On May 14, 2019, the Food and Drug Administration approved avelumab (BAVENCIO®, EMD Serono, Inc.) in combination with axitinib for first-line treatment of patients with advanced renal cell carcinoma (RCC).
Approval was based on JAVELIN Renal 101 (NCT02684006), a randomized, multicenter, open-label trial of avelumab plus axitinib in 886 patients with untreated advanced RCC regardless of tumor PD-L1 expression. Patients were randomized to receive either avelumab 10 mg/kg intravenous infusion every 2 weeks in combination with axitinib 5 mg twice daily orally or sunitinib 50 mg once daily orally for 4 weeks followed by 2 weeks off until radiographic progression or unacceptable toxicity.
The main efficacy endpoints were progression-free survival (PFS), assessed by blinded independent central review using RECIST 1.1, and overall survival (OS) in patients with PD-L1-positive tumors. Secondary endpoints were PFS and OS in the total population. A statistically significant improvement in PFS was demonstrated in patients with PD-L1-positive tumors (HR 0.61; 95% CI: 0.48, 0.79; p=0.0001). A statistically significant improvement in PFS in the total population was also demonstrated (HR 0.69; 95% CI: 0.56, 0.84; p=0.0002) at interim analysis. Median PFS in the total population was 13.8 months for patients on the avelumab plus axitinib arm and 8.4 months for patients who received sunitinib. With a median overall survival follow-up of 19 months, OS data were immature with 27% deaths in the intent-to-treat population.
The most common adverse reactions of avelumab in combination with axitinib in ≥ 20% of patients with RCC were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache. Grade 3 or 4 hepatotoxicity occurred in 9% of patients and resulted in in permanent discontinuation of avelumab or axitinib in 7%. Major cardiac adverse events occurred in 7% of patients treated with the combination.
The recommended avelumab dose for advanced RCC is 800 mg as an intravenous infusion every 2 weeks in combination with axitinib 5 mg orally twice daily.
This application used the Assessment Aid pilot program. 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.
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