PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non–small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.

Allelic variation in the apoE gene is a statistically significant predictor of CHD death in these samples of elderly Finnish men.

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.

indicate an inverse relation between ER expression levels and ixabepilone sensitivity. Neoadjuvant ixabepilone demonstrated promising activity and a manageable safety profile in patients with invasive breast tumors.