Phase 3 study of avelumab in combination with axitinib versus sunitinib as first-line treatment for patients with advanced renal cell carcinoma (aRCC)

Abstract

Background: Antiangiogenic tyrosine kinase inhibitors (TKIs) directed against key molecular targets in the pathogenesis of clear-cell RCC are typically used to treat advanced disease, although resistance develops in the majority of patients. Immunotherapy with agents targeting programmed death-1 pathway (PD-1/PD-L1) interactions has shown promising efficacy as monotherapy in patients with aRCC. Anti-PD-1/PD-L1 antibodies and TKIs may have complementary mechanisms of action in aRCC, providing a rationale for investigating combination treatment. Avelumab is an investigational fully human IgG1 anti-PD-L1 monoclonal antibody with clinical activity in several tumor types. Axitinib is a vascular endothelial growth factor receptor (VEGFR)-TKI approved for second-line treatment of aRCC (Rini et al., Lancet 2011), that has also shown clinical activity as a first-line therapy (Hutson et al., Lancet Oncol 2013). JAVELIN Renal 100 (NCT02493751), an ongoing phase 1b study testing the combination of avelumab + axitinib administered at full monotherapy doses, has shown encouraging safety and antitumor activity in treatment- naïve patients with aRCC, providing the rationale to initiate a phase 3 trial assessing this regimen. Trial Design: JAVELIN Renal 101 (NCT02684006) is a multicenter, international, randomized, open-label, parallel 2- arm, phase 3 trial comparing avelumab + axitinib vs sunitinib (a pan- TKI) as first-line treatment for patients with clear-cell aRCC. The primary objective is to demonstrate superiority of avelumab + axitinib in prolonging progression- free survival (PFS) compared with sunitinib monotherapy. Eligible patients have measurable (per RECIST v1.1) clear-cell aRCC, an ECOG PS of 0 or 1, and have had no prior systemic treatment for advanced disease. Approximately 580 patients will be randomized (1:1) and stratified based on ECOG PS (0 vs 1) and region (US vs Canada/Europe vs rest of the world). Patients receive either avelumab 10 mg/kg 1-hour IV Q2W plus axitinib 5 mg orally BID continuously on a 6-week cycle, or sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks off. The primary endpoint is PFS assessed by blinded independent central review (BICR) and RECIST v1.1. Secondary efficacy endpoints include PFS by investigator assessment, overall survival, objective response, disease control, duration of response, and time to response by BICR and investigator assessments. Other endpoints are adverse events and laboratory abnormalities graded by NCI-CTCAE v4.03, vital signs, pharmacokinetics parameters, tumor tissue biomarker status, antidrug antibodies, and patient-reported outcomes. Exploratory analyses of efficacy endpoints using immune-related response criteria will also be performed. Patients may continue treatment beyond progression per BICR assessment, provided that the treating physician favorably assesses the potential for clinical benefit. Treatment is discontinued for unacceptable toxicity or if any criteria for withdrawal are met. Patients in the avelumab + axitinib arm who discontinue one of these study drugs for a reason other than confirmed disease progression may continue on single-agent treatment with the other study drug. Crossover between treatment arms is not permitted. Enrollment in this pivotal phase 3 trial began in March 2016.