On July 21, 2021, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda®) in combination with lenvatinib (Lenvima®) for patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting, and are not candidates for curative surgery or radiation. 

FDA Grants Regular Approval to Pembrolizumab and Lenvatinib for Advanced Endometrial Carcinoma

FDA granted the indication accelerated approval on September 17, 2019. A multicenter, open-label, randomized, active-controlled trial (Study 309/KEYNOTE-775, NCT03517449) was required to confirm the clinical benefit of the accelerated approval. 

The trial enrolled 827 patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including neoadjuvant and adjuvant treatments. Patients were randomized 1:1 to receive either pembrolizumab 200 mg via IV infusion every three weeks with lenvatinib 20 mg orally once daily or investigator’s choice of doxorubicin or paclitaxel. 

The major efficacy outcome measurements were progression-free survival (PFS), as assessed by blinded independent central review (BICR), and overall survival (OS). Additional efficacy outcome measurements were objective response rate (ORR) and duration of response (DOR), also BICR-assessed. 

Among patients with advanced endometrial cancer that is not MSI-H or dMMR, the median PFS was 6.6 months (95% CI = 5.6, 7.4) for the pembrolizumab and lenvatinib group and 3.8 months (95% CI = 3.6, 5.0) for the group receiving investigator’s choice chemotherapy (HR = 0.60; 95% CI = 0.50, 0.72; p < 0.0001). Median OS was 17.4 months (95% CI = 14.2, 19.9) and 12 months (95% CI = 10.8, 13.3), respectively (HR = 0.68; 95% CI = 0.56, 0.84; p = 0.0001). ORR was 30% (95% CI = 26, 36) and 15% (95% CI = 12, 19), respectively (p < 0.0001). Median DOR was 9.2 months (1.6+, 23.7+) and 5.7 months (0.0+, 24.2+), respectively. 

The most common adverse reactions reported in at least 20% of patients during the clinical trials were hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, and rash. 

The recommended pembrolizumab dose for endometrial carcinoma is 200 mg every three weeks or 400 mg every six weeks with lenvatinib 20 mg orally once daily. 

View the full prescribing information for pembrolizumab

View the full prescribing information for lenvatinib

The review used Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. FDA approved the application six weeks prior to FDA’s goal date. 

The application was granted priority review. The combination of pembrolizumab and lenvatinib received breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions—Drugs and Biologics

Healthcare professionals should report all serious adverse events they suspect are associated with the use of any medicine or device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088. 

For assistance with single-patient oncology investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov