Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma.

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PD-1 inhibitor treatment can cause hyperprogressive disease (HPD), but the incidence, outcome, and predictive factors of HPD are unknown in hepatocellular carcinoma (HCC) patients treated with PD-1 blockade. Here, we assessed existence and factors predictive of HPD in advanced HCC patients treated with nivolumab.Advanced HCC patients treated with nivolumab (n=189) were enrolled. Occurrence of HPD was investigated using tumour growth dynamics based on tumour growth kinetics (TGK) and tumour growth rate (TGR) before and after treatment or time to treatment failure. We additionally analysed patients treated with regorafenib (n=95) or best supportive care (BSC)/placebo (n=103) after progression with sorafenib for comparison of tumour growth dynamics.A fraction of patients showed flare-up of tumour growth upon PD-1 blockade, indicating the occurrence of HPD. Based on distinct patterns of disease progression exclusively observed in nivolumab, but not in regorafenib or BSC/placebo-treated cohort, we determined 4-fold increases in TGK and TGR ratios and 40% increase in TGR as cut-off values to define HPD and found that 12.7% of the patients (24/189) treated with nivolumab met all these criteria. Patients with HPD had worse progression-free survival (hazard ratio [HR]: 2.194; 95% confidence interval [CI]: 1.214-3.964) and overall survival (HR: 2.238; 95% CI: 1.233-4.062) compared with patients with progressive disease without HPD. More than 90% of patients with HPD missed the opportunity for subsequent treatment because of rapid clinical deterioration. An elevated neutrophil-to-lymphocyte ratio (> 4.125) was associated with HPD and an inferior survival rate.HPD exists in a fraction of HCC patients who received PD-1 blockade. Analyses of the baseline immune profile and on-treatment tumour growth dynamics could promote optimal patient selection and earlier identification of rapid tumour growth induced by PD-1 inhibitors in HCC patients.


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