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

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.

Keywords: gastrointestinal neoplasms; genetic markers; immunotherapy; lung neoplasms.

Conflict of interest statement

Competing interests: Y-KK received honoraria for consultancy from ALX Oncology, Amgen, Bristol Myers Squibb, DAE HWA, MacroGenics, Novartis, Surface Oncology, and Zymeworks. MR received honoraria for lectures and consultancy from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Merck, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Roche, and Samsung. PN served as a paid consultant to EMD Serono and Pfizer; his institution received research support from Bristol Myers Squibb and EMD Serono. YF was employed by Bristol Myers Squibb at the time of manuscript preparation and owns Bristol Myers Squibb stock. HRK declares no conflicts of interest. TKO served as a paid consultant to Bristol Myers Squibb, Merck, Amgen, AstraZeneca, Roche/Genentech, Novartis, BeiGene, Lilly, and Oncocyte. His institution received grants from Bristol Myers Squibb, Merck, Amgen, AstraZeneca, Roche/Genentech, and Novartis. NB received honoraria for lectures from Ono and Taiho and received research funding from Ono and Takeda. L-TC is employed by Kaohsiung Medical University Hospital, Kaohsiung Medical University, and the National Institute of Cancer Research, National Health Research Institutes in Taiwan, received honoraria to their institution from PharmaEngine, Taivex, and OBI, received research grants to their institution from SynCore Biotechnology, TTY, Polaris, ACT Genomics, Pfizer, Bristol Myers Squibb, Novartis, and Merck Serono, served as a paid consultant to ONO, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Ipsen, TTY, SynCore Biotechnology, Novartis, AstraZeneca, and Stone, reports royalties by HuniLife, and is part of the board of directors of ScinoPharm Taiwan, Ltd. AB, HC, ML, WHL, GP, AR, and JS are employees of Bristol Myers Squibb and own Bristol Myers Squibb stock.

© 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.

Figures

Figure 1

Proportions of patients with ≥20%, ≥50%, and ≥100% increases from baseline in target lesion SLD at the first on-treatment scan in ATTRACTION-2. SLD, sum of the longest diameters.

Figure 2

Proportions of patients with ≥20%, ≥50%, and ≥100% increases from baseline in target lesion SLD at the first on-treatment scan in CheckMate 451. SLD, sum of the longest diameters.

Figure 3

OS in patients randomized to (A) placebo, (B) nivolumab 240 mg Q2W, and (C) nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q2W with increases in target lesion SLD of