On April 19, 2019, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck & Co. Inc.) plus axitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
Approval was based on KEYNOTE‑426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status and were randomly allocated to receive either pembrolizumab 200 mg intravenously every 3 weeks in combination with axitinib 5 mg orally twice daily, or sunitinib 50 mg orally once daily for 4 weeks and then off treatment for 2 weeks. Treatment continued until confirmed disease progression or unacceptable toxicity. Pembrolizumab was received for maximum of 24 months.
The main efficacy measures were overall survival (OS) and progression-free survival (PFS), assessed by blinded independent central review (RECIST 1.1.) The trial demonstrated a statistically significant improvement in OS in a pre-specified interim analysis for patients on the pembrolizumab plus axitinib arm (HR 0.53; 95% CI: 0.38, 0.74; p<0.0001). With deaths reported in 18% of patients, the median OS was not reached in either arm. The 12-month OS rate was 90% in the pembrolizumab plus axitinib arm and 78% for those treated with sunitinib. The trial also demonstrated a PFS improvement for patients receiving pembrolizumab plus axitinib (HR 0.69; 95% CI: 0.57, 0.84; p=0.0001). Median PFS was 15.1 and 11.1 months for those receiving pembrolizumab plus axitinib vs. sunitinib, respectively.
Grade 3 or 4 hepatotoxicity occurred in 20% of patients. Hepatotoxicity resulted in permanent discontinuation of pembrolizumab or axitinib in 13% of patients. The most common adverse reactions in > 20% of patients who received pembrolizumab plus axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.
The recommended pembrolizumab dose for this indication is 200 mg every 3 weeks with axitinib 5 mg orally twice daily.
FDA granted this application priority review and breakthrough therapy designation.