Original ResearchCutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy
Introduction
Nivolumab and pembrolizumab have been shown to enhance pre-existing immune responses including anti-tumour response by directly blocking programmed cell death receptor-1 (PD-1) which is a checkpoint of the effector stage of the immune system 1, 2. While the response rate of ipilimumab-treated patients is around 10–15% 3, 4, response rates of pembrolizumab- and nivolumab-treated patients are 33% [5] and 32% [6], respectively.
Grade 3–4 adverse events (AEs) are observed in 22–24% of ipilimumab-treated patients 7, 8, in 5–10% of nivolumab- and pembrolizumab-treated patients 5, 6 and in 54–55% of ipilimumab plus nivolumab-treated patients 8, 9. A permanent discontinuation of therapy due to side-effects has been reported in 5% of patients treated with anti-PD-1 antibodies [10]. All checkpoint inhibitors can potentially induce immune-related AEs (irAEs) in any organ system. In contrast to ipilimumab, treatment with anti-PD-1 antibodies is continuous with some studies finishing application after 2 years. Thus, irAEs can occur late after initiation of therapy but possibly also after cessation of therapy. To date, cases of rare life-threatening or even fatal side-effects have been reported after anti-PD-1 antibody therapy like severe skin reactions [11], diabetes mellitus type 1 [12], and rhabdomyolysis [13].
Both nivolumab and pembrolizumab are approved for treatment of metastatic melanoma, nivolumab also for squamous non-small-cell lung cancer (NSCLC) after prior chemotherapy. Since they are also effective in various other tumour entities, they are expected to be employed widely. Therefore, physicians should be aware of potential side-effects. To facilitate prompt diagnosis and adequate management, cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects are summarised. Rare and therapeutically challenging side-effects from 15 cancer centers in Germany and Switzerland are described in detail.
Section snippets
Ethics statement
This retrospective study was approved by the local institutional review board of the Friedrich-Alexander-University Erlangen-Nuremberg (approval number 17_16Bc). In addition, all clinical protocols were reviewed and approved by the local institutional review boards of each participating center and were performed according to Good Clinical Practice and the Helsinki Declaration.
Study centers and treatment settings
Fifteen participating study centers in Germany and Switzerland screened patient files for pembrolizumab- and
Results
A total of 496 melanoma patients were treated with nivolumab or pembrolizumab at 15 skin cancer centers; 242 irAEs were reported in 138 patients. In 116 of the 138 patients, side-effects affected skin (43 patients), endocrine system (30 patients), gastrointestinal tract (21 patients), liver (11 patients), pancreas (9 patients), and the renal system (2 patients).
Discussion
In this study, 496 patient records of 15 skin cancer centers were screened for anti-PD-1 AEs and 242 interesting, rare or unexpected, side-effects induced by nivolumab or pembrolizumab were documented in 138 patients (27.8%). Cutaneous, gastrointestinal, hepatic, endocrine, and renal AEs occurred in 116 of the 138 patients and were summarised: Some events are reported for the first time like lichen planus and pancreas insufficiency after pancreatitis. Furthermore, details of rare side-effects
Conflict of interest statement
Andrea Forschner is on the advisory board or/and has received honararia from Merck Sharp & Dohme, Bristol-Meyers Squibb, Roche, and Novartis and travel support from MSD, Roche, and Novartis. Carmen Loquai is on the advisory board or/and has received honararia or/and travel support from Roche, BMS, Merck, and Novartis. Simone Goldinger has received travel support from BMS, MSD, Roche, and Novartis and grants from University of Zurich. Lisa Zimmer is on the advisory board and/or has received
Funding
No additional funding was available for this study.
Acknowledgements
The authors would like to thank G. Metzler, Tübingen, and S. Schliep, Erlangen, for histopathologic diagnosis and reporting. The authors thank T. Bley, Würzburg, for kindly providing a radiologic image. C. Bender, Heidelberg, has kindly supported patient documentation. The present work was performed in fulfillment of the requirements for obtaining the degree ‘Dr. med’.
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We like to commemorate Martin Leverkus who was a wonderful colleague, a talented researcher and a good friend.