Differences in Response to Immunotherapy in Men vs Women

Sharon Worcester

December 02, 2021

More clinical data suggesting that men may have a better response to immunotherapy than women in certain circumstances have been reported.

In a population-based cohort study, women with advanced melanoma and prior ipilimumab treatment who then received combination nivolumab and ipilimumab immunotherapy had a more than twofold increase in the risk for death in comparison with their male counterparts.

The hazard ratio (HR) for mortality among women vs men treated with the combination immunotherapy after prior ipilimumab treatment was 2.06 (P = .003).

No such difference was observed among those receiving single-agent therapy with pembrolizumab or nivolumab (HR for mortality in women vs men, 0.97; P = .85) or among patients without prior ipilimumab use (HR, 0.85; P = .16).

Women with prior ipilimumab use also had a nearly threefold increase in the risk for death with combination immunotherapy vs with single-agent anti–programmed cell death protein–1 (anti-PD-1) therapy (HR, 2.82), but no such difference was seen among the men in the study.

The findings were published online on December 2 in JAMA Network Open.

They come from an analysis of Surveillance, Epidemiology, and End Results (SEERS)–Medicare linked data for 982 men and 387 women with stage III or IV melanoma whose median age was 75 years.

The findings suggest that the patient's sex should be considered in treatment planning in order to optimize outcomes, say the authors.

"These novel findings suggest that, for women with a prior history of ipilimumab, treatment with anti-PD-1 therapy may be preferable to combination therapy, whereas for men, it is unclear which treatment is better," they write.

In a press release, principal author Grace Lu-Yao, PhD, a professor at Thomas Jefferson University, Philadelphia, Pennsylvania, acknowledged that it remains unclear whether the increased risk for death in women is a result of treatment side effects or lack of efficacy, but she stressed that "this is a powerful signal in real-world data that we need to investigate further.

"This data is a wake-up call based on the experience of hundreds of patients on these drugs," said Lu-Yao. "This real-world data demonstrates that the results derived from men might not be applicable to women and it is critical to design studies with sufficient power to evaluate treatment effectiveness by sex."

Relevance for Routine Practice Is Unclear

The relevance of the findings for routine practice is unclear, given the median age of the cohort and a lack of data on whether excess mortality was cancer- or toxicity-related or due to another cause, Jeffrey S. Weber, MD, PhD, told Medscape Medical News. Weber is a professor and deputy director of the Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York City, and is a regular contributor to Medscape Oncology.

"The study is interesting and detailed, but it is a rather narrowly defined cohort that is over 65 and has a median of age 75, [which is] very different than most melanoma patient cohorts of patients treated with immunotherapy, whose median age is 10 years younger," Weber said in an interview.

Overall, these data would not impact on how I treat patients. Dr Jeffrey Weber

Furthermore, "in practice, almost no current patients will have been previously treated with ipilimumab and then receive combination immunotherapy," he said. "Overall, these data would not impact on how I treat patients," he commented.

Gender Differences in Response

This study is not the first to show a gender-based difference in outcomes after immunotherapy. As previously reported by Medscape, a meta-analysis published in The Lancet Oncology in 2018 showed that immune checkpoint inhibitors are twice as effective as standard cancer therapies in men with advanced solid tumors, compared with their female counterparts.

However, sex-based differences remain under-assessed despite "accumulating evidence of the potential role played by sex in drug effectiveness owing to the biological differences between men and women," the authors of the latest study in melanoma comment.

"This lack of attention on the association of sex with the effectiveness of immune checkpoint inhibitor (ICI)-based immunotherapy may have significant negative consequences, especially because these treatments are associated with high toxicity and high treatment cost. For future trials, it would be crucial to examine effect modification by sex," they add.

The study was funded by the Sidney Kimmel Cancer Center. Lu-Yao and co-authors have disclosed no relevant financial relationships. Weber is a regular contributor to Medscape. He reports relationships with Bristol-Myers Squibb, GlaxoSmithKline, Genentech BioOncology, Merck & Co, Novartis, EMD Serono, Celldex, CytomX, Nektar, Roche, Altor, Daiichi-Sankyo, and Eli Lilly and is named on patents filed for biomarkers for ipilimumab and nivolumab.

JAMA Netw Open. Published online December 2, 2021.

Sharon Worcester is an award-winning medical journalist at MDedge News, part of the Medscape Professional Network.

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