KEYNOTE-775 confirms broad efficacy of lenvatinib plus pembrolizumab in advanced endometrial cancer

The KEYNOTE-775 study systematically confirmed the broad efficacy of lenvatinib/lenvatinib combined with pembrolizumab in the treatment of advanced endometrial cancer, bringing landmark evidence-based evidence to this disease field. This study not only clarified the survival benefit of this combination regimen in the overall population, but also further proved that its efficacy can cover patients with endometrial cancer of different molecular subtypes, which has had a profound impact on clinical practice.

KEYNOTE-775 is an international multi-center, randomized, phase III clinical study, enrolling patients with advanced or recurrent endometrial cancer, and all patients have received platinum-based systemic chemotherapy. The molecular heterogeneity of endometrial cancer was fully considered in the design stage of the study. Patients were divided into mismatch repair proficient and mismatch repair deficient groups according to their mismatch repair status, and stratified randomization was performed on this basis. Patients received either lenvatinib plus pembrolizumab in a 1:1 ratio or a standard chemotherapy regimen selected by the physician, which mainly included doxorubicin or weekly paclitaxel. The core endpoints of the study are blinded and independently assessed progression-free survival and overall survival, and also focus on key efficacy indicators such as objective response.

Judging from the main research results, lenvatinib combined with pembrolizumab is significantly better than the traditional treatment options selected by doctors in multiple efficacy dimensions. The combination showed statistically and clinically meaningful improvements in both progression-free survival and overall survival, as well as a significant increase in objective response levels. This advantage was not limited to a specific population, but was consistent across mismatch repair proficient, mismatch repair deficient, and overall study populations. This stable efficacy across subtypes allowed this regimen to quickly establish an important position in the treatment landscape of advanced endometrial cancer, and eventually promoted it to become one of the standard treatment options for patients who have previously received systemic therapy.

BeforeKEYNOTE-775, lenvatinib combined with pembrolizumab had been explored in multiple solid tumor basket studies and initially showed its anti-tumor activity in endometrial cancer. It has been observed in these early studies that this combination induces relatively reliable disease control regardless of mismatch repair status. However, basket studies have limited sample sizes and lack direct controls, so high-quality randomized studies are still needed for validation. It is in this context that KEYNOTE-775 provides a more solid evidence base for this treatment strategy.

Of particular interest is the study's performance in mismatch repair-proficient endometrial cancer. After relapse or progression, the long-term effective treatment options for such patients are limited, and KEYNOTE-775 showed that lenvatinib combined with pembrolizumab also showed strong efficacy in this population and significantly improved survival outcomes. This finding has important implications for clinical practice because mismatch repair proficient patients account for a larger proportion of recurrent endometrial cancer. At the same time, the combination regimen also achieved encouraging therapeutic effects in people with mismatch repair deficiencies, further confirming its broad-spectrum activity.

From a mechanistic perspective, lenvatinib creates more favorable conditions for immunotherapy by inhibiting multiple signaling pathways related to tumor angiogenesis and the tumor microenvironment, while pembrolizumab enhances the body's immune response to tumors by lifting immune suppression. This complementary combination of mechanisms is considered to be an important reason for its efficacy in different molecular backgrounds. The results of KEYNOTE-775 also confirmed this theoretical hypothesis at the clinical level.

References: UpdatedOctober 21, 2025, https://www.pharmacytimes.com/view/keynote-755-confirms-broad-efficacy-of-lenvatinib-plus-pembrolizumab-in-advanced-endometrial-cancer