Assessment of hyperprogression versus the natural course of disease development with nivolumab with or without ipilimumab versus placebo in phase III, randomized, controlled trials

• Type of Material: Article
• Authors: Yoon-Koo Kang, University of Ulsan; Martin Reck, German Ctr Lung Res DZL; Paul Nghiem, University of Washington; Yan Feng, Bristol Myers Squibb; Gregory Plautz, Bristol Myers Squibb; Hye Ryun Kim, Yonsei University; Taofeek Owonikoko, Emory University; Narikazu Boku, National Cancer Center Hospital (NCCH); Li-Tzong Chen, National Health Research Institutes; Ming Lei, Bristol Myers Squibb; Han Chang, Bristol Myers Squibb; Wen Hong Lin, Bristol Myers Squibb; Amit Roy, Bristol Myers Squibb; Akintunde Bello, Bristol Myers Squibb; Jennifer Sheng, Bristol Myers Squibb
• Language: English
• Date: 2022-04-01
• Publisher: BMJ PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/jitc-2021-004273
• Title of Journal or Parent Work: JOURNAL FOR IMMUNOTHERAPY OF CANCER
• Volume: 10
• Issue: 4
• Grant/Funding Information: This work was supported by Bristol Myers Squibb. ATTRACTION-2 and CheckMate 451 were funded by Bristol Myers Squibb. PN was supported by the National Institutes of Health (P01-CA225517). The sponsor was involved in the study design, collection, analysis, and interpretation of data and information provided in the manuscript. However, the ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors.
• Keywords: Oncology; Immunology; Life Sciences & Biomedicine; PD-1; BLOCKADE; Science & Technology; IMMUNOTHERAPY
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

Background Retrospective studies have suggested a potential risk of hyperprogressive disease (HPD) in patients receiving immune checkpoint inhibitors (ICIs). We compared the incidence of HPD during treatment with nivolumab±ipilimumab versus natural tumor progression with placebo in post hoc analyses of two randomized, double-blind clinical trials. Methods ATTRACTION-2 randomized patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) and progression on ≥2 prior regimens to nivolumab 3 mg/kg Q2W or placebo. CheckMate 451 randomized patients with extensive-disease small cell lung cancer (ED SCLC) and ongoing complete/partial response or stable disease after first-line chemotherapy to nivolumab 240 mg Q2W, nivolumab 1 mg/kg+ipilimumab 3 mg/kg Q3W for four doses then nivolumab 240 mg Q2W, or placebo. Patients receiving ≥1 dose of study drug and with tumor scans at baseline and the first on-treatment evaluation were included in the HPD analyses. HPD definitions were ≥20%, ≥50%, and ≥100% increase in target lesion sum of the longest diameters (SLD) at the first on-treatment assessment. Results In the ATTRACTION-2 HPD-evaluable population, 243 patients received nivolumab and 115 placebo. Fewer patients receiving nivolumab versus placebo had increases in SLD ≥20% (33.7% vs 46.1%) and ≥50% (6.2% vs 11.3%); similar proportions had increases in SLD ≥100% (1.6% vs 1.7%). In the CheckMate 451 HPD-evaluable population, 177 patients received nivolumab, 179 nivolumab+ipilimumab, and 175 placebo. Fewer patients receiving nivolumab or nivolumab+ipilimumab versus placebo had increases in SLD ≥20% (27.1%, 27.4% vs 45.7%), ≥50% (10.2%, 11.2% vs 22.3%), and ≥100% (2.8%, 2.8% vs 6.3%). Conclusions Nivolumab±ipilimumab was not associated with an increased rate of progression versus placebo in patients with GC, GEJC, or ED SCLC, suggesting that previous reports of HPD may reflect the natural disease course in some patients rather than ICI-mediated progression. Trial registration number NCT02538666; NCT02267343.