Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis

Background: Despite the acknowledged sex-related dimorphism in immune system response, little is known about the effect of patients' sex on the efficacy of immune checkpoint inhibitors as cancer treatments. We did a systematic review and meta-analysis to assess the heterogeneity of immune checkpoint inhibitor efficacy between men and women. Methods: We systematically searched PubMed, MEDLINE, Embase, and Scopus, from database inception to Nov 30, 2017, for randomised controlled trials of immune checkpoint inhibitors (inhibitors of PD-1, CTLA-4, or both) that had available hazard ratios (HRs) for death according to patients' sex. We also reviewed abstracts and presentations from all major conference proceedings. We excluded non-randomised trials and considered only papers published in English. The primary endpoint was to assess the difference in efficacy of immune checkpoint inhibitors between men and women, measured in terms of the difference in overall survival log(HR) reported in male and female study participants. We calculated the pooled overall survival HR and 95% CI in men and women using a random-effects model, and assessed the heterogeneity between the two estimates using an interaction test. Findings: Of 7133 studies identified in our search, there were 20 eligible randomised controlled trials of immune checkpoint inhibitors (ipilimumab, tremelimumab, nivolumab, or pembrolizumab) that reported overall survival according to patients' sex. Overall, 11 351 patients with advanced or metastatic cancers (7646 [67%] men and 3705 [33%] women) were included in the analysis; the most common types of cancer were melanoma (3632 [32%]) and non-small-cell lung cancer (3482 [31%]). The pooled overall survival HR was 0·72 (95% CI 0·65–0·79) in male patients treated with immune checkpoint inhibitors, compared with men treated in control groups. In women treated with immune checkpoint inhibitors, the pooled overall survival HR compared with control groups was 0·86 (95% CI 0·79–0·93). The difference in efficacy between men and women treated with immune checkpoint inhibitors was significant (p=0·0019). Interpretation: Immune checkpoint inhibitors can improve overall survival for patients with advanced cancers such as melanoma and non-small-cell lung cancer, but the magnitude of benefit is sex-dependent. Future research should guarantee greater inclusion of women in trials and focus on improving the effectiveness of immunotherapies in women, perhaps exploring different immunotherapeutic approaches in men and women. Funding: None.