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

  • Author Footnotes
    † These authors equally contributed to this work.
    Chang Gon Kim
    Footnotes
    † These authors equally contributed to this work.
    Affiliations
    Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

    Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
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  • Author Footnotes
    † These authors equally contributed to this work.
    Chan Kim
    Footnotes
    † These authors equally contributed to this work.
    Affiliations
    Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
    Search for articles by this author
  • Author Footnotes
    † These authors equally contributed to this work.
    Sang Eun Yoon
    Footnotes
    † These authors equally contributed to this work.
    Affiliations
    Division of Hemato-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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  • Kyung Hwan Kim
    Affiliations
    Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea

    Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
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  • Seong Jin Choi
    Affiliations
    Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
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  • Beodeul Kang
    Affiliations
    Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
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  • Hye Ryun Kim
    Affiliations
    Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
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  • Su-Hyung Park
    Affiliations
    Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
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  • Eui-Cheol Shin
    Affiliations
    Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
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  • Yeun-Yoon Kim
    Affiliations
    Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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  • Dae Jung Kim
    Affiliations
    Department of Radiology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
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  • Hyun Cheol Chung
    Affiliations
    Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
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  • Hong Jae Chon
    Correspondence
    Corresponding authors: Addresses: Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Republic of Korea. Tel.: +82-31-780-7590, fax: +82-31-780-3929.
    Affiliations
    Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
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  • Hye Jin Choi
    Correspondence
    Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03772, Republic of Korea. Tel.: +82-2-2228-8133, fax: +82-2-393-4652.
    Affiliations
    Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
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  • Ho Yeong Lim
    Correspondence
    Division of Hemato-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea. Tel.: +82-2-3410-0918, fax: +82-2-3410-1757.
    Affiliations
    Division of Hemato-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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  • Author Footnotes
    † These authors equally contributed to this work.
Published:August 15, 2020DOI:https://doi.org/10.1016/j.jhep.2020.08.010

      Highlights

      • HPD occurs in a fraction of patients with HCC treated with PD-1 inhibitors.
      • HPD is associated with worse PFS and OS, depriving patients of the chance to receive subsequent treatments.
      • Elevated neutrophil-to-lymphocyte ratio predicts the occurrence of HPD and inferior survival rate after PD-1 blockade.

      Background & Aims

      Programmed cell death-1 (PD-1) inhibitor treatment can cause hyperprogressive disease (HPD), but the incidence, outcome, and predictive factors of HPD are unknown in patients with hepatocellular carcinoma (HCC). Herein, we assessed the existence and factors predictive of HPD in patients with advanced HCC treated with nivolumab.

      Methods

      We enrolled 189 patients with advanced HCC treated with nivolumab. 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 on sorafenib to compare tumour growth dynamics.

      Results

      Flare-up of tumour growth was observed in a fraction of patients upon PD-1 blockade, indicating the occurrence of HPD. Based on distinct patterns of disease progression exclusively observed in the nivolumab-treated cohort, but not in the regorafenib- or BSC/placebo-treated cohorts, 4-fold increases in TGK and TGR ratios as well as a 40% increase in TGR were the cut-off values used to define HPD; 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% CI 1.214–3.964) and overall survival (HR 2.238; 95% CI 1.233–4.062) compared to 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 occurs in a fraction of patients with HCC who receive PD-1 inhibitor treatment. Analyses of the baseline immune profile and on-treatment tumour growth dynamics could enable optimal patient selection and earlier identification of HPD.

      Lay summary

      Hyperprogressive disease is an unexpected response pattern observed in patients treated with an immune checkpoint inhibitor. This study revealed that hyperprogressive disease occurs in a fraction of patients with advanced hepatocellular carcinoma treated with an anti-PD-1 antibody, providing evidence to encourage careful monitoring of patients to prevent clinical deterioration induced by PD-1 blockade.

      Graphical abstract

      Keywords

      Linked Article

      • Hyperprogression in hepatocellular carcinoma: Illusion or reality?
        Journal of HepatologyVol. 74Issue 2
        • Preview
          Hyperprogressive disease (HPD) refers to the paradoxical occurrence of accelerated tumour growth following immunotherapy. The earliest reports of this phenomenon, published in 2016, described patients with cancers treated with programmed cell death 1 (PD-1) antibodies.1,2 Subsequent case series of patients with melanoma, head and neck, lung and gastric cancers suggest that the incidence of HPD ranges from 8% to 43% in patients undergoing treatment with anti-PD-1 or programmed cell death ligand 1 (PD-L1) antibodies (Table 1).
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