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. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s Medwatch Reporting System or by calling 1-800-FDA-1088.
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