medwireNews: The magnitude of the survival benefit associated with immune checkpoint inhibitor treatment appears to be sex dependent, with women benefiting less than men, according to a meta-analysis published in The Lancet Oncology.
The analysis included data from 11,351 participants (67% men) with advanced or metastatic cancer (most commonly non-small-cell lung cancer and melanoma) enrolled in 20 trials comparing checkpoint inhibitors – specifically, nivolumab, pembrolizumab, ipilimumab and tremelimumab – with a control, such as chemotherapy or other immunologic compounds.
Treatment with checkpoint inhibitors significantly improved overall survival (OS) relative to control in both sexes, but the pooled hazard ratio (HR) for men was 0.72 in favor of immunotherapy, while for women the HR was 0.86, where the difference in efficacy of checkpoint inhibitors between sexes was significant.
The findings were similar in subgroup analyses stratifying patients by cancer histotype, line of therapy, and type of drug, with men consistently deriving a greater relative survival benefit than women.
The study authors – led by Fabio Conforti, from the European Institute of Oncology in Milan, Italy – anticipated the results based on existing knowledge of sex dimorphism in immunity and cancer biology. They explain that women tend to mount stronger immune responses than men, which means that tumors in women likely undergo more intensive immuno-editing to become metastatic.
“This ability […] to evade immune surveillance could make advanced female tumours less immunogenic and enriched with stronger mechanisms of immune escape than similar tumours in men, and thus they might become more resistant to immunotherapies,” the team writes.
Furthermore, tumors in male patients have been reported to have a higher mutational burden than those in women, a factor that is associated with improved efficacy of checkpoint inhibitors.
In light of the results, Conforti et al conclude that “[f]uture research should focus on improving the effectiveness of immunotherapies in women, and perhaps explore different immunotherapeutic approaches in men and women.”
And noting that around two-thirds of the trial participants were male, they urge investigators planning new immunotherapy trials to “ensure a larger inclusion of women […], to avoid erroneously extending to women results that are obtained mainly in male patients.”
In a linked piece, commentator Omar Abdel-Rahman (Ain Shams University, Cairo, Egypt) describes the study findings as “very thought-provoking,” but points out that “caution needs to be exercised before jumping directly to radical conclusions and before changing the current standard of care among approved indications for immune checkpoint inhibitors.”
He highlights that there are a multitude of baseline characteristics across the diverse tumor types included in the analysis, as well as lifestyle and behavioral characteristics, which might differ in distribution between men and women.
Abdel-Rahman continues: “Female patients who are otherwise indicated for treatment with any immune checkpoint inhibitor should not be denied treatment solely on the basis of these findings.
“Further prospective studies that are disease-specific and that account thoroughly for potential confounders are needed before a final judgment can be made about the effect of the patient’s sex on the efficacy of immune checkpoint inhibitors.”
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