Original ResearchNeurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy
Introduction
Nivolumab and pembrolizumab have been shown to enhance pre-existing immune responses, including antitumour response, by directly blocking programmed cell death 1 (PD-1) receptor which is a checkpoint of the effector stage of the immune system [1], [2]. Currently, both nivolumab and pembrolizumab are approved for treatment of metastatic melanoma, nivolumab also for squamous non-small-cell lung cancer after prior chemotherapy and will soon be used against other cancer entities. Therefore, physicians should be aware of potential side-effects.
Grade 3 and 4 adverse events (AEs) are observed in 22–24% of ipilimumab-treated patients [3], in 5–10% of nivolumab- or pembrolizumab-treated patients, respectively [4], [5], and in 55% of ipilimumab plus nivolumab-treated patients [6]. In principle, all checkpoint inhibitors can potentially induce immune-related AEs (irAEs) in any organ. Since anti-PD-1 treatment is continuously applied, 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 under anti-PD-1 antibody therapy like acute heart failure [7], rhabdomyolysis [8], and dyspnoea due to myositis [9]. Prompt diagnosis and adequate management are indispensable to reduce morbidity of these patients.
Here, we have summarized neurological, respiratory, musculoskeletal, cardiac and ocular side-effects induced by anti-PD1 antibodies from 15 skin cancer centres in Germany and Switzerland. Rare and therapeutically challenging side-effects 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 centre and were performed according to Good Clinical Practice and the Helsinki Declaration.
Study centres and treatment settings
Fifteen participating study centres in Germany and Switzerland screened patient records for pembrolizumab- and
Results
A total of 496 melanoma patients were treated with nivolumab or pembrolizumab at 15 skin cancer centres. A total of 242 irAEs in 138 patients were reported. In 77 of the 138 patients, side-effects affected respiratory tract (24 patients), musculoskeletal system (21 patients), nervous system (16 patients), eyes (8 patients), heart (5 patients), and blood (3 patients). In addition, in 15 patients rare constitutional and/or infectious side-effects were reported.
Discussion
In this study 496 patient records of 15 skin cancer centres were screened for anti-PD-1 AEs. In total, 242 rare or unexpected side effects of nivolumab and pembrolizumab were documented in 138 patients (27.8%). Neurological, respiratory, musculoskeletal, cardiac, ocular and haematopoietic AEs occurred in 77 of the 138 patients and were summarised. Some events are reported for the first time like cardiac arrhythmia, paresis, aphasia, a meningo-(radiculitis), and parkinsonoid syndrome.
Conflict of interest statement
Lisa Zimmer is on the advisory board or/and has received honoraria from Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), GlaxoSmithKline (GSK), Novartis, Merck, and travel support from MSD, BMS and Novartis. Simone Goldinger has received travel support from BMS, MSD, Roche, Novartis and grants from University of Zurich. Carmen Loquai is on the advisory board or/and has received honoraria or/and travel support from Roche, BMS, Merck, Novartis. Selma Ugurel has received grants and
Acknowledgements
The authors thank G. Metzler, Tübingen and S. Schliep, Erlangen, for histopathologic diagnosis and reporting. We thank A. Cavallaro, Erlangen, for kindly providing a radiologic image. C. Bender, Heidelberg, has kindly supported patient documentation.
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We like to commemorate Martin Leverkus who was a wonderful colleague, a talented researcher and a good friend.