First-Line Avelumab/Axitinib Encouraging in Advanced RCC

First-line combination therapy with the programmed death ligand 1 (PD-L1) inhibitor avelumab and the vascular endothelial growth factor receptor tyrosine kinase inhibitor axitinib resulted in encouraging antitumor activity in patients with previously untreated renal cell carcinoma (RCC) and had a manageable toxicity profile, according to the results of the JAVELIN Renal 100 study published in Lancet Oncology.

“These findings support the pivotal, randomized, phase III JAVELIN Renal 101 trial (NCT02684006), which is comparing combined avelumab and axitinib with sunitinib monotherapy as first-line treatment for advanced renal-cell carcinoma,” wrote Toni K. Choueiri, MD, of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and colleagues.

According to the researchers, “the combination of an antibody that inhibits PD-L1 and PD-1 [programmed death 1] interactions with a targeted antiangiogenic agent might take advantage of complementary mechanisms of action to provide clinical benefit in patients with advanced renal cell carcinoma that exceeds the effects of the respective drugs alone, without increasing associated toxicity.”

Choueiri and colleagues conducted the phase I trial to test the safety and efficacy of this combination in previously untreated patients with RCC. The trial included 6 patients in a dose-finding phase, and 49 in a dose-escalation phase. All patients had advanced RCC with clear-cell component, and a life expectancy of at least 3 months.

In the dose-finding phase, patients received 5 mg axitinib twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab every 2 weeks and 5 mg axitinib twice daily. At the end of the dose-finding phase, the maximum-tolerated dose was avelumab at 10 mg/kg every 2 weeks and axitinib at 5 mg twice daily. Ten patients in the dose-expansion phase started on this therapy, and the remainder started directly with combination therapy.

At data cutoff with a median follow-up of 52.1 weeks, 100% of patients in the dose-finding phase and 53% of patients in the dose-expansion phase had confirmed objective responses.

Only one dose-limiting toxicity was reported during the dose-finding phase: grade 3 proteinuria due to axitinib. More than half of patients (58%) in both study phases had grade 3 or worse treatment-related adverse events. The most common were hypertension (29%) and increased concentrations of alanine aminotransferase, amylase, and lipase (7%), and palmar-plantar erythrodysesthesia syndrome (7%).

Of the 6 patients who died prior to data cutoff, f5 died due to disease progression and 1 from treatment-related autoimmune myocarditis.

In an editorial published with the study, Viktor Grunwald, of Hannover Medical School, Germany, wrote “these antitumour activity findings indicate the potential clinical benefit of targeted-immune combinations and suggest that further studies are warranted to explore whether a first-line targeted-immune combination might overcome the standard of sequential targeted and immune therapies.”

However, Grunwald added that in the absence of long-term safety data, no definitive conclusions can yet be made.