Solid tumor–specific patterns of immune-related adverse events due to immune checkpoint inhibitor.

Abstract

2648 Background: Immune checkpoint inhibitors (ICIs) are the backbone of therapy for several solid tumors; however, they have a unique toxicity profile that may limit treatment. The objective of this systematic review was to identify differences in type and frequency of immune-related adverse events (irAEs) across solid tumors. Methods: Using PubMed, we identified registrational phase 2 and 3 clinical trials of ICI-based therapy (i.e., single agent immunotherapy (single I/O), single I/O plus chemotherapy, single I/O plus kinase inhibitor, double immunotherapy combination (double I/O), double I/O plus chemotherapy) for first-line and second-line unresectable disease for which irAEs (dermatologic, endocrine, gastrointestinal, hepatic, renal, pulmonary) were specified for the following tumor types: melanoma, non-small cell lung (NSCLC), esophageal, colorectal (CRC), biliary tract (BTC), hepatic (HCC), renal (RCC), urothelial, endometrial, head and neck (H&N). Odds ratio (OR) were used to analyze effect size. All analysis performed on Microsoft Excel. Results: 105 trials (n = 32,896 patients) were identified with the most commonly studied regimens being those that were PD-1 or PD-L1-based. While endocrinopathies were the most frequent irAE (~15-20%) with first-line single I/O, one tumor type was not more likely than the other to develop endocrinopathies. Interestingly, patients with melanoma and RCC treated with first-line single I/O were significantly more likely to develop gastrointestinal irAE compared to those with NSCLC, CRC, HCC, urothelial, and H&N with OR of 3.41 – 30.64 and 2.96 – 26.60, respectively. Second-line single I/O led to increased frequency of irAE and greater variation in the predominant irAE for a given tumor type – four tumor types (melanoma, NSCLC, gastric, H&N) had dermatologic irAE as most frequent, five (esophageal, CRC, HCC, urothelial, endometrial) had endocrine irAE, and two (BTC, RCC) had gastrointestinal irAE. Overall odds of developing irAE were greater with double I/O than with single I/O in the first-line setting and more pronounced in the second-line. For example, in melanoma, OR for endocrine irAE was 2.55 (95% CI 1.27 – 5.10) in first-line and 17.03 (95% CI 8.04 – 36.05) in second-line and for hepatic irAE was 4.41 (95% CI 1.55 – 12.50) in first-line and 7.63 (95% CI 2.45 – 23.78) in second-line. The addition of chemotherapy or kinase inhibitor did not significantly alter irAE frequency across tumor types. In fact, there were fewer irAEs in some tumor types with addition of kinase inhibitor in first-line unresectable disease compared to single I/O alone; for example, OR for dermatologic irAE with kinase inhibitor compared to single I/O alone was 0.36 (95% CI 0.18 – 0.70) for melanoma and 0.22 (95% CI 0.08 – 0.59) for RCC. Conclusions: irAE profiles vary across tumor type, treatment regimen, and line of therapy and do not necessarily correlate with the primary tumor site.