AT SITC 2016
NATIONAL HARBOR, MD. – Sex difference in immune regulatory responses may drive the poorer responses to treatment with immune checkpoint inhibitors targeted against programmed death–1 (PD-1 inhibitors) seen in women with advanced melanoma, investigators report.
Among patients with advanced melanoma treated with either pembrolizumab (Keytruda) or nivolumab (Opdivo) monotherapy in four clinical trials, the median objective response rate (ORR) among women was 33.1%, compared with 54.6% among men. Median progression-free survival (PFS), respectively, was 5.5 months vs. 18 months, reported Katy K. Tsai, MD , a clinical instructor in cutaneous oncology at the University of California, San Francisco.
The reasons for the difference are not known. Possibly, sex hormones or factors unique to women, such as variations in populations of T-regulatory cells (T-regs) as a result of pregnancy, may be implicated, Dr. Tsai said in an interview.
“There has been a lot of interesting data coming out recently about the influence of sex hormones on the immune regulatory response in general, so I do think that is something that needs to be explored further,” Dr. Tsai said at the annual meeting of the Society for Immunotherapy of Cancer.
“There are some interesting data to suggest that perhaps women, and in particular pregnant women or perhaps even women who have higher parity than those who are nulliparous, may have higher circulating levels of T-regs that may contribute to dampening this immune response,” she said.
Response prediction model
Dr. Tsai and her colleagues had previously reported on a validated clinical scoring model for predicting response to anti–PD-1 therapy. In that study, they found that female sex was associated with a lower response rate with an odds ratio of 0.36 (95% confidence interval, 0.19-0.67).
In a separate study , they reported that relative abundance in tumors of a partially exhausted T-cell phenotype (PD-1high/CTLA-4–positive CD8 cells) was predictive of response to anti–PD-1 therapy.
In the current study, they looked at data on 118 women and 218 men who had advanced cutaneous melanoma and were treated in one of four clinical trials of pembrolizumab or nivolumab as monotherapy or in combination with an anti-CTLA4 agent such as ipilimumab (Yervoy) ( NCT01295827 , NCT01704287 , NCT01721746 , and NCT02156804 ).
On flow-cytometry analysis of pre-treatment tumor samples, women had a significantly lower proportion of PD-1high/CTLA-4–positive CD8 cells as compared with men (mean, 16.9% vs. 26%; P = .008).
“The mechanisms of this [discrepancy] may have an immunologic basis given the difference in pre-treatment T-cell profiles between women and men. Sex-related differences in tumor immunity and immunotherapy responses warrant further investigation,” the investigators wrote in a poster presentation.
The study was internally funded. Dr. Tsai and her colleagues reported no relevant disclosures.
