FDA Grants Full Approval For Lenvatinib and Pembrolizumab Combination in Advanced dMMR/MSI-H Endometrial Cancer


Phase 3 results demonstrating the superiority of the pembrolizumab plus lenvatinib combination vs standard chemotherapy served as a confirmatory trial for its approval in certain patients with advanced endometrial cancer.

The FDA granted approval to the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) for the treatment of patients with microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) advanced endometrial cancer who have progressed on prior systemic therapies and for whom surgery or radiation are not suitable treatment options.1

This approval was granted based on results of the phase 3 KEYNOTE-775/Study 309 trial (NCT03517449) which demonstrated improved overall survival (OS) and progression-free survival (PFS) vs physician’s choice of chemotherapy in an all-comer population of patients with advanced, metastatic, or recurrent endometrial cancer who had previously received 1 prior platinum-based regimen in any setting.

“With a five-year survival rate of just 17%, women with advanced endometrial cancer who are not candidates for curative therapy, particularly those with disease progression following prior systemic therapy, have limited treatment options,” Vicky Makker, MD, principal investigator and medical oncologist, Memorial Sloan Kettering Cancer Center, said in a press release. “This approval is an important step forward in helping patients fight this difficult-to-treat malignancy, as physicians can now provide an option that may improve survival outcomes.”

In patients with mismatch repair deficiency who were treated in KEYNOTE-775, statistically significant and clinically meaningful benefits to PFS were observed (HR, 0.60; 95% CI, 0.50-0.72; P <.0001), with medians of 6.6 months (95% CI, 5.6-7.4) and 3.8 months (95% CI, 3.6-5.0) with pembrolizumab/lenvatinib and the control therapy, respectively. The median OS was 17.4 months (95% CI, 14.2-19.9) with the combination vs 12.0 months (95% CI, 10.8-13.3) with chemotherapy (HR, 0.68; 95% CI, 0.56-0.84; P = .0001).2

The objective response rate (ORR) was also improved with pembrolizumab/lenvatinib at 30.3% (95% CI, 25.5%-35.5%), comprised of 5.2% complete responses and 25.1% partial responses, compared with 15.1% (95% CI, 11.5%-19.3%), made up of 2.6% complete responses and 12.5% partial responses. The median duration of response was 9.2 months (range, 1.6+ to 23.7+) vs 5.7 months (range, 0.0+ to 24.2+), respectively.

Discontinuations due to treatment-emergent adverse events (TEAEs) in the all-comer population occurred at a rate of 18.7% for pembrolizumab, 30.8% for lenvatinib, and 14.0% for both agents. In the physician’s choice arm, discontinuation of chemotherapy due to TEAEs occurred in 8.0%. Grade 5 TEAEs occurred in 5.7% of those treated with pembrolizumab plus lenvatinib and in 4.9% of those treated with chemotherapy. The most common any-grade AEs in the experimental group occurring in more than 25% of patients were hypertension (64.0%), hypothyroidism (57.4%), diarrhea (54.2%), nausea (49.5%), decreased appetite (44.8%), vomiting (36.7%), weight decrease (34.0%), fatigue (33.0%), and arthralgia (30.5%).

The recommended dose of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks with oral lenvatinib at 20 mg daily.

The results of KEYNOTE-775 serve as a confirmatory trial for an accelerated approval granted to the combination for this indication in 2019.3 Earlier this year, the FDA granted priority review to the combination for this indication.4


1. FDA approves Keytruda (pembrolizumab) plus Lenvima (lenvatinib) combination for patients with certain types of advanced endometrial carcinoma. News release. Merck. July 22, 2021. Accessed July 22, 2021. https://bit.ly/2V76N0X

2. Keytruda (pembrolizumab) plus Lenvima (lenvatinib) significantly improved progression-free survival and overall survival versus chemotherapy in patients with advanced endometrial cancer following prior platinum-based chemotherapy in phase 3 study. News release. Merck. March 19, 2021. Accessed July 22, 2021. https://bwnews.pr/3izKo4K

3. Simultaneous review decisions for pembrolizumab plus lenvatinib in Australia, Canada and US. FDA website. September 17, 2019. Accessed July 22, 2021. https://bit.ly/2mmwklD.

4. Merck and Eisai receive priority review from FDA for Keytruda (pembrolizumab) plus Lenvima (lenvatinib) applications for advanced renal cell carcinoma and for advanced endometrial carcinoma. News release. Merck and Eisai, Inc. May 6, 2021. Accessed July 22, 2021. https://bwnews.pr/3b9CzzA

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