Elsevier

European Journal of Cancer

Volume 60, June 2016, Pages 12-25
European Journal of Cancer

Original Research
Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor

https://doi.org/10.1016/j.ejca.2016.02.010Get rights and content

Highlights

  • This is the first meta-analysis to ascertain the incidence and risk of developing dermatologic adverse events (AEs) during treatment with the recently approved programmed death (PD)-1 inhibitors, pembrolizumab and nivolumab.

  • Skin rash, pruritus, and vitiligo are the most commonly reported AEs, although they appear to be primarily low-grade and manageable.

  • Among the PD-1 inhibitor–induced skin rashes, the maculopapular morphology is most frequent, often portraying a lichenoid tissue reaction/interface dermatitis on histology.

Abstract

Background

Dermatologic adverse events (AEs) are some of the most frequently observed toxicities of immune-checkpoint inhibitor therapy, but they have received little attention. The drugs, pembrolizumab and nivolumab are recently approved inhibitors of the programmed death (PD)-1 receptor that have overlapping AE profiles however, the incidence, relative risk (RR), and clinico-morphological pattern of the associated dermatologic AEs are not known.

Methods

We conducted a systematic review of the literature, and performed a meta-analysis of dermatologic AEs observed with the use of pembrolizumab and nivolumab in cancer patients. An electronic search was conducted using the PubMed, and Web of Science, and on the American Society of Clinical Oncology and European Society for Medical Oncology meeting abstracts' libraries for potentially relevant oncology trials, that employed the drugs at Food and Drug Administration-approved doses and reported dermatologic AEs. The incidence, RR and 95% confidence intervals were calculated using either random- or fixed-effects models based on the heterogeneity of included studies. The clinical presentation, histology of affected skin areas, and management strategies (based on institutional experience), are also presented.

Results

Rash, pruritus and vitiligo were found to be the most frequently reported dermatologic AEs. The calculated incidence of all-grade rash with pembrolizumab and nivolumab was 16.7% (RR = 2.6) and 14.3% (RR = 2.5), respectively. Other significant all-grade AEs included pruritus (pembrolizumab: incidence, 20.2% [RR = 49.9]; nivolumab: incidence, 13.2% [RR = 34.5]) and vitiligo (pembrolizumab: incidence, 8.3% [RR = 17.5]; nivolumab: 7.5% [RR = 14.6]). Interestingly, all the vitiligo events were reported in trials investigating melanoma. The RR for developing dermatologic AEs in general, was 2.95 with pembrolizumab, and 2.3 with nivolumab.

Conclusion

We found that pembrolizumab and nivolumab are both associated with dermatologic AEs, primarily low-grade rash, pruritus, and vitiligo, which are reminiscent of those seen with ipilimumab. Knowledge of these findings is critical for optimal care, maintaining dose intensity, and health-related quality of life in cancer patients receiving PD-1 inhibitors.

Introduction

Recent developments at the cellular and molecular level in cancer immunology have generated a renewed interest in immunotherapy for the treatment cancer. The cytotoxic T lymphocyte antigen-4 (CTLA-4) signalling pathway, and more recently, the programmed death receptor-1 (PD-1)/PD ligand-1 (PD-L1/PD-L2) signalling pathway are being increasingly recognised as critical mediators (‘checkpoints’) of tumour-induced immune suppression. While the former (CTLA-4, with its ligands CD80 and CD86) is crucial in attenuating the activation of naïve and memory T cells (in the early phase) after binding with the T cell receptor, the latter is active against T cell activity in peripheral tissues (PD-1, with its ligands PD-L1/ -L2) in chronic inflammatory states, infection or cancer, thus suppressing autoimmunity [1]. More specifically, interaction between the ligand and PD-1 receptor delimits the body’s normal anti-tumour immune response by inhibiting T-cell proliferation, thus down-modulating cytokines and anti-apoptotic molecules, and promoting induced T-reg cell proliferation—ultimately conferring immune resistance in tumour cells [2], [3], [4], [5].

Preclinical and clinical data have shown that pharmacological inhibition of the PD-1 signalling pathway is more beneficial (viv-a-vis CTLA-4 blockade), in terms of antitumour effects and adverse event (AE) rates [6], [7], [8], [9]. This led to the eventual approval of two novel anti-PD-1 receptor IgG4-κ monoclonal antibodies (mAbs)—pembrolizumab (humanised; Keytruda®, Merck & Co., Inc., Whitehouse Station, NJ), and nivolumab (fully human; Opdivo®, Bristol-Myers Squibb Company, Princeton, NJ). At the time of this writing, both drugs were indicated for the treatment of unresectable or metastatic melanoma and metastatic non-small cell lung cancer (NSCLC), with nivolumab being additionally approved for renal cell carcinoma; the precise treatment regimen with either agent however varies, and is subject to certain underlying criteria (e.g. BRAFV600 mutational status, prior treatment with ipilimumab/ platinum-based chemotherapy/antiangiogenic therapy, or PD-L1 expression) [10], [11]. In general, these drugs inhibit the key immune-compromising interaction between the tumour cell PD-L1 (B7-H1)/ PD-L2 (B7-DC) and T cell PD-1 receptors [12].

In terms of AEs, their overall safety profiles appear impressive. However, the potential for developing dermatologic AEs remains significant—moreover, the pattern is understood to be different in frequency and character from most other chemotherapy and targeted therapy-induced AEs [13]. Some of these AEs manifest with signs of autoimmunity (‘immune-related adverse events’, irAEs), and are thought to be due to treatment-related nonspecific hyperfunctioning of the immune system. Our current understanding stems mostly from the ipilimumab experience, wherein the development of rash, pruritus, alopecia, and vitiligo (in 20–30% of patients) [14] may lead to anticancer therapy dose modifications and/or termination, besides impairing patients’ health-related quality of life (HRQoL). Since very little is known about PD-1 inhibitor-induced dermatologic AEs, we sought to determine the incidence and risk, and describe the clinical characteristics in patients evaluated at our oncodermatology program.

Section snippets

Data sources and search strategy

We conducted a systematic search of the literature to identify clinical trials of pembrolizumab and nivolumab, that reported dermatologic AEs. The Medline (via PubMed) and Thomson-Reuters’ Web of Science databases were searched for studies published between January, 1960, and July, 2015. The following generic drug names and synonyms were used as search terms: pembrolizumab (MK-3475/ lambrolizumab/ Keytruda) and nivolumab (BMS-963558/ ONO-4538/ MDX-1106/ Opdivo). In addition, pertinent abstracts

Results

Our online search strategy yielded a total of 427 potentially relevant records related to nivolumab and 102 records for pembrolizumab. Of these, eight studies (phase I [n = 2] [19], [20], phase II [n = 2] [21], [22], phase III randomised controlled [n = 4] [8], [23], [24], [25]) investigating nivolumab, and five studies (phase I [n = 4] [26], [27], [28], [29], expanded access program [n = 1] [30]) of pembrolizumab were included in the final statistical analysis (Table 1).

Discussion

Our study is the first to estimate the burden of dermatologic AEs with the use of PD-1 receptor inhibitors in cancer immunotherapy. The most commonly reported AEs were rash, pruritus, and vitiligo—the incidence and risk of developing all-grade and high grade events however, appears to be low with both the drugs, pembrolizumab (P) and nivolimumab (N). Pembrolizumab is a humanised mAb, which may have a slightly greater immunogenic potential than nivolumab (fully human mAb). Nevertheless, the AEs

Conflict of interest statement

VRB, BB, MDH, NHS, RJM, and KJB have no conflicts of interest to declare.

MAP has had a consulting or advisory role with Amgen and Bristol-Myers Squibb, and receives research support from Bristol-Myers Squibb and Novartis (Inst).

AML has a consulting or advisory role with Bristol-Myers Squibb, Janssen, Aduro, Efranat, Jounce, and Novartis, and receives research funding from Bristol-Myers Squibb (Inst), Janssen (Inst.), and Genentech (Inst).

SW has a speaking arrangement with Novartis, Bayer-Onyx,

Acknowledgements

This work was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748.

The authors thank the information systems’ data delivery group (DataLine) at the Memorial Sloan-Kettering Cancer Center, especially Galina Yusim (data administrator) and Stuart Gardos (project manager), for their swift assistance with the complex task of medical data acquisition and electronic medical record search. The authors thank Bernadette Murphy

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    Submission declaration: The contents of this manuscript have not been presented earlier, and are not under consideration for publication elsewhere.

    1

    These authors, VRB and BB, contributed equally to this manuscript, and should be regarded as joint first authors.

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