Hyperprogressive disease with anti PD-1/PD-L1 therapy

Purpose While Immune checkpoint inhibitors are disrupting the management of cancer patients, 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 cancer patients treated by anti PD-1/PD-L1 remain unknown. Experimental design Medical records from all patients (N =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") and upon ("EXPERIMENTAL") anti-PD-1/PD-L1 therapy was compared to identify patients with accelerated tumor growth. Associations between TGR, clinico-pathological characteristics and overall survival (OS) were computed. Results HPD was defined as a RECIST progression at the first evaluation and as a ≥ two-fold increase of the TGR between the REF and the EXP periods. Out of 131 evaluable patients, 12 patients (9%) were considered as HPD. HPD was not associated with higher tumor burden at baseline, nor with any specific tumor type. At progression, HPD patients had a lower rate of new lesions than progressive non-HPD patients (p<0.05). HPD is associated with a higher age (p<0.05) and a worse outcome (Overall Survival). Interestingly, REFERENCE TGR (before treatment) was inversely correlated with response to anti-PD-1/PD-L1 (P<0.05). Conclusion A novel aggressive pattern of hyper-progression exists in a fraction of patients treated with anti-PD-1/PD-L1. This observation raises potentially some concerns about treating elderly patients (>65 y.o) with anti-PD-1/PD-L1 monotherapy.

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