Background: CheckMate 227 (NCT02477826) is a large phase 3 study of first-line nivolumab or nivolumab-based regimens vs chemotherapy in advanced NSCLC.
Objectives: Here we report results from Part 1, including a preplanned coprimary end point evaluating progression-free survival (PFS) of nivolumab + ipilimumab vs chemotherapy in patients with high TMB (≥10 mut/Mb), safety of nivolumab + low-dose ipilimumab, and patient-reported outcomes (PROs).
Methods: Patients (N = 1739) with chemotherapy-naive, stage IV/recurrent NSCLC without known sensitizing EGFR/ALK alterations were randomized 1:1:1 to nivolumab (3 mg/kg every 2 weeks [Q2W]) + ipilimumab (1 mg/kg Q6W), nivolumab monotherapy (240 mg Q2W), or chemotherapy for patients with ≥1% tumor programmed death-ligand 1 (PD-L1) expression and to nivolumab + ipilimumab, nivolumab (360 mg Q3W) + chemotherapy, or chemotherapy for patients with <1% tumor PD-L1 expression. Coprimary end points were overall survival for nivolumab + ipilimumab vs chemotherapy in patients with PD-L1–selected tumors and PFS (blinded independent central review) for nivolumab + ipilimumab vs chemotherapy in patients with high TMB ≥10 mut/Mb. TMB was determined from tumor tissue using the FoundationOne CDx assay. Safety analyses included time to onset and time to resolution of select treatment-related adverse events (select TRAEs; those with a potential immunologic cause) and corticosteroid use. PROs were assessed using the Lung Cancer Symptom Scale and EQ-5D instruments.
Results: Minimum follow-up was 11.2 months. PFS was significantly longer with nivolumab + ipilimumab vs chemotherapy in patients with high TMB ≥10 mut/Mb (HR = 0.58 [97.5% CI, 0.41-0.81]; P = .0002); results were consistent across subgroups, including PD-L1 expression and tumor histology. Rates of TRAEs leading to discontinuation were 17% with nivolumab + ipilimumab and 9% with chemotherapy. Grade 3/4 TRAEs were reported in 31% and 36% of patients treated with nivolumab + ipilimumab and chemotherapy, respectively. Grade 3/4 select TRAEs by category with nivolumab + ipilimumab included hepatic (8%), endocrine (4%), and skin (4%), and were consistent with previous reports. Median time to onset of select TRAEs ranged from 2 to 15 weeks, and the majority resolved (median time to resolution, ≤10 weeks). PRO results will be reported in the final presentation.
Conclusions: First-line nivolumab + ipilimumab significantly prolonged PFS vs chemotherapy in patients with NSCLC and high TMB ≥10 mut/Mb regardless of PD-L1 expression. These results validate the role of TMB as a biomarker for the use of nivolumab + ipilimumab in first-line NSCLC. Safety of nivolumab + low-dose ipilimumab was manageable.
Prior Presentation at Congress: Abstract is an adaptation from data originally presented in part at the 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL, USA, and the American Association for Cancer Research Annual Meeting, April 14-18, 2018; Chicago IL, USA. The adapted abstract has been submitted to: German Society for Hematology and Medical Oncology 2018, International Association for the Study of Lung Cancer Latin America Conference on Lung Cancer 2018, Sociedad Española de Oncología Médica 2018, and American Society of Clinical Oncology Quality Care Symposium 2018.