Men respond better than women to cancer immunotherapy

Last Updated: 2018-05-25

By Will Boggs MD

NEW YORK (Reuters Health) - Within the same indications, men have a greater magnitude of response than women do to cancer immunotherapy, according to a systematic review and meta-analysis.

Women generally mount stronger innate and adaptive immune responses than men do, but they also account for roughly 80% of all patients with systemic autoimmune diseases. Whether these differences translate into sex differences in response to immune-checkpoint inhibitors, which are used to treat a variety of cancers, has not been determined.

Dr. Fabio Conforti from the European Institute of Oncology, in Milan, Italy and colleagues used data from 13 randomized controlled trials with PD-1 inhibitors (nivolumab and pembrolizumab), six trials with CTLA-4 inhibitors (ipilimumab and tremelimumab), and one trial with both classes of immune-checkpoint inhibitors to investigate whether the benefit from therapy relative to control treatments differs between men and women.

The targets of immunotherapy in these trials included melanoma, non-small-cell lung cancer, head and neck cancer, small-cell lung cancer, renal cell carcinoma, urothelial tumors, gastric tumors and mesothelioma.

In the combined trials, men had a 28% reduced risk of death associated with immunotherapy (versus controls) and women had a 14% reduced risk of death associated with immunotherapy (versus controls). This sex difference was significant at P=0.0019, the researchers report in The Lancet Oncology, online May 16.

Results were similar in analyses stratified by cancer histotype, line of treatment, type of immune-checkpoint inhibitor given in the intervention group and type of control treatment.

"The results of this study show that immune checkpoint inhibitors can improve overall survival for patients of both sexes with some types of advanced cancers, such as melanoma and non-small-cell lung cancer, but that men have a larger treatment effect from these drugs versus control treatments than do women," the researchers note.

"Two main conclusions can be drawn from this study," they write. "The first is that patients' sex should be taken into account in the assessment of risk versus benefit, as an important variable predicting the relative benefit of anti-PD-1 or anti-CTLA-4 drugs compared with available standard therapies."

The researchers add, "The second point is that researchers who are designing new immunotherapy studies should ensure a larger inclusion of women in trials, to avoid erroneously extending to women results that are obtained mainly in male patients."

Dr. Omar Abdel-Rahman from Ain Shams University, in Cairo, Egypt, and the University of Calgary, Canada, who wrote a linked editorial, told Reuters Health by email, "In the recent decade, a number of parameters were hypothesized to play a role in predicting response and survival among patients treated with immune-checkpoint inhibitors; these include patient-related and disease-related parameters. This meta-analysis provides the strongest clinical evidence till now regarding a possible impact of the sex of the patients on treatment outcomes with these agents."

"We need to pay additional attention to the effect of gender on the outcomes of immune-checkpoint inhibitors among future clinical trials," he said. "We have to note that the current study pooled data from a diverse group of tumors/patients. We need to evaluate further the impact of gender in the context of each tumor site separately, because that hypothesized impact of gender might differ based on the tumor site."

"Although the current study is hypothesis-generating and thought-provoking," Dr. Abdel-Rahman added, "I do not believe that the current study is practice-changing. In other words, female patients who are otherwise indicated for treatment with an immune-checkpoint inhibitor should never be denied that treatment based only on these results."

Dr. Walter Malorni from the Italian National Institute of Health's Center for Gender-Specific Medicine, in Rome, told Reuters Health by email, "This work comes after a plethora of articles underscoring the relevance of sex differences in the response to therapy. Even in cancer. The novelty is represented by the fact that even in immunotherapy of cancer sex disparity could be of relevance."

"We have published several works on sex differences at the cellular level to understand the fine mechanisms of sex differences," said Dr. Malomi, who was not involved in the new work. "This could help physicians to improve therapeutic strategies and pharma companies to find new and more-tailored drugs and therapeutic tools."

Dr. Conforti did not respond to a request for comments.

SOURCE: https://bit.ly/2s8RAew and https://bit.ly/2IGcnjU

Lancet Oncol 2018.