Gastrointestinal Adverse Events with Combination of Checkpoint Inhibitors in Advanced Melanoma: A Systematic Review

Abstract

Introduction:Immunotherapies, including checkpoint inhibitors (CIs) such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) inhibitors, are revolutionizing the treatment of advanced melanoma. Combining CTLA-4 and PD-1 inhibitors provides additional clinical benefit compared with single agents alone. However, combination therapy can increase the incidence of gastrointestinal adverse events (GI AEs). This systematic review assessed the epidemiological, clinical, economic, and humanistic burden of GI AEs due to combination CIs in advanced melanoma.Methods:MEDLINE, EMBASE, and the Cochrane Library were systematically searched (December 2011 to December 2016) to identify primary studies, systematic reviews, meta-analyses, and conference proceedings (2014–2016) evaluating adults treated with ≥2 CIs for advanced melanoma.Results:Of the 3391 identified articles, 14 were included. Most studies examined the ipilimumab plus nivolumab combination. Any grade and grade 3–4 GI AEs occurred in more patients receiving ipilimumab plus nivolumab versus ipilimumab or nivolumab alone. The most common grade 3–4 GI AEs were diarrhea and colitis. Grade 3–4 colitis occurred in more patients receiving ipilimumab plus nivolumab. However, grade 3–4 diarrhea occurred at the same rate as ipilimumab alone. GI AEs developed with ipilimumab plus nivolumab approximately 6.6 weeks after initiating treatment. No studies assessing the economic or humanistic burden of GI AEs were identified.Conclusion:GI AEs occurred at a higher rate and greater severity in patients treated with ipilimumab plus nivolumab versus ipilimumab or nivolumab monotherapy. The lack of research on economic and humanistic burden of GI AEs with combination CIs for advanced melanoma represents an unmet need in the literature and should be explored in future studies.

Gastrointestinal Toxicities of Immune Checkpoint Inhibitors Are Associated With Enhanced Tumor Responsiveness and Improved Survival

“…GI adverse events were graded using the US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. These criteria generally grade irAEs on a scale of 1 - 5 (1 = mild event/reaction, 2 = moderate event/reaction, 3 = severe event/reaction, 4 = life-­threatening event/reaction, 5 = death) [ 22 ].…”

Current Perspectives in Cancer Immunotherapy

“…Ntali and colleagues (2017) have made a careful review of the literature regarding the endocrine sequelae of cancer immunotherapy, showing that these treatments may lead to hypophysitis, adrenalitis and both hypothyroidism and hyperthyroidism depending on specific characteristics of patients [196]. Finally, as observed for several chemotherapeutic agents, also the administration of immune checkpoint inhibitors is correlated to several gastrointestinal side effects mainly including diarrhea, colitis, nausea, vomiting and abdominal pains [197]. Furthermore, adverse effects including rash or pruritus, thyroiditis, hypothyroidism or hypophysitis and asymptomatic pancreatitis were reported in dMMR cancer patients treated with PD-1 blockade [198].…”

Adverse Events of Oncologic Immunotherapy and Their Management

“…[66] For example, a systematic review that assessed the clinical, epidemiological, humanistic, and economic burden of gastrointestinal AEs due to combination checkpoint inhibitors in advance melanoma reported that patients who received combination of ipilimumab plus nivolumab experienced more AEs than patients who received monotherapy checkpoint inhibitors. [68] Similarly, an observational study of patients with nonsmall cell lung cancer receiving nivolumab plus an EGFR-tyrosine kinase inhibitor (TKI) reported higher incidents of interstitial pneumonitis for nivolumab in combination with EGFR-TKI versus treatment with either drug alone. [69]…”