Yoon-Koo Kang,¹ Martin Reck,² Paul Nghiem,³ Yan Feng,⁴ Gregory Plautz,⁵ Hye Ryun Kim,⁶ Taofeek K Owonikoko,⁷ Narikazu Boku,^8,9 Li-Tzong Chen,^10,11,12 Ming Lei,¹³ Han Chang,¹⁴ Wen Hong Lin,¹⁵ Amit Roy,⁴ Akintunde Bello,⁴ Jennifer Sheng⁴

¹Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
²Thoracic Oncology, LungenClinic, Airway Research Center North (ARCN), German Center of Lung Research (DZL), Grosshansdorf, Germany
³Department of Medicine, Division of Dermatology, University of Washington & Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
⁴Clinical Pharmacology & Pharmacometrics, Bristol Myers Squibb, Princeton, New Jersey, USA
⁵Medical Safety Assessment, Bristol Myers Squibb, Princeton, New Jersey, USA
⁶Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
⁷Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
⁸Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital (NCCH), Tokyo, Japan
⁹Department of Medical Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan
¹⁰National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
¹¹Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
¹²National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
¹³Precision Medicine, Bristol Myers Squibb, Princeton, New Jersey, USA
¹⁴Translational Bioinformatics, Bristol Myers Squibb, Princeton, New Jersey, USA
¹⁵Oncology Clinical Development, Bristol Myers Squibb, Princeton, New Jersey, USA

Correspondence to Dr Jennifer Sheng

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.