Abstract CT078: Tumor mutational burden (TMB) as a biomarker for clinical benefit from dual immune checkpoint blockade with nivolumab (nivo) + ipilimumab (ipi) in first-line (1L) non-small cell lung cancer (NSCLC): identification of TMB cutoff from CheckMate 568
Authors: Ramalingam Suresh S. , Hellmann Matthew D. , Awad Mark M. , Borghaei Hossein , Gainor Justin , Brahmer Julie , Spigel David R. , Reck Martin , O'Byrne Kenneth J. , Paz-Ares Luis , Zerba Kim , Li Xuemei , Geese William J. , Green George , Lestini Brian , Szustakowski Joseph D. , Chang Han , Ready Neal 
Published: August 2018

Abstract
Background: Several studies have demonstrated the potential clinical utility of TMB as a biomarker of immune checkpoint blockade in multiple tumor types, including lung cancer. Prior analyses have been retrospective and exploratory, with varying cutoffs and methodologies used to assess TMB. The establishment of a clinically validated cutoff for nivo + ipi is required to confirm the clinical utility of TMB as a predictive biomarker in future studies. CheckMate 568 (NCT02659059) is a large, single-arm, phase 2 study of nivo + ipi in 1L NSCLC. TMB was assessed using Foundation One CDx™ (Foundation Medicine, Inc.) to identify an appropriate TMB cutoff to select patients for 1L nivo + ipi therapy. This cutoff was subsequently validated through a preplanned analysis in CheckMate 227, which evaluated progression-free survival in patients with high TMB as a co-primary endpoint (NCT02477826).
Methods: In CheckMate 568, 288 patients with chemotherapy-naive stage IV NSCLC received nivo 3 mg/kg Q2W + ipi 1 mg/kg Q6W for up to 2 years. EGFR- and ALK-targetable NSCLC were excluded. The primary endpoint was objective response rate (ORR) as per independent review. ORR by TMB was a secondary endpoint. TMB was assessed using the validated FoundationOne® CDx assay (Foundation Medicine, Inc.). TMB classification performance with receiver operating characteristic (ROC) curves was used to determine an appropriate TMB cutoff associated with enhanced efficacy of nivo + ipi in 1L NSCLC. Prevalence analyses of TMB and PD-L1 were also conducted.
Results: Baseline characteristics and efficacy were similar in both the all treated and TMB-evaluable populations. With a minimum follow-up of 3 months, ORR was 27% in all treated patients. ORR increased in patients with higher TMB, and plateaued with the threshold of ≥10 mutations (mut)/Mb (ORR: 4%, 10%, 44%, and 39% in patients with TMB &lt;5, &lt;10, ≥10, and ≥15 mut/Mb, respectively). ROC analysis of TMB vs ORR for nivo + ipi demonstrated optimal classification performance at 10 mut/Mb. The safety profile for nivo + ipi was consistent with previous reports and no new safety signals were observed.
Conclusions: TMB ≥10 mut/Mb was associated with enhanced response to nivo + ipi regardless of PD-L1 expression, with ORRs &gt;40%. This response rate, coupled with the known durability of responses to immuno-oncology agents, compares favorably to historical data with platinum-doublet chemotherapy. Therefore, a cutoff of ≥10 mut/Mb was chosen to define the TMB patient population for the co-primary efficacy endpoint in CheckMate 227.
Citation Format: Suresh S. Ramalingam, Matthew D. Hellmann, Mark M. Awad, Hossein Borghaei, Justin Gainor, Julie Brahmer, David R. Spigel, Martin Reck, Kenneth J. O'Byrne, Luis Paz-Ares, Kim Zerba, Xuemei Li, William J. Geese, George Green, Brian Lestini, Joseph D. Szustakowski, Han Chang, Neal Ready. Tumor mutational burden (TMB) as a biomarker for clinical benefit from dual immune checkpoint blockade with nivolumab (nivo) + ipilimumab (ipi) in first-line (1L) non-small cell lung cancer (NSCLC): identification of TMB cutoff from CheckMate 568 [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 CT078.