A phase III open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice in advanced melanoma patients progressing post anti-CTLA-4 therapy.

Abstract

TPS9105^ Background: Despite the recent approval of ipilimumab and vemurafenib for advanced melanoma, there is still a large unmet need for patients (pts) who have progressed on anti-CTLA-4 therapy and a BRAF inhibitor (depending on BRAF status). Programmed death-1 (PD-1) is a co-stimulation inhibitory receptor that negatively regulates T-cell activation and is upregulated in tumor-infiltrating lymphocytes. Upregulation of PD-1 is also associated with advanced disease in melanoma. Nivolumab, an anti-PD-1 receptor blocking monoclonal antibody, demonstrated durable antitumor activity in a phase 1 study in 106 pts with advanced melanoma with objective responses (OR) observed in 31% and stable disease ≥24 weeks in 6% with a manageable safety profile (Topalian SL et al; ESMO 2012 [Abstr 453P]). Here we describe a phase III study designed to compare the clinical benefit of nivolumab to chemotherapy of investigator’s choice in previously treated pts with unresectable or metastatic melanoma. Methods: In this two arm open-label study, approximately 390 pts will be randomized 2:1 to receive either nivolumab 3 mg/kg IV every two weeks (Arm A) or either dacarbazine 1000 mg/m2 IV or carboplatin AUC6/paclitaxel 175 mg/m2 IV every 3 weeks (Arm B) until disease progression or treatment discontinuation. Pts included are those with ≤2 regimens for advanced melanoma who have progressed on anti-CTLA-4 therapy as well as a BRAF inhibitor if BRAF V600-mutation positive. Pts without active brain metastases are eligible. All pts require baseline fresh biopsy to determine PD-L1 expression. Pts will be stratified by tumor PD-L1 expression, BRAF status, and prior anti-CTLA-4 best response. Tumor response per RECIST 1.1 will be assessed 9 weeks following randomization and every 6 weeks thereafter for the first year. After the first year, response will be assessed every 12 weeks until disease progression or treatment discontinuation. The co-primary endpoints are overall survival (OS) and OR rate. Secondary endpoints include progression-free survival, correlation of PD-L1 expression with clinical outcome, and health-related quality of life. Clinical trial information: NCT01721746.