Abstract SY43-03: Sex differences in severe adverse events in patients receiving immunotherapy, targeted therapy, or chemotherapy in Cancer clinical trials: An evidentiary perspective

Abstract Introduction: For patients with cancer receiving cytotoxic therapy, adverse events (AEs) have been found to be more common in women than men. Yet few studies have investigated potential sex differences in AEs among patients receiving immune or targeted therapies. Moreover, no prior research has examined whether patient-reported outcomes (PROs) - which directly measure the patients’ treatment experience and have been shown to predict many cancer outcomes - may be used to identify differences in risk of AEs overall or by patient sex. Methods: We analyzed treatment-related AEs by sex in phase II and III clinical trials conducted by the SWOG Cancer Research Network between 1980 and 2019, excluding sex-specific cancers. We used the Common Terminology Criteria for Adverse Events (CTCAE) to categorize AE codes and grade. Symptomatic AEs were defined as those aligned with the National Cancer Institute’s PRO-CTCAE; laboratory-based or observable/measurable AEs were designated as objective (hematologic v nonhematologic). Thirteen symptomatic and 14 objective AE categories were examined. Baseline fatigue was used as an indicator of patient-reported symptoms that reflects a key aspect of quality of life. Fatigue was derived from the Functional Assessment of Cancer Therapy (FACT) or the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Fatigue scores were dichotomized as clinically significant (yes vs. no). The association of sex and clinically significant fatigue were examined separately; also, we examined whether the association of severe AEs by sex differed according to levels of clinically significant fatigue using interaction tests. Multivariable logistic regression was used, adjusting for age, race, and disease prognosis. Analyses were conducted among all cancer treatment domains combined; separately according to categories of cytotoxic therapy, immune-based therapy, and targeted therapy; and were delineated according to symptomatic AEs vs. observable/measurable AEs. Results: As previously reported, we examined N=23,296 patients (women, n=8,838; men, n=14,458) receiving chemotherapy (n=17,417), immunotherapy (n=2,319), or targeted therapy (n=3,560). Among 202 trials, 274,688 AEs were identified. Women were found to have an overall 34% increased risk of Grade 3 or higher (severe) AEs compared to men (odds ratio [OR] =1.34; 95% CI, 1.27 to 1.42; P<.001). In patients receiving immunotherapy, the risk for women was 49% higher (OR=1.49; 95% CI, 1.24 to 1.78; P<.001). Women experienced an increased risk of severe symptomatic AEs among all treatments, especially immunotherapy (OR=1.66; 95% CI, 1.37 to 2.01; P<.001). Women receiving chemotherapy or immunotherapy experienced increased severe hematologic AEs. No statistically significant sex differences in risk of nonhematologic AEs were found. Analyses by patient-reported baseline fatigue will be presented. Conclusions: We found increased risk of severe symptomatic AEs and severe hematologic AEs for women compared to men across multiple treatment modalities. Possible reasons for these differences include differences in mechanisms related to pharmacogenomics of drug metabolism/disposition or differences in total dose received and/or adherence to therapy. Based on the large sex differences in AEs we identified among patients receiving immunotherapy, continued study of the association of sex and AEs for immune-based treatments is a priority. Taken together, these findings suggest that in an era of precision medicine, patient sex may be an important component of the evaluation of risks of treatment. The potential use of patient-reported outcomes to predict the risk of severe toxicity in patients receiving systemic therapy for cancer could aid in decision-making between patients and their clinical care team. Citation Format: Joseph M. Unger, Dawn L. Hershman. Sex differences in severe adverse events in patients receiving immunotherapy, targeted therapy, or chemotherapy in Cancer clinical trials: An evidentiary perspective. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY43-03.