Immune-Related Adverse Events (irAEs) of Immune Checkpoint Inhibitors (ICIs) in Advanced Melanoma Patients

Abstract

Abstract (1): Background: The use of ipilimumab, nivolumab, and pembrolizumab as monotherapies or in combination has transformed the management of advanced melanoma even though these drugs are associated with a new profile of immune-related adverse events (irAEs). The incidence of irAEs from clinical trials of these agents is an important factor for clinicians when treating patients with advanced melanoma. In the current study, we aimed to profile the incidence of potential irAEs of these agents when used as monotherapy and as combination therapy. Methods: We searched the Medline, Embase, and Cochrane databases; clinicaltrials.gov; and websites of regulatory agencies in the USA, Europe, Australia, and Japan for phase 1-3 trials of ipilimumab, nivolumab, and pembrolizumab for advanced melanoma. Random effect meta-analysis was utilized to profile the incidence of potential irAEs. Results: A total of 58 reports of 35 trials including 6331 patients with advanced melanoma and reporting irAE data were included in the meta-analyses. We found higher incidences of potential irAEs in combination therapies versus monotherapies for most of the types of irAEs. Among the monotherapies, ipilimumab users had the most frequent incidence of potential irAEs related to the gastrointestinal system (diarrhea, 29%; and colitis, 8%) and skin (rash, 31%; pruritus, 27%; and dermatitis, 10%), with hypophysitis in 4% of the patients. The most frequent potential irAEs among nivolumab users were maculopapular rash (13%), erythema (4%), hepatitis (3%), and infusion-related reactions (3%), while they were arthralgia (12%), hypothyroidism (8%), and hyperglycemia (6%) among pembrolizumab users. Conclusion: Especially the combination therapies tend to elevate the incidence of potential irAEs. Clinicians should be vigilant about irAEs following combination therapy as well as gastrointestinal and skin irAEs following ipilimumab therapy, in addition to being aware of potential irAEs leading to hyperglycemia, thyroid, hepatic, and musculoskeletal disorders following nivolumab and pembrolizumab therapy. Abstract (2): Importance Anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) antibody (ipilimumab) and anti-programmed cell death 1(anti-PD1) antibodies (nivolumab and pembrolizumab), have been shown to have a beneficial effect in treating melanoma but their risk of immune-related hypothyroidism (ir-hypothyroidism) in elderly patients from a real-world setting is limited. Objective To estimate the risk of ir-hypothyroidism in elderly with advanced melanoma treated with anti-CTLA4 or anti-PD1 in real-world setting. Design, Setting, and Participants SEER-Medicare data was used to identify elderly patients (≥65 years) diagnosed with advanced melanoma between 2011 and 2015 who were de novo users of anti-CTLA4 or anti-PD1. We estimated the risk of ir-hypothyroidism between users of anti-PD1 and anti-CTLA4. We used a propensity weighting approach by using the inverse probability of treatment weighting (IPTW) method to adjust for potential confounders. We utilized proportional hazards models to estimate the risk of ir-hypothyroidism and performed several sensitivity analyses to estimate the risk over ranges of follow-up periods as well as including patients with different stages of melanoma. Exposure Anti-CTLA4 or anti-PD1. Main Outcomes and Measures The risk of ir-hypothyroidism between the initiation of the treatment and up to 90 days from the last dose was measured as a hazard ratio (HR) and its 95% confidence interval (95%CI). Results Our sample had 210 elderly patients with advanced melanoma (164 anti-CTLA4, and 46 anti-PD1 (11 nivolumab, 35 pembrolizumab)). There was no statistical difference in the risk of ir-hypothyroidism between anti-PD1 and anti-CTLA4 (HR 2.15, 95%CI 0.83-5.53). Comparing the individual medications to each other showed a lower risk among users of ipilimumab versus nivolumab (HR 0.15, 95%CI 0.06-0.40) and pembrolizumab versus nivolumab (HR 0.13, 95%CI 0.03-0.55). Sensitivity analyses using a cohort of all-stages melanoma did not show a difference in the risk of ir-hypothyroidism between anti-CTLA4 and anti-PD1 and between individual medications. Conclusions and Relevance In our retrospective study of claims data of elderly patients diagnosed with melanoma, there was no statistical difference in the risk of ir-hypothyroidism between users of anti-CTLA4 or anti-PD1. However, advanced melanoma patients treated with ipilimumab or pembrolizumab may have a lower risk of ir-hypothyroidism compared to nivolumab users. Abstract (3): Purpose Melanoma treatment was advanced significantly by the approval of anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) agents (ipilimumab) and anti-programmed cell death 1 (anti-PD1) agents (nivolumab and pembrolizumab). However, these agents have been associated with gastrointestinal immune-related adverse events (irAEs) including colitis, which could lead to treatment discontinuation. We aimed to estimate the incidence and the risk of colitis in elderly patients with advanced melanoma treated with anti-CTLA4 and anti-PD1 in the real-world setting. Patients and Methods Elderly patients (age ≥ 65 years) diagnosed with advanced melanoma between 2011 and 2015 and treated with anti-CTLA4 or anti-PD1 agents were identified from the SEER-Medicare data. We estimated the risk of colitis from starting the treatment up to 90 days from the last dose of therapy. We used the log-rank test and logistic regression with adjustment for potential confounders using the inverse probability of treatment weighting (IPTW) method. Also, we conducted several sensitivity analyses using different follow-up periods and including all-stages of melanoma. Results A total of 274 elderly patients with advanced melanoma were included in our cohort. The risk of colitis was similar between the anti-PD1 users of and anti-CTLA4 groups based on log-rank test (p=0.17) and logistic regression model (OR 2.86, 95%CI 0.36-25). The 12-month cumulative incidence of colitis was 9.27% in the anti-CTLA4 vs. 4.64% in the anti-PD1 group. Sensitivity analyses for patients with all-stage melanoma showed a significantly lower risk of colitis in anti-PD1 compared to anti-CTLA4 treated patients based on a log-rank test (p=0.017) and logistic regression model (OR of 0.21, 95%CI 0.09-0.53). Conclusion Elderly with advanced melanoma who were treated with anti-CTLA-4 or anti-PD1 had a statistically similar risk of developing colitis. However, there was a statistical difference in the risk of colitis between anti-CTLA4 or anti-PD1 users among all-stages melanoma patients.