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Hyperprogressive disease: recognizing a novel pattern to improve patient management

Nature Reviews Clinical Oncology volume 15, pages 748–762 (2018)Cite this article

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Abstract

Anti-PD-1/PD-L1 monoclonal antibodies have substantially improved the overall survival of a subset of patients across multiple solid tumour types, but other patients can have a deterioration of their disease as a result of such therapies. This paradoxical phenomenon is defined as hyperprogression. In this Review, we present the available evidence of hyperprogressive disease following immune-checkpoint inhibition, the pathophysiological hypotheses that might explain hyperprogressive disease and the current challenges for patient management in routine clinical settings. Finally, we also discuss how the risk of hyperprogressive disease should be taken into account in clinical decisions involving immune-checkpoint inhibition.

Key points

  • Hyperprogressive disease is a paradoxical acceleration of tumour growth kinetics after the initiation of treatment with anti-PD-1/PD-L1 agents, but it has also been reported in patients receiving other treatments.

  • The incidence of hyperprogressive disease observed across different solid tumour types is variable (~10%); no consistent predictor of hyperprogressive disease has been reported thus far.

  • Possible explanations as to why PD-1/PD-L1 blockade might paradoxically lead to hyperprogressive disease include the expansion of PD-1+ regulatory T cells, exhaustion of compensatory T cells, modulation of pro-tumorigenic immune cell subsets, activation of aberrant inflammation or activation of oncogenic signalling.

  • Most of the current immune-related response criteria are designed to identify pseudoprogression but not hyperprogression; implementation of an early disease assessment tool and the integration of pretreatment tumour kinetics is crucial to improving the evaluation of patients receiving anti-PD-1/PD-L1 antibodies.

  • The evaluation of tumour biopsy samples obtained at the time of tumour growth acceleration will be key to evaluating the biological mechanisms underlying hyperprogressive disease, to interrogate the immunological nature of this phenomenon and to identify the best therapeutic strategies.

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Fig. 1: Acceleration of tumour growth after starting therapy with an anti-PD-1 antibody.
Fig. 2: Crossing survival curves in clinical trials.
Fig. 3: Evaluation of tumour response using RECISTv1.1 or integrating tumour kinetics.
Fig. 4: Biological hypotheses for immune-checkpoint-related hyperprogressive disease.
Fig. 5: Proposed assessment methods of progressive tumours under immune-checkpoint inhibition.

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Acknowledgements

The authors are grateful to N. Chaput, S. Ammari, A. Hollebecque and S. Postel-Vinay (all at Gustave Roussy, Villejuif, France) for helpful discussions. S.C. receives funding support from the Philanthropia Fondation.

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Nature Reviews Clinical Oncology thanks A. Goodman, M. A. Postow and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Département d’Innovation Thérapeutique et des Essais Précoces (DITEP), Gustave Roussy, Université Paris Saclay, Villejuif, France

    Stéphane Champiat, Christophe Massard, Aurélien Marabelle, Jean-Charles Soria & Charles Ferté

  2. Faculté de Médecine, Université Paris-Saclay, Université Paris-Sud, Le Kremlin Bicêtre, France

    Stéphane Champiat, Benjamin Besse & Jean-Charles Soria

  3. Département d’Oncologie Médicale, Gustave Roussy, Université Paris Saclay, Villejuif, France

    Roberto Ferrara

  4. INSERM, U1015, Gustave Roussy, Villejuif, France

    Aurélien Marabelle

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S.C. has received honoraria from AstraZeneca, BMS, Janssen, MSD, Novartis and Roche. B.B. has received institutional grants for clinical and translational research from AstraZeneca, BMS, Boehringer-Ingelheim, Inivata, Lilly, Loxo, OncoMed, Onxeo, OSE Pharma, Pfizer, Roche-Genentech, Sanofi-Aventis and Servier. J-.C.S. has received honoraria from MedImmune/AstraZeneca, Pierre Fabre, Roche, Sanofi, Servier and Tarveda, and became a full-time employee of Medimmune/AstraZeneca after this article was commissioned. C.F. became a full-time employee of Medimmune/AstraZeneca after this article was commissioned. The other authors declare no competing interests.

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Champiat, S., Ferrara, R., Massard, C. et al. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol 15, 748–762 (2018). https://doi.org/10.1038/s41571-018-0111-2

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