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Ann Oncol. 2018 Jan 1;29(1):250-255. doi: 10.1093/annonc/mdx642.

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.

Author information

Department of Pharmacy, Vanderbilt University Medical Center, Nashville, USA.
Department of Pharmacy, Vanderbilt Ingram Cancer Center, Nashville, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.
Department of Medicine, Melanoma Institute Australia, The University of Sydney, Sydney, Australia.
Department of Medicine, Vanderbilt University Medical Center, Nashville, USA.
Department of Medicine, Vanderbilt Ingram Cancer Center, Nashville, USA.
Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, USA.
Department of Medical Oncology, Royal North Shore Hospital, Sydney, Australia.
Department of Medical Oncology, Mater Hospital, Sydney, Australia.



Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known.

Patients and methods:

We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs.


Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03).


Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.


colitis; immune-related adverse events; ipilimumab; melanoma; nivolumab; pembrolizumab

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