On August 10, 2021, the combination of lenvatinib plus pembrolizumab was approved for first-line treatment of adults with advanced renal cell carcinoma.^1,2

Supporting Efficacy Data

Approval was based on findings from the three-arm, open-label, phase III CLEAR trial (Study 307/KEYNOTE-581; ClinicalTrials.gov identifier NCT02811861), with the efficacy population for the approval consisting of patients randomly assigned to lenvatinib plus pembrolizumab (n = 355) vs  sunitinib (n = 357).

Median progression-free survival on independent radiologic review was 23.9 months (95% confidence interval [CI] = 20.8–27.7 months) in the lenvatinib/pembrolizumab group vs 9.2 months (95% CI = 6.0–11.0 months) in the sunitinib group (hazard ratio [HR] = 0.39, 95% CI = 0.32–0.49, P < .0001). Median overall survival was not reached in either group (HR = 0.66, 95% CI = 0.49–0.88, P = .0049), with death occurring in 23% vs 28% of patients. An objective response occurred in 71% vs 36% of patients (P < .0001).

How It Is Used

The recommended dosages in the current indication are lenvatinib at 20 mg once daily with pembrolizumab at 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression or 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.

Safety Profile

The most common adverse events reported in at least 20% of patients in trials of lenvatinib and pembrolizumab in combination have been fatigue, diarrhea, musculoskeletal pain, hypothyroidism, hypertension, stomatitis, decreased appetite, rash, nausea, decreased weight, dysphonia, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, hemorrhagic events, vomiting, constipation, hepatotoxicity, headache, and acute kidney injury.

In the CLEAR study (KEYNOTE-581), the most common grade 3 or 4 adverse events in the lenvatinib/pembrolizumab group were hypertension (29% vs 20% with sunitinib), diarrhea (10% vs 6%), and fatigue (9% vs 8%). Serious adverse events occurred in 51% of the combination group, most commonly hemorrhagic events (5%), diarrhea (4%), and hypertension, myocardial infarction, pneumonitis, and vomiting (3% each). Adverse events led to discontinuation of either agent in 37% and both in 13%, most commonly due to pneumonitis, myocardial infarction, hepatotoxicity, acute kidney injury, and rash (3% each). Adverse events led to death in 4.3%, most commonly due to cardiorespiratory arrest and sepsis (0.9% each).

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/impairment, proteinuria, diarrhea, gastrointestinal perforation and fistula formation, QT 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. 

REFERENCES

1. Lenvima (lenvatinib) capsules prescribing information. Eisai, Inc, August 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/206947s019lbl.pdf. Accessed September 8, 2021.

2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck & Co, Inc, August 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s102lbl.pdf. Accessed September 8, 2021.