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Lenvatinib Plus Pembrolizumab Doubles Five-Year Survival Over Chemotherapy in Advanced Endometrial Cancer
At five years of follow-up, nearly 20% of all-comer patients with previously treated advanced endometrial cancer remained alive on lenvatinib plus pembrolizumab compared with 7.7% on chemotherapy, representing a more than twofold survival advantage that was sustained across both mismatch repair subgroups. This durable benefit, confirmed after a median follow-up exceeding five and a half years, reinforces the combination’s standing as a reference regimen in this setting.
What Was Studied
This study examined whether the long-term survival benefit of lenvatinib combined with pembrolizumab over standard chemotherapy, originally demonstrated at primary analysis, is maintained at five years in patients with advanced, recurrent, or metastatic endometrial cancer who had progressed after one prior platinum-based regimen. The question carries particular weight given the historically poor prognosis of this population and ongoing debate about the durability of immunotherapy-based responses.
How It Was Studied
Study 309/KEYNOTE-775 is a randomized, open-label, phase 3 trial (NCT03517449) that enrolled 827 participants with measurable advanced or recurrent endometrial cancer who had received one prior platinum-based chemotherapy and had no prior exposure to PD-1 or PD-L1 inhibitors. Participants were assigned in a 1:1 ratio to receive either lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every three weeks (for up to 35 cycles) or physician’s choice chemotherapy with doxorubicin or paclitaxel. The current report reflects a data cut-off of February 26, 2025, yielding an overall median follow-up of 68.8 months. Co-primary endpoints were overall survival and progression-free survival assessed by blinded independent central review per RECIST v1.1; objective response rate and safety were secondary endpoints.
What Was Observed
- Overall survival at five years was more than doubled across all patient groups. In the all-comer population, 19.9% of patients on lenvatinib plus pembrolizumab were alive at five years versus 7.7% on chemotherapy. The benefit was most pronounced in mismatch repair-deficient tumors (36.5% vs. 9.8%) but remained meaningful in the larger mismatch repair-proficient subgroup (16.7% vs. 7.3%).
- Progression-free survival at five years similarly favored the combination across all subgroups. In all-comers, 9.8% of combination-arm patients remained progression-free at five years versus 3.2% on chemotherapy. In mismatch repair-deficient disease, this gap widened substantially (26.4% vs. 10.8%), indicating a subset of patients with enduring disease control potentially consistent with long-term remission.
- Treatment-related discontinuation rates were considerably higher with the combination than with chemotherapy. Any treatment discontinuation due to treatment-related adverse events occurred in 32.3% of combination-arm participants versus 5.9% in the chemotherapy arm, a pattern consistent with the known toxicity profile of this regimen and without new safety signals emerging at extended follow-up.
- Despite more frequent use of subsequent therapies in the chemotherapy arm, the survival advantage was preserved. Subsequent systemic anticancer therapy was received by 51.2% of chemotherapy-arm patients versus 44.8% in the combination arm, and notably 10.1% of chemotherapy-arm patients later crossed over to lenvatinib plus pembrolizumab. The authors report that efficacy results remained consistent with the primary analysis despite this crossover.
Why This Matters
Five-year outcome data from phase 3 trials in recurrent endometrial cancer are rare, and this report provides some of the most mature evidence available for an immunotherapy-based combination in this disease. The persistence of a survival benefit in both mismatch repair-proficient and mismatch repair-deficient tumors challenges earlier assumptions that checkpoint inhibitor benefit in endometrial cancer might be restricted to biomarker-selected populations. The data also help characterize the long-term toxicity landscape, an important consideration for treatment planning research.
How to Read This Result
While the extended follow-up substantially strengthens confidence in durability, the open-label design and the presence of crossover in the chemotherapy arm introduce potential confounders that may modestly underestimate the true magnitude of benefit.
Limitations
The abstract does not explicitly report study limitations, though the authors note that increased use of subsequent systemic therapies and crossover to lenvatinib plus pembrolizumab in the chemotherapy group represent contextual factors that could influence interpretation of long-term survival outcomes.