Immune Checkpoint Inhibitors Demonstrate Better Response in Men Than Women

A patient’s sex might play a role in how they respond to immunotherapy, according to new study findings.

Noting differences in the immune system between men and women, researchers hypothesized that these differences could be relevant to conditions such as cancer, as well as their reaction to therapies. Men have an almost 2-times higher risk of mortality from all cancers, which is likely to reflect differences not only in behavioral and biological factors, but also in the immune system, according to the authors of the study.

“Cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed death receptor-1 (PD-1) pathways play an important role in tumor-induced immunosuppression, and they are increasingly being exploited as therapeutic targets in several types of advanced malignancies,” wrote the authors. “Sex hormones regulate the expression and function of PD-1 and PD-L1, and the hormonal effects on the PD-1 pathway are important in mediating autoimmunity.”

The study, published in Lancet Oncology, combined data from 20 previously published randomized trials including 11,351 patients who received immune checkpoint inhibitors—ipilimumab, tremelimumab, nivolumab, or pembrolizumab—for advanced metastatic cancers. Of the patients, 7646 (67%) were male and 3705 (33%) were female.

When compared with control cohorts, the authors observed a significant difference in the efficacy of immune checkpoint inhibitors between the men and women. Male patients treated with immune checkpoint inhibitors as monotherapy or as combination therapy had a significantly reduced risk of mortality compared with men treated in the control cohorts (pooled overall survival HR 0.72, 95% CI 0.65-0.79). For female patients, the benefits yielded from the immune checkpoint inhibitors compared with the control cohorts was smaller, in comparison (HR 0.86, 95% CI, 0.79-0.93).

The higher survival benefit for men was seen regardless of cancer type or drug administered, and, on average, the relative survival gain was double the size for men.

The authors did note that in small-cell lung cancer, the addition of ipilimumab to standard chemotherapy was not effective in improving overall survival for both men and women.

“Despite the obvious biological and physiological differences between men and women, and the extensive literature on the potential role played by sex in influencing drug pharmacokinetics, pharmacodynamics, and efficacy, new therapeutic approaches are rarely tested taking sex into account,” explained the authors.

They argued that patients’ sex should be taken into account in the assessment of risk versus benefit as an important variable in predicting the relative benefit of immunotherapy drugs compared with available standard therapies. While checkpoint inhibitors significantly improve overall survival in both sexes, the magnitude of benefit is dependent on sex.

Taking these results into account, the authors also urged that future research focus on improving outcomes for women, such as exploring different immunotherapeutic approaches in men and women. They concluded by recommending that researchers conducting immunotherapy studies should ensure a larger inclusion of women in the trials.

Reference:

Conforti F, Pala L, Bagnardi V, et al. Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis. [published online May 16, 2018]. Lancet Oncol. doi: https://doi.org/10.1016/S1470-2045(18)30261-4.