Abstract CT077: Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227
Authors: Hellmann Matthew D. , Ciuleanu Tudor Eliade , Pluzanski Adam , Lee Jong Seok , Otterson Gregory , Audigier-Valette Clarisse , Minenza Elisa , Linardou Helena , Burgers Sjaak , Salman Pamela , Borghaei Hossein , Ramalingam Suresh S. , Brahmer Julie , Reck Martin , O'Byrne Kenneth J. , Geese William J. , Green George , Chang Han , Szustakowski Joseph D. , Bhagavatheeswaran Prabhu , Healey Diane , Fu Yali , Nathan Faith , Paz-Ares Luis 
Published: August 2018

Abstract
Background: Nivo + ipi showed promising clinical activity and tolerability as 1L tx for advanced NSCLC in a phase 1 study. Tumor mutation burden (TMB) has emerged as an important biomarker for benefit of immune checkpoint blockade in lung cancer. CheckMate 227 (NCT02477826) is a large, open-label, phase 3 study of 1L nivo + ipi, nivo, or nivo + PT-DC vs PT-DC in advanced NSCLC. A preplanned co-primary endpoint was based on TMB to evaluate progression-free survival (PFS) of nivo + ipi vs PT-DC. This is the first phase 3 study to evaluate TMB as a predictive biomarker for immunotherapy as a co-primary endpoint. We report initial results from Part 1 of the study.
Methods: Patients (pts; N=1739) with chemotherapy-naive, histologically confirmed stage IV or recurrent NSCLC, ECOG PS 0−1, and no known sensitizing EGFR/ALK mutations were enrolled in 2 groups: PD-L1 ≥1% or PD-L1 &lt;1%. Pts with ≥1% tumor PD-L1 expression were randomized 1:1:1 to nivo + ipi, nivo, or PT-DC; pts with &lt;1% tumor PD-L1 expression were randomized 1:1:1 to nivo + ipi, nivo + PT-DC, or PT-DC. Tx regimens were nivo 3 mg/kg Q2W + ipi 1 mg/kg Q6W, nivo 240 mg Q2W, or nivo 360 mg Q3W with PT-DC. Pts were treated until disease progression or unacceptable toxicity, up to 2 y. TMB was determined from tumor tissue using the validated FoundationOne CDx™ assay (Foundation Medicine, Inc.). Co-primary endpoints were overall survival (OS) for nivo + ipi vs PT-DC in pts with PD-L1-selected tumors and PFS (blinded independent central review) for nivo + ipi vs PT-DC in pts with TMB ≥10 mutations (mut)/Mb.
Results: Baseline characteristics were similar in pts with evaluable TMB and all randomized pts and were balanced between nivo + ipi and PT-DC arms. Minimum follow-up was 11.5 mo. PFS was significantly longer with nivo + ipi vs PT-DC in pts with TMB ≥10 mut/Mb (HR=0.58 [97.5% CI: 0.41, 0.81]; P=0.0002); results were broadly consistent across subgroups, including PD-L1 and histology. The HR for PFS was 1.07 (95% CI: 0.84, 1.35) in pts with TMB &lt;10 mut/Mb. In all randomized pts, the HR for PFS with nivo + ipi vs PT-DC was 0.83 (95% CI: 0.72, 0.96). Objective response rate was 45.3% with nivo + ipi vs 26.9% with PT-DC in pts with TMB ≥10 mut/Mb; median duration of response (95% CI) was not reached (12.2 mo, NR) vs 5.4 (4.2, 6.9) mo, respectively. In treated pts, grade 3-4 treatment-related adverse events rates were 31.3% and 36.1% with nivo + ipi and PT-DC, respectively. Part 1 continues for final OS in the PD-L1-selected co-primary population.
Conclusions: CheckMate 227 met its co-primary endpoint of significantly prolonged PFS with 1L nivo + ipi vs PT-DC in NSCLC with TMB ≥10 mut/Mb regardless of PD-L1 expression. Safety was consistent with previous reports of 1L nivo + ipi for this dose regimen. These results validate the benefit of dual immune checkpoint blockade and the role of TMB as a biomarker to select pts in 1L NSCLC.
Citation Format: Matthew D. Hellmann, Tudor Eliade Ciuleanu, Adam Pluzanski, Jong Seok Lee, Gregory Otterson, Clarisse Audigier-Valette, Elisa Minenza, Helena Linardou, Sjaak Burgers, Pamela Salman, Hossein Borghaei, Suresh S. Ramalingam, Julie Brahmer, Martin Reck, Kenneth J. O'Byrne, William J. Geese, George Green, Han Chang, Joseph D. Szustakowski, Prabhu Bhagavatheeswaran, Diane Healey, Yali Fu, Faith Nathan, Luis Paz-Ares. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT077.