Authors: Martin Reck, Tudor-Eliade Ciuleanu, Manuel Cobo Dols, Michael Schenker, Bogdan Zurawski, Juliana Menezes, Eduardo Richardet, Jaafar Bennouna, Enriqueta Felip, Oscar Juan-Vidal, Aurella Alexandru, Hiroshi Sakai, Arnaud Scherpereel, Shun Lu, Thomas John, David Paul Carbone, Stephanie Meadows-Shropshire, Jinchun Yan, Luis G. Paz-Ares; Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, LungClinic, Grosshansdorf, Germany; Institutul Oncologic Prof. Dr. Ion Chiricuta and UMF Iuliu Hatieganu, Cluj-Napoca, Romania; Hospital Carlos Haya de Málaga, Málaga, Spain; SF. Nectarie Oncology Center, Craiova, Romania; Ambulatorium Chemioterapii, Bydgoszcz, Poland; Hospital Nossa Senhora Da Conceição, Porto Alegre, Brazil; Instituto Oncologico de Córdoba, Córdoba, Argentina; Thoracic Oncology Unit, University Hospital of Nantes, Nantes, France; Vall d’Hebron University Hospital, Barcelona, Spain; Hospital Universitario y Politécnico La Fe, Valencia, Spain; Institute of Oncology “Prof. Dr. Alexandru Trestioreanu” Bucha, Bucharest, Romania; Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan; Regional University Hospital Center of Lille, Hospital Calmette, Lille, France; Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; Austin Hospital, Victoria, Australia; The Ohio State University Comprehensive Cancer Center, Columbus, OH; Bristol-Myers Squibb, Princeton, NJ; Hospital Universitario 12 de Octubre, CNIO, Universidad Complutense & CiberOnc, Madrid, Spain
Research Funding: Bristol-Myers Squibb and Ono Pharmaceutical
Background: NIVO + IPI was shown to improve overall survival (OS) and durability of response vs chemo in 1L advanced NSCLC in CheckMate 227 Part 1, regardless of PD-L1 expression. We hypothesized that a limited course of chemo combined with NIVO + IPI could provide rapid disease control while building on the durable OS benefit seen with dual PD-1 and CTLA-4 inhibition. CheckMate 9LA (NCT03215706) is a phase 3 randomized study evaluating NIVO + IPI + 2 cycles chemo vs chemo in 1L stage IV/recurrent NSCLC.
Methods: Adults with tx-naive, histologically confirmed stage IV/recurrent NSCLC, ECOG performance status 0–1, and no known sensitizing EGFR/ALK alterations were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles) (n = 361) or chemo (4 cycles) alone (n = 358), stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous). Chemo was based on histology. Pts with non-squamous NSCLC in the chemo-only arm could receive optional pemetrexed maintenance. Pts were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 y. The primary endpoint was OS; the interim analysis using Lan–DeMets alpha spending function with O’Brien–Fleming boundary was planned at ~80% information fraction (ie, after observing ~322 total events). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability.
Results: Baseline characteristics were balanced across arms. At a preplanned interim analysis (minimum follow-up 8.1 mo), OS was significantly prolonged with NIVO + IPI + chemo vs chemo (HR 0.69, 96.71% CI: 0.55–0.87; P = 0.0006); statistically significant improvements in PFS and ORR were seen. With longer follow-up (minimum 12.7 mo), NIVO + IPI + chemo vs chemo continued to provide longer OS; median 15.6 vs 10.9 mo (HR 0.66, 95% CI: 0.55–0.80); 1-y OS rates were 63 vs 47%. Clinical benefit was consistent across all efficacy measures in key subgroups including by PD-L1 and histology. Grade 3–4 tx-related adverse events were reported in 47 vs 38% of pts in the NIVO + IPI + chemo vs chemo arms, respectively.
Conclusions: CheckMate 9LA met its primary endpoint: a statistically significant improvement in OS was observed with NIVO + NSCLC-optimized IPI + a limited course of chemo vs chemo (4 cycles) in 1L advanced NSCLC. No new safety signals were reported. Clinical trial information: NCT03215706.