Immunotherapy Responses Differ by Sex, Study Says

Immunotherapy responses may not be equal between the sexes, according to new research. 

The new meta-analysis of the role of biological sex in cancer treatments was presented at the European Society for Medical Oncology (ESMO) Congress 2019. The research followed up on work published last year in The Lancet Oncology. 

The ESMO results showed a benefit for women with immunotherapy-plus-chemotherapy, while the previous results showed better overall survival for men with immunotherapy alone, according to the study. 

Lead researcher Fabio Conforti of the Istituto Europeo di Oncologia, Milan, Italy, told CancerNetwork® that the fundamental differences between the sexes could mean a whole new way to understand immunotherapy dynamics. 

“Since has an important impact on multiple elements and function of both innate an adaptative immune system it is plausible that some immunotherapeutic strategies are more effective in women and others in men,” said Conforti.

“This is the main message of our work: given the sex dimorphism in response to anti-cancer immunotherapies, it is necessary to properly assess effectiveness of each new therapeutic strategy in both sexes, in order to improve treatment efficacy for both sexes,” he added. “For example, ensuring a proper accrual of women in randomized clinical trials.” 

The ESMO abstract showed a search of PubMed, MEDLINE, Embase, and Scopus for all randomly controlled trials testing anti-PD-1 or anti-PD-L1 treatments for patients with advanced or metastatic solid tumors, and either given alone or in combination with chemotherapy. 

The 16 phase III trials included monotherapy versus standard chemo in 9,291 patients. The trials included a variety of tumors (2 melanoma trials, 8 for non–small cell lung cancer (NSCLC), 2 in head and neck squamous cell carcinoma, 2 gastric cancer studies, and a study apiece in kidney and urothelial cancer. 

Fifteen of the 16 studies showed men with better pooled overall survival (OS) than women in the studies: for men the hazard ratio (HR) was 0.73 (95% CI, 0.69-0.78), while for the women the HR was 0.86 (95% CI, 0.78-0.94). (This follows, and echoes, the same team’s results published last year in The Lancet Oncology journal, among more than 11,000 patients administered immune checkpoint inhibitors). 

But in 5 of the studies examined, the combination of chemo-plus-immunotherapy was compared against chemotherapy alone in 2,979 patients. (Four of the studies were in NSCLC and 1 in small cell lung cancer). 

In these five studies, the women showed “impressively larger OS benefit,” according to the abstract: the pooled OS HR was 0.50 (95% CI, 0.41-0.60), compared to an HR of 0.76 for men (95% CI, 0.66-0.87).

Conforti said the results of the benefits for women could show different characteristics of tumors based on biology of the sexes – and it could also explain why some treatments work better than others currently. 

“It could be hypothesized that such heterogeneity of response is due to the ability of chemotherapy to increase the mutational burden and neoantigenic load of female lung cancer tumors that are statistically significantly lower than those of male tumors, with this being also a potential biological rationale to explain the lower efficacy of anti-PD-1 alone in women,” said Conforti. “Furthermore, different efficacy of chemotherapy in modulating the anti-cancer immune responses of men and women could be speculated.” 

Conforti further told CancerNetwork® that they are looking at identify at sex-based differences down to the level of molecular mechanisms of anti-cancer immuno-responses. Preliminary responses will be presented at the upcoming Society of Immunotherapy of Cancer meeting.

“To date, we have preliminary results showing relevant differences in the cell-type composition of the intra-tumoral immune-infiltrates of tumors arising in men and women,” said the researcher. 

References:

Conforti F. “Sex-based heterogenetity of efficacy of anticancer immunotherapy.” ESMO Congress 2019. Presented September 27, 2019. Abstract 1285p.

Conforti F, Pala L, Bagnardi, V. “Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis.” Lancet Oncol. 2018; (published online May 16)