Elsevier

European Journal of Cancer

Volume 60, June 2016, Pages 190-209
European Journal of Cancer

Original Research
Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy

https://doi.org/10.1016/j.ejca.2016.02.025Get rights and content

Highlights

  • Anti-PD-1 antibodies can induce a plethora of immune-related adverse events (irAEs).

  • IrAEs of the skin, gastrointestinal tract, liver, endocrine and renal system were analyzed.

  • Diabetes mellitus, lichen planus and pancreas insufficiency due to pancreatitis were reported.

  • If symptoms are autoimmune-related, prompt treatment has to be initiated to reduce morbidity.

  • Since irAEs can start asymptomatic or with minimal symptoms, careful monitoring is essential.

Abstract

Background

Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.

Methods and findings

In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis.

Conclusion

Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

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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