Table 3. Recent meta-analyses examining sex differences in efficacy of ICIs in treating NSCLC.
| Meta-analysis, year published | Number of patients included [number of studies included] | Number of female participants (%) | Intervention vs. control arms, and clarifying comments | Pooled HR (95% CI) | Conclusions |
|---|---|---|---|---|---|
| Conforti, 2018 (60) | 3,482 [6] | 1,167 (33.5) | PD-1 inhibitor or CTLA-4 inhibitor plus chemotherapy vs. chemotherapy or chemotherapy plus placebo | Overall survival compared to controls: male: 0.72 (0.61–0.86); female: 0.89 (0.71–1.11) | Advanced or metastatic cancers were studied, of which NSCLC was a subgroup. In the overall study of 20 trials and 11,351 patients, pooled male survival was 0.72 (0.65–0.79) and female survival 0.86 (0.79–0.93) with a significant difference in efficacy between sexes (P=0.0019), demonstrating sex-specific benefit in overall survival with ICI therapy |
| Conforti, 2019 (96) | 2,970† [5] | 991 (33.4) | PD-1/PD-L1 inhibitor plus chemotherapy vs. chemotherapy. When excluding the trial with SCLC patients, a statistically significant overall survival benefit for females compared to males remained | Overall survival: male: 0.76 (0.66–0.87); female: 0.48 (0.35–0.67) | Females with advanced NSCLC derive greater benefit from combination chemoimmunotherapy than males, though both demonstrate improved survival with combination therapy over chemotherapy alone. However, only males demonstrate benefit from anti-PD-1 alone over chemotherapy |
| 4,923‡ [8] | 1,578 (32.1) | Progression-free survival: male: 0.64 (0.58–0.71); female: 0.56 (0.49–0.65) | |||
| 3,974 [6] | 1,335 (33.6) | PD-1/PD-L1 inhibitor plus chemotherapy vs. chemotherapy (first-line treatment). Three studies tested PD-1 alone; 3 studies tested PD-1/PD-L1 with chemotherapy | Overall survival for anti-PD-1: male: 0.78 (0.60–1.01); female: 0.97 (0.79–1.19) | ||
| Overall survival for anti-PD-1/PD-L1 with chemotherapy: male: 0.76 (0.64–0.91); female: 0.44 (0.25–0.76) | |||||
| Wang, 2019 (97) | 8,023 [12] | 2,601 (32.4) | PD-1/PD-L1 inhibitor alone or PD-1 or CTLA-4 inhibitor plus chemotherapy or PD-L1 plus chemoradiotherapy vs. chemotherapy or chemoradiotherapy | Overall survival: male: 0.76 (0.71–0.82); female: 0.73 (0.58–0.91) | Males experience more reliable benefit from ICIs than females. However, CTLA-4 inhibitors did not demonstrate survival benefit for either sex |
| 5,622 [10] | 1,934 (34.4) | PD-1 alone, PD-1 plus CTLA-4 inhibitor, PD-1 plus chemotherapy, PD-L1 inhibitor plus chemotherapy or chemoradiotherapy vs. chemotherapy or chemoradiotherapy | Progression-free survival: male: 0.67 (0.58–0.77); female: 0.73 (0.56–0.95) | ||
| Xue, 2021 (98) | 12,037 [19] | 3,751 (31.2) | PD-1, PD-L1, CTLA-4 inhibitor, or CTLA-4 plus PD-1 inhibitor together or PD-1, PD-L1, CTLA-4 inhibitor plus chemotherapy vs. chemotherapy or chemotherapy plus placebo | Overall survival: male: 0.73 (0.67–0.79); female: 0.73 (0.61–0.85) | Both males and females benefit from treatment with ICI over chemotherapy. There is no significant difference in overall survival (P=0.97) and progression-free survival (P=0.43) between the sexes |
| 6,940 [14] | 2,088 (30.1) | PD-1, PD-L1, or CTLA-4 plus PD-1 inhibitor together or PD-1 or PD-L1 inhibitor plus chemotherapy vs. chemotherapy or chemotherapy plus placebo | Progression-free survival: male: 0.62 (0.55–0.70); female: 0.68 (0.55–0.81) | ||
| Liang, 2022 (99) | 10,155 [16] | 3,370 (33.2) | PD-1/PD-L1 or CTLA-4 inhibitor alone, in combination, or with chemotherapy vs. chemotherapy or placebo. Six studies tested ICI plus chemotherapy vs. chemotherapy, 9 studies compared ICI vs. chemotherapy, and 1 study reviewed ICI vs. placebo | Overall survival: male: 0.76 (0.71–0.81); female: 0.74 (0.63–0.87) | In general, females benefitted more from combination chemoimmunotherapy, while males benefitted more from ICIs alone. However, in squamous cell carcinoma, only males demonstrated a statistically significant benefit from ICI therapy, either with or without chemotherapy |
| Madala, 2022 (100) | 9,270 [12] | 3,144 (33.9) | PD-1/PD-L1 inhibitor alone or combined with chemotherapy vs. chemotherapy, placebo, or their combination | Overall survival: male: 0.74 (0.66–0.83); female: 0.72 (0.63–0.82) | No statistical difference was found in overall survival (P=0.709) and progression-free survival (P=0.372) between the sexes |
| 6,193 [11] | 2,059 (33.2) | Progression-free survival: male: 0.63 (0.53–0.75); female: 0.72 (0.58–0.88) | |||
| Takada, 2022 (101) | 5,280 [8] | 1,554 (29.4) | PD-1/PD-L1 or CTLA-4 inhibitor, or PD-1 plus CTLA-4 inhibitor in combination, or PD-L1 + VEGF inhibitor in combination plus chemotherapy vs. chemotherapy, placebo plus chemotherapy, or VEGF inhibitor plus chemotherapy | Overall survival: male: 0.80 (0.72–0.87); female: 0.69 (0.54–0.89) | During first-line treatment, patients with advanced NSCLC demonstrated both improved overall survival and progression-free survival when treated with combined chemoimmunotherapy rather than chemotherapy alone, though this favors females to a greater degree |
| 3,701 [6] | 1,184 (32.0) | PD-1/PD-L1 inhibitor or PD-1 plus CTLA-4 inhibitor in combination, or PD-L1 + VEGF inhibitor in combination plus chemotherapy vs. chemotherapy, placebo plus chemotherapy, or VEGF inhibitor, placebo, and chemotherapy | Progression-free survival: male: 0.60 (0.55–0.66); female: 0.56 (0.44–0.70) |
†, 13.6% of patients with SCLC; ‡, 8.2% of patients with SCLC. ICI, immune checkpoint inhibitor; NSCLC, non-small cell lung cancer; HR, hazard ratio; CI, confidence interval; SCLC, small cell lung cancer; VEGF, vascular endothelial growth factor.