Sex differences in tolerability and response to immune checkpoint inhibitors in non-small cell lung cancer patients

Background: Sex differences in non-small cell lung cancer (NSCLC) outcomes have been described. Immunerelated adverse events (IRAEs) have emerged as a serious clinical problem in the use of immune checkpoint inhibitors (ICI). Risk factors for IRAEs and their association with response to therapy remain controversial. Sex differences in innate and adaptive immune responses have been observed but the association of these differences with IRAEs remains unclear. Therefore, we studied sex differences in IRAEs and their association with response to therapy. Methods: All patients with metastatic NSCLC treated with anti-PD1 and anti-PDL1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Patients receiving treatment at an outside facility with history autoimmune disorders or radiation-induced pneumonitis were excluded. Chi-square test was used to estimate differences in categorical data. Kaplan-Meier method was used for time-to-event analysis. Results: A total of 231 patients were identified; 120 (52%) were women and 111 (48%) were men. Baseline characteristics and ICI distribution were similar among groups. Women were more likely to experience IRAEs compared to men (48% vs. 31%, p<0.008). Among patients with IRAEs, women were more likely to be prescribedsystemic steroids (63% vs. 41%, p<0.02). On the other hand, no significant differences were observed in theadministration of intravenous steroids. Women were more likely to develop pneumonitis (23% vs. 12%, p<0.03) andarthralgias (17% vs. 3%, p<0.04). However, dermatologic toxicities (35% vs. 9%, p<0.002) were more commonlyseen in men. In 17% of women the ICI was discontinued due to toxicity (men 7%). Besides sex, no other clinicalcharacteristic was associated with increased IRAEs. Women with IRAEs were more likely to have a radiographicresponse compared with women without IRAEs (78% vs. 23%, p<0.0001), although this was not observed in men(37% vs. 26%, p>0.22). Better PFS was observed in women with IRAEs (10 months vs. 3.3 months, p<0.0006)compared to women without IRAEs.Conclusions: Women with metastatic NSCLC are more likely to experience IRAEs compared to men. We alsoobserved sex differences in the frequency of certain IRAEs. In addition, an association between IRAEs andresponse to therapy was observed in women. Larger studies are needed to investigate the mechanisms underlyingthese associations .