A phase III, randomized, double-blind study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus dacarbazine in patients (pts) with previously untreated, unresectable, or metastatic melanoma (MEL).

Abstract

TPS9106 Background: The 5-year survival rate for late-stage MEL is currently only 15%. Despite recent advances with ipilimumab and vemurafenib, a considerable unmet need remains for pts with previously untreated, unresectable or metastatic BRAF wild-type MEL. Objective response rate (ORR) with first-line dacarbazine, a widely used chemotherapy in MEL, is 13%, with median overall survival (OS) ranging from 5.6 to 11 months. Programmed death-1 (PD-1) is an immune checkpoint receptor that negatively regulates T-cell activation through interaction with its ligand, PD-L1. This ligand is overexpressed by multiple tumor types, including advanced MEL. The PD-1 receptor blocking antibody nivolumab demonstrated clinical activity at 0.1-10 mg/kg in a phase I study in pts with advanced MEL (n = 106), with OR in 33 pts and stable disease ≥24 weeks in 6 pts. We describe a double-blind, randomized phase III study designed to compare the clinical benefit of nivolumab vs dacarbazine in pts with advanced MEL. Methods: Approximately 410 pts with untreated, unresectable stage III or stage IV MEL will be randomized 1:1 to receive either nivolumab 3 mg/kg IV every two weeks or dacarbazine 1000 mg/m2 IV every three weeks until disease progression or unacceptable toxicity. All pts must be BRAF wild-type as per V600 mutational testing. Pts will be stratified by PD-L1 status (positive vs negative/indeterminate) and metastatic (M) stage (M0/M1a/M1b vs M1c). PD-L1 positivity will be defined as ≥5% total membrane staining in tumor cells. 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. Treatment may continue beyond initial progression at the investigator’s discretion for pts showing clinical benefit and tolerating therapy. The primary endpoint is OS. Secondary endpoints include progression-free survival, ORR, whether PD-L1 expression is a predictive biomarker for OS, and health-related quality of life. Clinical trial information: NCT01721772.