Original ResearchCharacterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor☆
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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These authors, VRB and BB, contributed equally to this manuscript, and should be regarded as joint first authors.