FDA Approves Lenvatinib/Pembrolizumab for Select Patients With Advanced Endometrial Cancer

FDA

The FDA has approved the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) for the treatment of patients with advanced endometrial cancer that is not microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic treatment and who are not candidates for curative surgery or radiation.1

“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,” said principal investigator Vicky Makker, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, in a statement. “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.”

Approval for the combination was based on findings from the pivotal phase 3 KEYNOTE-775/Study 309 trial (NCT03517449). The immunotherapy/tyrosine kinase inhibitor (TKI) combination led to a median overall survival (OS) of 17.4 months in patients with mismatch repair proficient (pMMR) disease versus 12.0 months with chemotherapy, resulting in a 32% improvement in the risk of death (HR, 0.68; 95% CI, 0.56-0.84; P < .0001). Amongst all patients, the median OS was 18.3 months with pembrolizumab and lenvatinib as compared with 11.4 months with chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; P < .0001).1,2

Median progression-free survival (PFS) with the combination was 6.6 months versus 3.8 months with chemotherapy in pMMR patients (HR, 0.60; 95% CI, 0.50-0.72; P < .0001) and 7.2 versus 3.8 months, respectively, in all patients (HR, 0.56; 95% CI, 0.47-0.66; P < .0001).

Objective response rate (ORR) was 30.3% with the combination in pMMR patients treated with the immunotherapy/TKI regimen versus 15.1% with chemotherapy (P < .0001); complete responses were observed in 5.2% and 2.6% of patients, respectively. The median duration of response (DOR) was 9.2 months versus 5.7 months with the combination and chemotherapy, respectively.

Among all patients, the ORR was 31.9% with the combination regimen and 14.7% with chemotherapy (P < .0001), with complete responses in 6.6% and 2.6% of patients, respectively. The median DOR was 14.4 months with pembrolizumab and lenvatinib versus 5.7 months with chemotherapy.

Common treatment-emergent adverse events (TEAEs) with the combination included hypertension (64.0%), hypothyroidism (57.4%), diarrhea (54.2%), nausea (49.5%), and decreased appetite (44.8%). Frequent grade 3 or higher TEAEs reported with pembrolizumab/lenvatinib were hypertension (37.9%), weight decrease (10.3%), decreased appetite (7.9%), and diarrhea (7.6%). The most common serious adverse events were hypertension (4.4%) and urinary tract infections (3.2%).

In the study, 69.2% of patients treated with pembrolizumab/lenvatinib had TEAEs leading to dose interruption, 58.6% discontinued lenvatinib due to TEAEs, 50.0% discontinued pembrolizumab, and 30.8% discontinued both agents due to TEAEs.

Fatal adverse events were reported in 4.7% of patients, including 2 cases of pneumonia and ne of multiple adverse effects.

The KEYNOTE-775/Study 309 trial enrolled 827 patients with advanced endometrial cancer who were previously treated with at least 1 prior platinum-based chemotherapy regimen in any setting. Patients were randomized to receive either oral lenvatinib at 20 mg daily plus pembrolizumab at 200 mg intravenously (IV) every 3 weeks or investigator’s choice of chemotherapy: doxorubicin at 60 mg/m2 IV every 3 weeks or paclitaxel at 80 mg/m2 IV weekly on a 3-weeks-on and 1-week-off schedule. Treatment was continued until disease progression or unacceptable toxicity.

Primary end points were PFS and OS by blinded independent central review per RECIST criteria and additional end points included ORR and DOR.

“When compared to the chemotherapies used in this trial, this combination treatment regimen was proven to extend the lives of certain patients diagnosed with previously treated, advanced endometrial cancer,” stated Gregory Lubiniecki, MD, vice president, Oncology Clinical Research, Merck Research Laboratories. “Based on phase 3 data, today’s approval acts as the confirmatory trial to our previous accelerated approval of Keytruda plus Lenvima in patients with certain types of advanced endometrial cancer and reinforces the impact of our joint research with Eisai in exploring the potential of this combination to treat more patients with challenging types of cancer.”

_References

_{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/36S6ZE3}

_{2. Makker V, Colombo N, Herráez AC, et al. A multicenter, open-label, randomized, phase 3 sdtudy to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: Study 309/KEYNOTE-775. Presented at: 2021 SGO Virtual Annual Meeting on Women’s Cancer; March 19-26, 2021; virtual.}