The FDA has approved the combination of lenvatinib and everolimus for use in patients with renal cell carcinoma who have failed at least 1 anti-angiogenic treatment. The approval raises questions around the sequencing these agents when a patient fails on first-line care.
The FDA has approved the combination of lenvatinib and everolimus for use in patients with renal cell carcinoma (RCC) who have failed at least 1 anti-angiogenic treatment. The approval raises questions around the sequencing these agents when a patient fails on first-line care.
The FDA announcement last week was based on the review of a randomized, multicenter study in 153 patients with advanced or metastatic RCC who have advanced on previous anti-angiogenic therapy. Patients were randomized to receive either lenvatinib plus everolimus, lenvatinib alone, or everolimus alone (all oral). The primary outcome monitored was progression-free survival (PFS). The investigator-assessed hazard ratio for the PFS between the combination and everolimus alone was 0.37 (95% CI, 0.22-0.62); median PFS for the combination arm was 14.6 months (95% CI, 5.9-20.1), compared with 5.5 months (95% CI, 3.5-7.1) for patients being treated with everolimus alone.
According to the FDA announcement, the most common adverse reactions with lenvatinib in combination with everolimus were diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, bleeding events, and proteinuria. Diarrhea was increased with the combination of lenvatinib plus everolimus, 19 % grade 3-4, and was added to the package insert as a new safety Warning.
The approval increases options for this population of patients, following the previous approval of an immunotherapeutic treatment and a small molecule inhibitor. The anti—PD-1 agent, nivolumab, was approved by the FDA 6 months back after the results of the CheckMate-025 trial showed improved overall survival (OS) with nivolumab treatment. Patients in the nivolumab group had significantly better overall survival (25 months; 95% CI, 21.8-not estimable) compared with those treated with everolimus (19.6 months; 95% CI, 17.6-23.1).
Less than a month back, the small molecule inhibitor, cabozantinib, which binds c-Met and VEGFR2, was approved following phase 3 results of the METEOR trial in patients with advanced RCC. Cabozantinib resulted in a 42% reduction in the rate of disease progression or death compared with patients treated with everolimus; additionally, the drug resulted in a significantly better PFS (7.4 months) compared with everolimus (3.8 months) (HR, 0.58; 95% CI 0.45-0.74, P<.0001).
Open questions that remain following these approvals would be the possibility of combinations and how would these agents be sequenced? Current standard of care for these patients who have failed their first-line treatment with a VEGF-inhibitor is axitinib, with everolimus as an alternative. Since both CheckMate-25 and METEOR chose everolimus as the comparator arm, there still lack of clarity on how either nivolumab or cabozantinib would fair against axitinib.
Other considerations would be how well a patient tolerates each of these treatments. Also, cabozantinib and the newly approved lenvatinib and everolimus are oral treatments, while the PD-1 inhibitor nivolumab is an infusion. This raises issues around adherence and coverage under medical (infusion) versus pharmacy benefit (oral) for these drugs.