For the treatment of non-small cell lung cancer (NSCLC), anti-PD-1/anti-PD-L1 monotherapy is highly effective in men but not in women, even in NSCLC that expresses high PD-L1 levels, explain Fabio Conforti, MD, and Laura Pala, MD, both from the Division of Medical Oncology for Melanoma, Sarcoma, and Rare Tumors, European Institute of Oncology, IEO, in Milan, Italy. “The biologic differences between men and women can potentially affect immune response against tumors,” Dr. Conforti adds. “On average, women mount stronger innate and adaptive immune responses than men. These sex-based differences reflect complex interactions between genes, hormones, environment, and commensal microbiome composition. Given the complexity of the sex dimorphism of the immune system function and responses, it is possible that women and men obtain different benefits from anticancer immunotherapy.”

For a paper published in ESMO Open, Drs. Conforti and Pala assessed the sex-based heterogeneity of anti-PD-1/anti-PD-L1 efficacy when given as monotherapy for NSCLC expressing high PD-L1 levels, to evaluate if available evidence supports this therapeutic option for both women and men. “In our previous research, we demonstrated that patients’ sex affects the efficacy of immune checkpoint inhibitors (ICIs) in patients with several advanced solid tumors, including NSCLC,” said Dr. Pala. “We carried out a systematic review and meta-analysis including all randomized controlled trials (RCTs) testing anti-PD-1/anti-PD-L1 drugs in monotherapy, as first-line treatment of advanced NSCLC expressing high PD-L1 levels. The primary endpoint was the difference in efficacy of anti-PD-1/anti-PD-L1 drugs versus chemotherapy, between men and women, measured in terms of the difference in overall survival (OS) reported in male and female study participants.”

Females Received Limited Benefit from ICIs

The study team analyzed four RCTs that included 1,672 patients, of whom 1,224 (73.2%) were men and 448 (26.8%) were women. The pooled overall survival (OS) hazard ratio (HR) comparing anti-PD-1/anti-PD-L1 versus chemotherapy was 0.59 (95% CI, 0.50-0.69) for men and only 0.84 (95% CI, 0.64-1.10) for women. The pooled ratio of the OS HR reported in men versus women was 0.71 (95% CI, 0.52-0.98), indicating a significantly greater effect for men. No heterogeneity among single-study estimates was observed in either male or female patients.

“We found a statistically significant and clinically meaningful sex-based heterogeneity of efficacy of anti-PD-1/anti-PD-L1 antibodies, even in patients selected for tumors expressing high PD-LI levels and, therefore, considered as highly responsive to ICIs,” Dr. Conforti said. “Such heterogeneity of efficacy strongly penalizes female patients, who obtained a very limited survival benefit from ICIs as compared with a poor control arm, such as platinum-based chemotherapy.” Indeed, he added, the reduction of the relative risk of death observed in women was only 16% (OS HR, 0.84; 95% CI, 0.64-1.10), whereas in men, it was 41% (OS HR, 0.59; 95% CI, 0.50-0.69).

The study results, along with the researchers’ previous work, suggest sex as a relevant variable that should be considered when choosing the best treatment option for patient with NSCLC expressing high PD-LI levels, according to Dr. Pala. “While anti-PD-1/anti PD-L1 drugs given in monotherapy were confirmed as highly effective in men, the modest results consistently reported for women in all of the RCTs induce consideration of their combination with chemotherapy as the best treatment option for female patients,” she says.

The researchers stressed that their findings are hypothesis-generating since they are based on a meta-analysis of aggregate published results derived from RCTs and, as such, require further validation in prospective future trials before being considered sufficient to support any change in clinical practice. “We recommend that future research for anticancer immunotherapy take into account sex-related heterogeneity of responsiveness to treatments,” Dr. Conforti notes. “For example, accrual and design of clinical trials of immunotherapy might best be performed separately for men and women, with proper sample size planning for both. Furthermore, prospective trials testing sex-based tailored immunotherapy strategies are urgently needed.”