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Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination

Key Points

  • CTLA-4 regulates T-cell activation upon initiation of an immune response, in the lymphoid organs, where naive T cells are primed, and potentially in the periphery via regulatory T-cell (TREG) depletion

  • This diverse role of CTLA-4 in initiating and mounting immune responses might explain the plethora of immune-related adverse events (irAEs) experienced by patients receiving treatment with anti-CTLA-4 antibodies

  • PD-1 suppresses T-cell activity, mostly within the peripheral tissues and in the tumour microenvironment, which might explain the distinct spectrum and reduced incidence of adverse effects of anti-PD-1 antibodies

  • Thyroid disorders are more frequent adverse effects of treatment with anti-PD-1 antibodies (pembrolizumab and nivolumab) whereas colitis and hypophysitis are more frequent with anti-CTLA-4 antibodies (ipilimumab)

  • General guidelines on the management of irAEs recommend treatment of symptoms; corticosteroids are generally indicated together with dose skipping or discontinuation in patients with persistent grade ≥2 adverse events

Abstract

Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.

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Figure 1: Immune checkpoints and control of T-cell activation in melanoma.
Figure 2: The most common adverse events in patients treated with ipilimumab, pembrolizumab, nivolumab, or ipilimumab plus nivolumab.
Figure 3: Adverse events of special interest noted with immune-checkpoint inhibitors.
Figure 4: Management of immune-related adverse events excluding skin and endocrine toxicities.

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Acknowledgements

The authors would like to thank Cedric Verjat for assisting with the creation of Figs 1, 2 and 3.

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C.B., E.L. and C.R. researched data for this article, C.B., A.T. and C.R. made a substantial contribution to discussions of content. C.B., A.T. and C.R. wrote the manuscript, and all authors edited and/or reviewed the manuscript prior to submission. C.B. and A.T. contributed equally to this Review.

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Correspondence to Caroline Robert.

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Competing interests

A.T. has acted as consultant of BMS and Merck. He has also conducted contract research for Amgen, BMS, Merck and Novartis. E.R. has acted as a consultant of and BMS and Roche. O.L. has acted as a consultant of Genzyme and MSD. F.C. has acted as consultant of Abbvie, Enterome, Ferring, Genentech, Hospira, Jansen, Mayoly, MSD, Otsuka, Splindler, and Takeda and Vifor. A.M. has acted as an advisor and has received honoraria from Amgen, BMS, Pfizer, MSD, Novartis and Roche. A.E. is a member of the scientific advisory board of BMS, Incyte, Medimmune and Merck. J-C.S. has acted as a consultant of Astra-Zeneca, Merus, MSD, Pfizer, Roche, Servier and Symphogen. C.M. has acted as consultant of BMS and Merck. C.R. has acted as a consultant of Amgen, BMS, GSK, Merck, Novartis and Roche. C.B, F.L.L, H.I., S.C., A.B., E.L., M.T. and C.L. declare no competing interests.

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Supplementary information S1 (table)

Incidence per 1000 person-months of all grade and grade 3 to 5 adverse events under immunotherapy using the SAS Sytstem. The results include data from the following studies: CA-184-002, KEYNOTE-001, KEYNOTE-001 (randomized cohorts), KEYNOTE-002, KEYNOTE-006, CheckMate-037, CheckMate-066, CheckMate-067, and CheckMate-069. (PDF 2014 kb)

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Boutros, C., Tarhini, A., Routier, E. et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 13, 473–486 (2016). https://doi.org/10.1038/nrclinonc.2016.58

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