Hyperprogressive disease during PD-1 blockade in patients with advanced gastric cancer

Abstract

Background: Investigations for programmed cell death-1 (PD-1) blockade-induced hyperprogressive disease (HPD) have not been stringently conducted in patients with advanced gastric cancer (AGC). We explored the occurrence of HPD and its clinical implica-tions in patients with AGC and treated with PD-1 inhibitors.Methods: We enrolled 169 patients with AGC and treated with either the PD-1 blockade (ni-volumab or pembrolizumab; N = 112) or irinotecan monotherapy (N = 57) as a single agent. Tumour growth dynamics based on tumour growth kinetics and tumour growth rate (TGR) and time to treatment failure were analysed to define HPD. The incidence, clinical consequences and predictive markers of HPD were investigated.Results: The optimal criteria for HPD were 4-fold increases in both tumour growth kinetics and TGR ratios and a 40% increase in TGR based on the analysis for patients treated with irinotecan. In total, 10.7% (12/112) of patients experienced HPD after PD-1 inhibitor treat-ment. Patients with HPD had both shorter progression-free survival (hazard ratio: 2.318; 95% confidence interval: 1.205-4.460) and overall survival (hazard ratio: 2.542; 95% confi-dence interval: 1.314-4.918) than patients with progressive disease without HPD, losing op-portunities for subsequent systemic treatments. Although other variables including PD-L1 expression were not associated with the occurrence of HPD, hypoalbuminemia (<3.25 mg/ dL) at baseline was significantly associated with the occurrence of HPD (P < 0.001) and infe-rior survival outcomes.Conclusions: HPD occurs in a proportion of patients with AGC and treated with PD-1 inhib-itors. PD-1 inhibitor-induced HPD is associated with worse outcome, loss of eligibility for subsequent treatment and hypoalbuminemia, warranting further investigation. 2022 Elsevier Ltd. All rights reserved.