Survival Benefit of Lenvatinib/Pembrolizumab in Advanced Endometrial Cancer Confirmed, Securing FDA Indication

Globally, there is no established standard of care treatment for this patient population once patients failed on front-line platinum-based chemotherapy. Lenvatinib plus pembrolizumab is a new option.

Progression-free survival (PFS) in patients with advanced endometrial cancer was significantly extended with the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda), according to published results from the KEYNOTE-775/Study 309 trial (NCT03517449).1

The 5-year survival among patients with advanced endometrial cancer who have distant metastases is about 17%. But globally, there is no established standard of care treatment for this patient population once patients failed on front-line platinum-based chemotherapy. Further, the targeted therapies and chemotherapies available at this stage of disease have demonstrated modest efficacy. Following positive results from KEYNOTE-146/Study 111, investigators of KEYNOTE-775 sought to confirm the results.

“While rates of endometrial carcinoma continue to rise globally, patients with advanced or recurrent disease have limited options available to them once the disease progresses following platinum-based chemotherapy,” said Dr. Gregory Lubiniecki, vice president, oncology clinical research, Merck Research Laboratories, in a press release.2

Overall, 827 patients with advanced endometrial cancer, of whom 697 with had mismatch repair–proficient (pMMR) disease and 130 had mismatch repair–deficient disease (dMMR), were included in the study. Patients were randomly assigned in a 1:1 ratio to receive either pembrolizumab 200 mg administered by intravenous (IV) infusion on day 1 of each 21-day cycle plus lenvatinib 20 mg administered orally once daily during each 21-day cycle or the physician’s choice of either paclitaxel or doxorubicin. In the physician’s choice arm, paclitaxel 80 mg/m2 was administered by IV infusion on a 28-day cycle, and doxorubicin 60 mg/m2 was administered by IV infusion on day 1 of each 21-day cycle.

The study was 90% powered to detect an improvement in overall survival (OS) of at least 0.049 level of significance, and it was 99% powered to detect an extension in PFS with a 0.001 significance level, which were the coprimary end points of the study. The key secondary end points included objective response rate (ORR), health-related quality of life (HRQOL), and the number of patients with adverse events (AEs).

Lenvatinib combined with pembrolizumab achieved a median PFS of 6.6 months compared with 3.8 months in the physician’s choice arm (HR, 0.60; 95% CI, 0.50-0.72; P < .001 in the pMMR cohort. In the overall study population lenvatinib/pembrolizumab led to a median PFS of 8.3 months vs 11.4 months with physician’s choice. (HR, 0.56; 95% CI, 0.47-0.66; P < .001).

In terms of OS, the median observed with the combination of lenvatinib and pembrolizumab compared with chemotherapy in the pMMR population was 17.4 months vs 12.0 months, respectively (HR, 0.68; 95% CI, 0.56 to 0.84; P < .001). In the overall population, the median OS observed with lenvatinib/pembrolizumab combination was 8.3 months compared with 11.4 months with physician’s choice of chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; P < .001).

Looking at the results of the secondary study end points, the ORR achieved with lenvatinib/pembrolizumab versus chemotherapy was 30.3% versus 15.1%, respectively, in patients with pMMR tumors. In the overall population, the ORR was 31.9% compared with 14.7%, respectively.

With 231 days (range, 1-817) of exposure to lenvatinib plus pembrolizumab and 104.5 days (range, 1-785) of exposure to chemotherapy, 99.8% of patients experienced an AE of any grade. The most common AEs observed were hypertension (64.0%), hypothyroidism (57.4%), and diarrhea (54.2%).

A HRQOL assessment was completed for 95% of the study population. Those who received lenvatinib plus pembrolizumab reported a score of 80% compared with 62% in the chemotherapy arm; however, the difference was not considered to be significant over time.

“Keynote-775/Study 309 is an important phase 3 study that supported recent approvals of Keytruda plus Lenvima for certain types of advanced endometrial carcinoma in the US and other countries around the world, where it became the first immunotherapy and tyrosine kinase inhibitor combination approved for these patients,” Lubiniecki said in the release.2

Lenvatinib in combination with pembrolizumab was granted accelerated FDA approval in September of 2019 for the treatment of patients with advanced endometrial cancer that is not microsatellite instability–high or mismatch repair deficient, who have disease progression following prior systemic treatment and who are not candidates for curative surgery or radiation.3 Final results from KEYNOTE-775 served as confirmatory evidence, leading to a full FDA approval for lenvatinib/pembrolizumab in advanced endometrial cancer for this indication in July 2021.


1. Makker V, Colombo N, Herraez AC, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. Published online ahead of print January 19, 2022. doi: 10.1056/NEJMoa2108330.

2. Results from pivotal phase 3 KEYNOTE-775/Study 309 trial of Keytruda® (pembrolizumab) plus Lenvima® (lenvatinib) in advanced endometrial carcinoma published in the New England Journal of Medicine. News release. Merck. January 20, 2022. Accessed January 25, 2022.

3. Arora S, Balasubramaniam S, Zhang W, et al. FDA approval summary: pembrolizumab plus lenvatinib for endometrial carcinoma, a collaborative international review under project orbis. Clin Can Res. 2020;26(19). doi: 10.1158/1078-0432.CCR-19-3979