Optimizing the Safety Profile of Immune Checkpoint Blockade in Renal Cell Carcinoma In this review, current information on the diagnosis, monitoring, and management of immune-related adverse reactions of anti-PD-1 antibody therapy is presented. Recent literature highlights optimal strategies for managing specific adverse events related to antibodies that target this pathway. In only a few years immune checkpoint blockade has rapidly moved from the bench to a transformative position in cancer therapy, and by 2017, molecularly targeted immunotherapeutics directed against Programmed Death 1 (PD1), its ligand PD-L1 and Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA4) have become an approved standard across a number of solid tumor malignancies, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer and head and neck cancer. This new generation of drugs augments cancer-directed immune response of the host by modulating the effects of regulatory surface receptors on human immune cells, so-called immune checkpoints. Through activation of cancer-antigen specific T effector cells these agents can achieve powerful anti-cancer effect and induce long-lasting treatment responses. A growing list of targets is being explored in the treatment of RCC. The PD-1 directed humanized monoclonal antibody nivolumab is FDA approved for the treatment of tyrosine kinase inhibitor (TKI) pretreated advanced RCC. Exploiting function of immune regulators therapeutically can lead to treatment induced adverse events (AE) via immune-activation and resulting inflammatory changes in healthy tissues. Immune-related adverse events (irAEs) can affect any organ system, most commonly the skin, gastrointestinal, hepatic, and endocrine systems. Early data suggest that temporary use of immunosuppressive medications administered to suppress these side effects does not eliminate the possibility of a favorable antitumor effect. Our review of current literature offers important perspectives from which to explore the principles of immune-related adverse events recognition and management. These are increasingly important considerations beyond kidney cancer as the use of these antibodies expands. Although guidelines are emerging on the optimal management of irAEs, there is a relative scarcity of prospective trials on evaluating the best treatment approaches to manage these unique side effects. Treatment Administration and Safety: The Pivotal Nivolumab Study The phase 3 CheckMate 025study reported by Motzer et al1 established the benefits of nivolumab for RCC and delineated the safety profile of this agent in the largest cohort reported to date. It showed that patients with advanced RCC who had received previous antiangiogenic treatment achieved longer overall survival (OS) with nivolumab treatment than with everolimus treatment. The separation of the OS curves occurred early in the study, and there was a 5.4 months absolute difference in median OS with nivolumab than with everolimus (25.0 months vs. 19.6 months), a difference that crossed the prespecified boundary for significance at the time of the interim analysis.1 The median duration of treatment was 5.5 months (range, <0.1 to 29.6) with nivolumab and 3.7 months (range, 0.2 to 25.7) with everolimus. While the protocol did not allow dose reductions for AEs, 51% patients treated with nivolumab (51%) had at least one dose delay, and 66% patients treated with everolimus (66%) had dose delays (including interruptions). A total of 102 of the 397 patients in the everolimus group (26%) had at least one dose reduction. The authors reported that treatment-related adverse events of any grade occurred in 79%of patients treated Martin H. Voss, MD Assistant Attending Department of Medicine Memorial Sloan Kettering Cancer Center New York, New York Keywords: Immune checkpoint blockade, immune-related adverse events, PD1, PD-L1, nivolumab, dermatologic, hepatic, endocrinopathy, diarrhea, colitis, pneumonitis. Address for reprints and correspondence: Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY, 10065. Email: vossm@mskcc.org 38 Kidney Cancer Journal
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