FDA Grants Regular Approval to Pembrolizumab/Lenvatinib Combination for Endometrial Carcinoma

Endometrial carcinoma.

The FDA has granted regular approval to pembrolizumab (Keytruda®, Merck), in combination with lenvatinib, (Lenvima®, Eisai), 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. Prior to this regular approval, the FDA granted accelerated approval to the pembrolizumab/lenvatinib combination in September 2019 for patients with advanced endometrial carcinoma.

“Patients with advanced endometrial carcinoma have limited treatment options,” wrote Vicky Makker, MD, an oncologist at Memorial Sloan Kettering Cancer, and colleagues in their September 2020 published article in the Journal of Clinical Oncology. “Although early-stage endometrial carcinoma is associated with a favorable 5-year relative survival rate (96%), the rate is 18% in patients with distant metastases.”

The confirmatory study, Study 309/KEYNOTE-775 (NCT03517449), a multicenter, open-label, randomized, active-controlled trial on which the regular approval was based, 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 either 200 mg pembrolizumab intravenously every three weeks in combination with lenvatinib 20 mg orally once daily, or investigator’s choice of either doxorubicin or paclitaxel. The primary end points were progression-free survival and overall survival. Secondary end points were objective response rate and duration of response.

For patients with endometrial cancer that was not MSI-H or dMMR, the median progression-free survival was 6.6 months for those in the pembrolizumab/lenvatinib combination arm compared with 3.8 months in the investigator’s choice arm. The median overall survival for patients receiving the pembrolizumab/lenvatinib combination was 17.4 months compared with 12.0 months in the investigator’s choice treatment arm. The overall response rate for those receiving pembrolizumab and lenvatinib was 30%, while the investigator’s choice group had an overall response rate of 15%. The median durations of response were 9.2 months and 5.7 months, respectively.

The most common adverse events occurring in at least 20% of patients in trials of pembrolizumab/lenvatinib 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.

“Lenvatinib plus pembrolizumab demonstrated statistically significant and clinically meaningful improvements in progression-free survival, overall survival, and overall response rate versus treatment of physician’s choice,” concluded Dr. Makker in her presentation at the March 2021 Society of Gynecologic Oncology (SGO) Virtual Annual Meeting on Women’s Cancer. “The safety profile of lenvatinib plus pembrolizumab was manageable and consistent with previously reported studies.”

The recommended dose of pembrolizumab is 200 mg every three weeks or 400 mg every six weeks, and the recommended dose of lenvatinib is 20 mg orally once daily.

For More Information

Makker V (2021). A muticenter, open-label, randomized, phase III study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab versus treatment of physician’s choice in patients with advanced endometrial cancer. SGO Virtual Annual Meeting on Women’s Cancer. Abstract 11512.

Makker V, Taylor MH, Aghajanian C, et al (2020). Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol, 38(26):2981-2992. DOI:10.1200/JCO.19.02627

Clinicaltrials.gov (2021). Lenvatinib in combination with pembrolizumab versus treatment of physician’s choice in participants with advanced endometrial cancer (MK-3475-775/E7080-G000-309 per Merck standard convention [KEYNOTE-775]). NLM identifier: NCT03517449.

Keytruda® (pembrolizumab) prescribing information (2021). Merck. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s105lbl.pdf

Lenvima® (lenvatinib) prescribing information (2021). Eisai. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/206947s020lbl.pdf

US Food & Drug Administration (2021). FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-regular-approval-pembrolizumab-and-lenvatinib-advanced-endometrial-carcinoma

Image credit: Nephron. Licensed under CC BY-SA 3.0

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