Correlation between sex and efficacy of immune checkpoint inhibitors (PD‐1 and CTLA‐4 inhibitors)

Abstract

Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on immune response, which is affected by sex difference, where both biological and sociological factors are involved. The role of sex in ICI trials has been overlooked. How sex correlates with ICI efficacy is incompletely understood. Clinical trials evaluating ICI versus other therapies in male and female patients were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and progression-free survival (PFS) were used. Six thousand and ninety-six patients from 11 trials were included. More improvement of OS was observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on the overall survival in melanoma patients versus NSCLC patients. Overall survival of patients treated with CTLA-4 inhibitor was more influenced by sex variable compared with PD-1 inhibitors. A significant sex-related efficacy difference was observed between female and male melanoma patients. Although male patients had longer OS and PFS than females when treated with ICIs versus controls, the difference was not significant. Sex difference should be more considered in future clinical trials, guidelines and clinical practice.

Effect of sex on the efficacy of patients receiving immune checkpoint inhibitors in advanced non‐small cell lung cancer

“…The previous study indicated that men treated with PD‐1 inhibitor had two‐times lower the risk of death than women . The result was partly in accordance with Grassadonia’s study (male: HR 0.67, 95% CI 0.55‐0.80; female: HR 0.77, 95% CI 0.57‐1.05) and Wu’s study (male: HR 0.60, 95% CI 0.36‐0.84; female: HR 0.88, 95% CI 0.68‐1.08), which revealed no significant improvement in PFS in women in NSCLC . Therefore, it remains a controversy and under‐investigated issue whether magnitude of overall survival and progression‐free survival advantage from immunotherapy are sex‐dependent.…”

“…It still remains unknown which is better efficacy of PD‐1, PD‐L1, or CTLA‐4 inhibitors for men and women. A previous meta‐analysis emphasized that PD‐1 inhibitors for men would consequently have better OS benefit than women . Our result indicated that women had a lower HR of OS meaning a higher magnitude of overall survival efficacy, but no significant PFS benefit from PD‐1 inhibitors.…”

“…Five different meta‐analysis have been reported to investigate the efficacy of immune checkpoint inhibitors according to the sex of cancer patients . In the previous meta‐analysis conducted by Botticelli and colleagues, there was no significant improvement of overall survival in male cancer patients treated with anti‐PD‐1 or anti‐CTLA‐4 antibodies.…”

“…No available data of OS data and PFS data was found in the stratified analysis of cancer type like NSCLC according to the sex. In the meta‐analysis of Wu and colleagues, subgroup analysis by type of cancer, four trails of NSCLC including 2192 patients showed that men had the better survival benefit compared with women. Grassadonia et al reported that male patients had both the better OS advantage from six RCTs and PFS advantage from eight RCTs than female patients in NSCLC .…”

“…31 The result was partly in accordance with Grassadonia's study (male: HR 0.67, 95% CI 0.55-0.80; female: HR 0.77, 95% CI 0.57-1.05) and Wu's study (male: HR 0.60, 95% CI 0.36-0.84; female: HR 0.88, 95% CI 0.68-1.08), which revealed no significant improvement in PFS in women in NSCLC. 32,33 Therefore, it remains a controversy and under-investigated issue whether magnitude of overall survival and progression-free survival advantage from immunotherapy are sex-dependent. Five different meta-analysis have been reported to investigate the efficacy of immune checkpoint inhibitors according to the sex of cancer patients.…”