Men with advanced cancers respond much better than women do to treatment with anti-PD-1 or anti-CTLA-4 immune checkpoint inhibitors, a pooled analysis of multiple clinical trial results found.
Future research needs to optimize immunotherapies for female patients, and clinical trials should aim to include more women to better ensure they capture a potential treatment’s effectiveness in ways that reflect all who might be using it, the study’s writers said.
The study, “Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis,” was published in the journal The Lancet Oncology.
Researchers in Italy and the U.S. reviewed the published results of 20 clinical trials (mostly Phase 3) that tested the efficacy of the immune checkpoint inhibitors Yervoy (ipilimumab), Opdivo (nivolumab), Keytruda (pembrolizumab) or tremelimumab, alone or in combination, to treat a variety of advanced cancers.
Their goal was to compare rates of overall survival between male and female patients treated with these immunotherapies. (Immune checkpoint inhibitors work to make a person’s natural immune response against cancer more effective by targeting protein on either immune cells or cancer cells.)
The team hypothesized that women benefit less from treatment than men do, because of sex-related differences in the immune system, in tumor mutation rates, and in exposure to mutagenic agents (cigarette smoke or ultraviolet light).
Generally, women mount stronger immune responses than men and tend to have tumors with lower mutational rates, all factors that can contribute to poorer responses to checkpoint inhibitors. [Men, however, as the researchers note, tend to die of cancer (all types) at twice the rate women do, again because of factors both biological (immune system and mutations) and behavioral (smoking and sunscreen use).]
In total, researchers collected data on 11,351 patients — 7,646 men and 3,705 women — with several types of advanced cancers, including melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, head and neck squamous-cell carcinoma, and gastric cancer.
Pooled analysis showed that men treated with immune checkpoint inhibitors had a 28 percent lower risk of death, but women only a 14 percent lower risk, compared with a control group of patients mostly treated with standard therapies.
Such difference in the efficacy of immune checkpoint inhibitors between men and women was statistically significant.
Relative survival rates were also consistently higher for men, regardless of cancer type, line of treatment, and type of inhibitor administered.
“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,” the researchers wrote. “The pooled reduction of risk of death was double the size for male patients than for female patients.”
These findings, they added, have important implications to clinical practice and the design of clinical studies.
A patient’s sex “should be taken into account in the assessment of risk versus benefit when making decisions about treatment strategies,” they said.
Future research should focus on improving the effectiveness of immunotherapies for women, and possibly explore different therapeutic approaches optimized to each sex.
Finally, researchers should work to include more women in clinical trials to obtain better, unbiased estimations of both efficacy and safety for the therapies being evaluated.
“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,” the researchers concluded.
As “immune checkpoint inhibitors are associated with specific adverse events, efforts are ongoing to identify predictive biomarkers” that might pinpoint patients most likely to “derive the maximum potential benefit” from their use. These efforts must be alert to “sex-related differences in the benefit achievable from immunotherapies,” but to date “remains an under-investigated issue.”