CheckMate 592: a phase 2 exploratory study of biomarkers associated with the efficacy of first-line nivolumab (nivo) plus ipilimumab (ipi) in patients (pts) with stage IV or recurrent NSCLC

Background Combining PD-1 and CTLA-4 inhibitors can augment antitumor immune responses. In the phase 1 CheckMate 012 study, first-line nivo (anti–PD-1 antibody) plus ipi (anti–CTLA-4 antibody) exhibited a higher objective response rate (ORR) and 2-year overall survival (OS) rate than nivo alone in pts with stage IIIB/IV NSCLC. Pts whose tumors expressed PD-L1 or had a high tumor mutational burden (TMB) showed better outcomes. High TMB was identified in the phase 2 CheckMate 568 (nivo + ipi) and phase 3 CheckMate 026 (nivo alone) studies and validated in phase 3 CheckMate 227 (nivo + ipi) as a potential predictive biomarker, independent of PD-L1 expression. High TMB may result in high expression of neoantigens, which could prime responses to checkpoint inhibitors. Beyond PD-L1 and TMB, there may be other important potential predictive biomarkers. CheckMate 592 (NCT03001882) is a two-part, exploratory, open-label phase 2 study exploring potential biomarkers, including PD-L1 and TMB, among others, and their association with clinical benefit with first-line nivo + ipi for stage IV or recurrent NSCLC.

Trial design Pts aged ≥ 18 years with treatment-naïve stage IV or recurrent NSCLC and who had ECOG performance status 0 – 1 are being enrolled in the United States (parts 1 and 2) and Europe (part 2). Pts are ineligible if they have active autoimmune disease. In part 1, approximately 100 pts will be analyzed according to PD-L1 status (≥ 1% vs. < 1%) before treatment. In part 2, approximately 150 pts will be treated regardless of PD-L1 status. The primary endpoint in part 1 is the association of ORR with baseline TMB, and candidate peripheral blood and tumor biomarkers at baseline and on treatment; secondary endpoints are ORR, disease control rate, response duration, time to response, progression-free survival (PFS), OS, and the association of enteric biomarkers with efficacy. Primary endpoints in part 2 are the association of ORR with baseline tissue and blood TMB; secondary endpoints are ORR, PFS, OS, safety, and the association of enteric biomarkers with efficacy. The start date was March 2017. The estimated primary completion date is March 2019.