respectively.
Clinical Significance
"Endometrial carcinoma is difficult-to-treat in the recurrent or advanced stage, especially when tumors are mismatch repair proficient and therefore harder to target with immunotherapy alone," said Dr. Vicky Makker, Principal Investigator and Gynecologic Medical Oncologist at Memorial Sloan Kettering Cancer Center. "Five-year follow-up data from the KEYNOTE-775/Study 309 trial show sustained survival benefit in patients treated with pembrolizumab plus lenvatinib and underscore the role of this combination as an effective treatment option."
Dr. Corina Dutcus, Senior Vice President, Oncology Global Clinical Development Lead at Eisai Inc., noted that "the five-year results from KEYNOTE-775/Study 309 represent the longest reported follow-up for a trial evaluating an immunotherapy plus tyrosine kinase inhibitor combination in advanced endometrial carcinoma."
Safety Profile
Treatment-related adverse events (TRAEs) occurred in 97.3% of patients receiving KEYTRUDA plus LENVIMA versus 93.8% of patients receiving chemotherapy. The combination led to discontinuation of treatment in 40.1% of patients (16.0% discontinued both drugs) versus 8.0% for chemotherapy. The most common adverse events (≥20%) in the combination group 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%), decreased weight (22.7%) and palmar-plantar erythrodysesthesia syndrome (20.7%).
The five-year analysis revealed no new safety signals, and the safety profile remained consistent with previously reported data on the combination.
Study Design and Patient Population
KEYNOTE-775/Study 309 is a Phase 3, multicenter, open-label, randomized, active-controlled study evaluating KEYTRUDA plus LENVIMA versus chemotherapy (doxorubicin or paclitaxel) in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen. The primary efficacy outcome measures were OS and PFS as assessed by blinded independent central review according to RECIST v1.1.
At the data cut-off (February 26, 2025), 86 patients were alive after treatment with KEYTRUDA plus LENVIMA, compared to 53 patients treated with chemotherapy. In the all-comers population, 44.8% of patients treated with the combination and 51.2% of patients treated with chemotherapy used subsequent systemic anticancer therapy.
Disease Context
Endometrial carcinoma begins in the inner lining of the uterus and is the most common type of uterine cancer, representing more than 90% of uterine body cancers. In the U.S., approximately 69,120 patients are estimated to be diagnosed with uterine body cancer and approximately 13,860 patient deaths are expected from the disease in 2025. Globally, endometrial cancer is the sixth most common cancer in women and the 15th most common cancer overall.
Based on the primary analysis results from this trial, KEYTRUDA plus LENVIMA is approved in the U.S. for patients with advanced endometrial carcinoma that is pMMR or not microsatellite instability-high (MSI-H), as determined by an FDA-approved test, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.
