We previously showed that therapy with anti-CTLA-4 or anti-PD-1 agents was more effective for men as compared with women. Here we investigated whether women derive larger benefit than men from different immunotherapeutic strategies.
We performed a systematic review and a meta-analysis, including all RCTs testing anti-PD-1 or anti-PD-L1 given either alone or combined with chemotherapy in patients with advanced/metastatic solid tumors, to assess different efficacy of these two immunotherapeutic strategies according to patients’ sex. The primary endpoint of the study was to assess the difference of treatments efficacy between males and females, measured in terms of difference of the overall survival log(HR) reported in males and in females for each treatment strategy For this purpose, the pooled OS HR and 95% confidence interval (CI) was calculated in males and females using random-effects model and the heterogeneity between the two estimates was evaluated using an interaction test.
16 phase III RCTs testing anti-PD1 or anti-PD-L1 in monotherapy versus standard chemotherapy in 9291 patients with advanced solid tumors were included in the analysis. Two RCTs were performed in patients with melanoma, 8 in NSCLC, 2 in HNSCC, 2 in gastric cancer, and 1 each in kidney and urothelial cancer. In 15 out of 16 of such RCTs, men derived larger OS benefit than women. The pooled-OS HR was 0.73 (95% CI, 0.69-0.78) in men versus 0.86 (95% CI, 0.78-0.94) in women (heterogeneity-p=0.0079). 5 phase III RCTs testing the combination of chemotherapy plus anti-PD-1 or anti-PD-L1 versus chemotherapy in 2979 patients were included in the analysis. Four RCTs were performed in NSCLC and 1 in SCLC. All these 5 RCTs showed impressively larger OS benefit in women. The pooled-OS HR was 0.50 (95% CI, 0.41-0.60) in women versus 0.76 (95% CI, 0.66-0.87) in men (heterogeneity p = 0.0003).
We confirmed a large and significant interaction between patients’ sex and the efficacy of anti-PD-1/anti-PD-L1 drugs given in monotherapy or combined with chemotherapy. The direction of such interaction was the opposite for the two immunotherapeutic strategies: women derived impressively larger benefit from the addition of chemotherapy to anti-PD1/PD-L1 as compared with men.
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All authors have declared no conflicts of interest.