한빛사 논문
Chang Gon Kim1,2,†, Chan Kim3,†, Sang Eun Yoon4,†, Kyung Hwan Kim2,5, Seong Jin Choi2, Beodeul Kang3, Hye Ryun Kim1, Su-Hyung Park2, Eui-Cheol Shin2, Yeun-Yoon Kim6, Dae Jung Kim7, Hyun Cheol Chung1, Hong Jae Chon3,*, Hye Jin Choi1,*, Ho Yeong Lim4,*
1Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
2Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
3Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
4Division of Hemato-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
5Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
6Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
7Department of Radiology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
†These authors equally contributed to this work.
*Corresponding Author
Abstract
Background and Aims
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.
Methods
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.
Results
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.
Conclusions
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.
Keywords : Hepatocellular carcinoma; PD-1 blockade; Tumour growth dynamics; Hyperprogressive disease; Neutrophil-to-lymphocyte ratio
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