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FDA Grants Frontline Avelumab/Axitinib Breakthrough Designation for RCC

Jason M. Broderick @jasoncology
Published: Thursday, Dec 21, 2017

Chris Boshoff, MD, PhD
Chris Boshoff, MD, PhD
The FDA has granted the PD-L1 inhibitor avelumab (Bavencio) a breakthrough therapy designation for use in combination with the VEGF inhibitor axitinib (Inlyta) in treatment-naïve patients with advanced renal cell carcinoma (RCC).

The designation, which will expedite the development and review of this combination, is based on findings from the phase Ib JAVELIN Renal 100 trial. In the study, frontline avelumab/axitinib induced a response rate of 58.2% in patients with advanced RCC. The complete response (CR) rate was 5.5%, the partial response rate was 52.7% and the disease control rate was 78.2%.

"A combination approach with an immunotherapy, whose activity may complement existing agents such as Inlyta, has the potential to improve outcomes for patients with advanced renal cancer—a disease where the 5-year survival rate remains low," Chris Boshoff, MD, PhD, senior vice president and head of Immuno-Oncology, Early Development and Translational Oncology, Pfizer Global Product Development, said in a statement. Pfizer co-develops avelumab with Merck KGaA.

The JAVELIN Renal 100 study included 55 patients with advanced clear-cell RCC. Patients had a median age of 60 years (range, 42-76), no prior systemic therapy for advanced RCC, and an ECOG performance status ≤1. 

Over 95% of patients had favorable or intermediate risk per MSKCC criteria. Patients had 1 (45.5%), 2 (41.8%), or 3 (12.7%) metastatic sites. 

In the dose-finding stage of the study, patients received a lead-in dose of axitinib of 5 mg orally twice daily for 7 days, followed by 10 mg/kg of avelumab IV every 2 weeks plus axitinib at 5 mg orally twice a day. In the dose-expansion phase, patients could receive the same regimen as the dose-finding phase, or just start with 10 mg/kg of avelumab IV every 2 weeks plus axitinib at 5 mg orally twice a day.

Fifty-four of 55 patients received the combination, with 1 patient never receiving avelumab. At the April 13, 2017, data cutoff, treatment was ongoing in 30 patients receiving avelumab and 31 patients receiving axitinib. 

The median duration of avelumab treatment was 36.5 weeks, and the median duration of axitinib treatment was 34 weeks. Thirty-one patients had at least 1 dose reduction of axitinib, and 10 patients had at least 1 dose escalation of axitinib. 

Thirty-two patients had confirmed responses, including 3 CRs, and 29 PRs. An additional patient still receiving therapy had an unconfirmed response. Eleven patients had stable disease, 10 had progressive disease, and 2 were not evaluable. 

In 20 of 32 responders, the response occurred at the time of the first tumor assessment, and responses were ongoing in 24 of the responders. Late responses occurred, as well. Six patients had a late response—on or after week 18––and 5 of these patients remained on treatment.

Forty-five patients had tumor shrinkage, including 34 patients with shrinkage ≥30%. PD-L1 status was evaluable in 52 patients, and the researchers evaluated responses for PD-L1 cutoffs of ≥1% and ≥5%. 

At the 1% cutoff, the ORR was 65.9% (27/41) in PD-L1–positive patients and 36.4% (4/11) in PD-L1–negative patients. At the 5% cutoff, the ORR was 67.9% (19/28) in PD-L1–positive patients and 50.0% (12/25) in PD-L1–negative patients. Progression-free and overall survival data are not yet mature.   

All-grade adverse events (AEs) related to the treatment combination occurred in 53 patients. The most common all-grade AEs were diarrhea (52.7%), hypertension (45.5%), dysphonia (43.6%), and fatigue (43.6%).

Twenty-seven patients experienced grade 3 AEs, and 5 patients had grade 4 AEs. One patient died due to myocarditis. No patients who had a response died. Fewer grade 3 or higher AEs were considered related to avelumab than to axitinib.

The majority of infusion-related reactions were grade 1 or 2 and occurred mainly during the first 2 infusions of avelumab. Seventeen patients experienced an immune-related AE, with only 3 being grade 3. Myocarditis was the only immune-related AE that led to death.
Choueiri TK, Larkin JMG, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): results from a phase Ib trial. J Clin Oncol 35, 2017 (suppl; abstr 4504).

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