Better Responses to Immunotherapy in Men

Kristin Jenkins

May 16, 2018

Immune checkpoint inhibitors are twice as effective as standard cancer therapies in the treatment of men with advanced solid tumors compared to their female counterparts, says an international team of researchers.

The findings come from a meta-anlysis published online May 16 in the Lancet Oncology.

"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," say the authors. The team was led by Fabio Conforti, MD, of the European Institute of Oncology in Milan, Italy, and colleagues.

Men have a larger treatment effect from these drugs versus control treatments than do women. Dr Fabio Conforti

These findings do not imply that treatment guidelines should be changed for either male or female patients with advanced cancer, Conforti and colleagues emphasize.

Currently, immune checkpoint inhibitor therapies, including CTLA-4, PD-1, and PD-L1 inhibitors, remain the standard of care for patients with several types of cancer, they point out. Improved survival with immune checkpoint inhibitors in comparison with standard therapies has been demonstrated in patients with difficult-to-treat malignancies, such as malignant melanoma, non–small cell lung cancer, bladder cancer, and head and neck cancer.

"Treatment for women should not be altered based on these findings, rather we need to understand more about the mechanisms to ensure that these novel treatments can be optimized for both men and women," said Conforti in a statement issued by the Lancet Oncology.

"As we seek to improve immunotherapy further by identifying predictive biomarkers of response," he added, "sex differences should be further investigated."

Nevertheless, these findings have clinical implications, the researchers insist. The sex of patients with advanced cancer should be considered an important predictive variable when assessing the risks and benefits of immune checkpoint inhibitors compared to standard therapies, they suggest.

Details of the Findings

The meta-analysis included 20 randomized controlled trials involving more than 11,351 patients with various solid tumors treated with immunotherapy. The drugs included ipilimumab (Yervoy, Bristol-Myers Squibb), tremelimumab (MedImmune, AstraZeneca), nivolumab (Opdivo, Bristol-Myers Squibb), and pembrolizumab (Keytruda, Merck & Co).

About two thirds of the patients (7646, 67%) were male; the remaining third (3705, 31%) were female. Melanoma and non–small cell lung cancer were the most common types of cancer (32% and 31%, respectively). Other cancers included renal cell carcinoma, urothelial cancer, and head and neck cancer.

The results show a large difference in responses between male and female patients.

When compared with control patients who were given standard therapies or placebo, among men treated with immune checkpoint inhibitors, the relative reduction in the risk for death was twice that achieved in female patients (P = .0019).

This significantly increased relative survival benefit in favor of men was observed for all types of cancer with the exception of small cell lung cancer and was independent of lines of treatment or class of immune checkpoint inhibitor administered.

Similarly, the pooled overall survival hazard ratio following treatment with immune checkpoint inhibitors was 0.72 in men compared to control patients and was 0.86 in women compared to control patients.

Analyses of studies comparing immunotherapies to nonimmunologic drugs also showed a significantly higher survival benefit in male vs female patients treated with immune checkpoint inhibitors compared to control patients (P heterogeneity = .007).

Speculating on why there should be a difference between male and female responses to immunotherapy, the authors suggest that sex differences in the immune system based on complex interactions between genes, hormones, the environment, and microbiome composition may modulate some of the immune checkpoint inhibitor (CTLA-4 and PD-1) pathways.

Women Underrepresented in Trials?

Although the large number of patients in this study was one of its strengths, the relatively low number of women enrolled in each of the trials was one of its limitations, the investigators point out.

It has been widely recognized for more than 20 years that female patients are underrepresented in biomedical research, and the current study highlights the low number of women enrolled in clinical trials of anticancer immunotherapy, they note.

In about half of the trials included in the meta-analysis, women made up less than a third of the overall study population. This made it difficult to definitively demonstrate an interaction between patients' sex and treatment efficacy, the researchers write.

More women need to be included in new clinical trials of immunotherapies "to avoid erroneously extending to women results that are obtained mainly in male patients," they say. Different immunotherapeutic approaches might also be be explored separately in men and women, they suggest.

"Because the results of this study showed significant heterogeneity in the efficacy of immunotherapy between male and female patients, sex-corrected accrual to immune therapeutic trials is needed in order to obtain a better and unbiased estimation of both efficacy and safety."

Hypothesis-Generating Study

In an accompanying commentary, Omar Abdel-Rahman, MBBCh, MD, of the Faculty of Medicine at Ain Shams University, in Cairo, Egypt, and the Department of Oncology at the University of Calgary, Tom Baker Cancer Center, in Calgary, Alberta, Canada, warned against "jumping directly to any radical conclusions."

Describing the study as a "thought-provoking and hypothesis-generating piece of work," Abdel-Rahman emphasized that clinicians should proceed with caution and that the current standard of care for immune checkpoint inhibitor therapy should not be changed.

Female patients...should not be denied treatment solely on the basis of these findings. Dr Omar Abdel-Rahman

"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," he said. "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."

Abdel-Rahman suggested that the baseline characteristics of the many diverse solid tumors studied may differ between men and women, and that different sex-based lifestyle or behavioral characteristics might also have confounding effects.

When asked to comment, Don S. Dizon, MD, director of women's cancers at Lifespan Cancer Institute, in Providence, Rhode Island, said he found the study findings somewhat surprising but agreed that more research needs to be done. "First and foremost, I agree with the authors in one important aspect: We must include more women in randomized trials," he told Medscape Medical News.

Dizon, who is also director of medical oncology at Rhode Island Hospital and associate professor of medicine at the Alpert Medical School of Brown University, called the findings "provocative." He also said he hopes research does not take a step backward and involve "trials that only include male patients because of the potential larger survival advantage" as a result.

The study's small sample size of women compared to men may have been a more influential factor "than a true interaction between gender and immunotherapy outcome," he suggested. "I would think that stimulation of the immune response pharmacologically is not a gender-specific phenomenon," Dizon added.

He pointed out that although the point estimate in the hazard ratio for overall survival indicated an advantage in men, "the findings were still statistically significant independent of gender. The confidence interval did not cross 1.0 in either men or women."

There are data to suggest the presence of sex-specific immunity differences in infectious diseases, Dizon noted. "Novel approaches might be needed for women vs men with cancer," he said. "Still, access to immunotherapy is important where the indications exist. As a women's cancer specialist, this report provides evidence that where single-agent immunotherapy has not worked very well, we need novel trial designs in order to further exploit their use."

The study received no funding. The study authors and Dr Abdel-Rahman have disclosed no relevant financial relationships. Dr Dizon has relationships with Pfizer, Tesaro, and Teva.

Lancet Oncol. Published online May 16, 2018.

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