Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1

Abstract

<b>Purpose:</b> While immune checkpoint inhibitors are disrupting the management of patients with cancer, anecdotal occurrences of rapid progression (i.e., hyperprogressive disease or HPD) under these agents have been described, suggesting potentially deleterious effects of these drugs. The prevalence, the natural history, and the predictive factors of HPD in patients with cancer treated by anti-PD-1/PD-L1 remain unknown.<b>Experimental Design:</b> Medical records from all patients (<i>N</i> = 218) prospectively treated in Gustave Roussy by anti-PD-1/PD-L1 within phase I clinical trials were analyzed. The tumor growth rate (TGR) prior ("REFERENCE"; REF) and upon ("EXPERIMENTAL"; EXP) anti-PD-1/PD-L1 therapy was compared to identify patients with accelerated tumor growth. Associations between TGR, clinicopathologic characteristics, and overall survival (OS) were computed.<b>Results:</b> HPD was defined as a RECIST progression at the first evaluation and as a ≥2-fold increase of the TGR between the REF and the EXP periods. Of 131 evaluable patients, 12 patients (9%) were considered as having HPD. HPD was not associated with higher tumor burden at baseline, nor with any specific tumor type. At progression, patients with HPD had a lower rate of new lesions than patients with disease progression without HPD (<i>P</i> < 0.05). HPD is associated with a higher age (<i>P</i> < 0.05) and a worse outcome (overall survival). Interestingly, REF TGR (before treatment) was inversely correlated with response to anti-PD-1/PD-L1 (<i>P</i> < 0.05) therapy.<b>Conclusions:</b> A novel aggressive pattern of hyperprogression exists in a fraction of patients treated with anti-PD-1/PD-L1. This observation raises some concerns about treating elderly patients (>65 years old) with anti-PD-1/PD-L1 monotherapy and suggests further study of this phenomenon. <i>Clin Cancer Res; 23(8); 1920-8. ©2016 AACR</i><i>See related commentary by Sharon, p. 1879</i>.