On July 21, 2021, pembrolizumab in combination with lenvatinib was granted regular approval for treatment of patients with advanced endometrial carcinoma that is not microsatellite instability–high or mismatch repair–deficient who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.1,2
Supporting Efficacy Data
Regular approval was supported by the confirmatory Study 309/KEYNOTE-775 trial (ClinicalTrials.gov identifier NCT03517449), in which 827 patients who had received at least one prior platinum-based chemotherapy regimen in any setting were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks with lenvatinib at 20 mg once daily (n = 342) or investigator’s choice of doxorubicin or paclitaxel (n = 325).
On blinded independent central review, median progression-free survival was 6.6 months in the pembrolizumab/lenvatinib group vs 3.8 months in the control group (hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.50–0.72, P < .0001). Median overall survival was 17.4 months vs 12.0 months (HR = 0.68, 95% CI = 0.56–0.84, P = .0001).
How It Is Used
The recommended doses for the combination are pembrolizumab at 200 mg every 3 weeks or 400 mg every 6 weeks and lenvatinib at 20 mg once daily until disease progression, unacceptable toxicity, or up to 24 months for pembrolizumab.
No dose reductions of pembrolizumab are recommended. Sequential dose reductions of lenvatinib for adverse reactions are to 14, 10, and 8 mg once daily.
The most common adverse events of any grade reported in ≥ 20% of patients in trials of pembrolizumab combined with lenvatinib are 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.
In Study 309/KEYNOTE-775, the most common grade 3 or 4 adverse events in patients receiving pembrolizumab and lenvatinib were hypertension (39%), fatigue (11%), and weight loss (10%).
Serious adverse events occurred in 50% of patients, most commonly hypertension (4.4%) and urinary tract infection (3.2%). Adverse events led to discontinuation of pembrolizumab in 15% of patients and lenvatinib in 26%. Fatal adverse events occurred in 4.7% of patients.
Pembrolizumab has warnings/precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryofetal toxicity.
Lenvatinib has warnings/precautions for hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure and impairment, proteinuria, diarrhea, gastrointestinal perforation and fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid-stimulating hormone suppression/thyroid dysfunction, wound-healing complications, osteonecrosis of the jaw, and embryofetal toxicity.
1. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck & Co, Inc, July 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s105lbl.pdf. Accessed September 2, 2021.
2. Lenvima (lenvatinib) capsules prescribing information. Eisai, Inc, July 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/206947s020lbl.pdf. Accessed September 2, 2021.