A meta-analysis of 16 phase III randomized clinical trials evaluating programmed cell death protein 1/ligand 1 (PD-1/-L1) inhibitors either alone or in combination with chemotherapy for solid tumors has found that women derived significantly greater benefit from the addition of chemotherapy to immunotherapy compared with their male counterparts. The findings also showed that men benefited more from immunotherapy when administered as a monotherapy than women. The study by Conforti et al was presented at the European Society for Medical Oncology (ESMO) Congress 2019 (Abstract 1285P).

“We confirmed a large and significant interaction between patients’ sex and the efficacy of anti–PD-1/PD-L1 drugs given [as] monotherapy or combined with chemotherapy. The direction of such interaction was the opposite for the two immunotherapeutic strategies: women derived impressively larger benefit from the addition of chemotherapy to anti–PD-1/PD-L1 as compared with men.”

— Conforti et al

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Fabio Conforti, MD, of the European Institute of Oncology, and colleagues had previously reported in The Lancet Oncology that chemotherapy with anti–CTLA-4 or anti–PD-1 immune checkpoint inhibitors was more effective in men than women with advanced solid tumors, especially in melanoma and non–small cell lung cancer (NSCLC). The researchers’ current investigation centered on whether women derive greater benefit than men from different immunotherapeutic strategies.

Methods

The researchers first performed a systematic review and a meta-analysis of randomized controlled trials testing anti–PD-1 or anti–PD-L1 given as monotherapy or in combination with chemotherapy in patients with advanced/metastatic solid tumors to assess different efficacy of the two immunotherapeutic strategies based on patients’ sex.

The primary endpoint of the study was to assess the difference in treatment efficacy between men and women, measured in terms of difference in overall survival and expressed as log hazard ratio (HR). The pooled overall survival HR and 95% confidence interval (CI) was calculated in the patients using random-effects model and the heterogeneity between the two estimates was evaluated using an interaction test.

The researchers identified 16 phase III randomized controlled clinical trials of anti–PD-1 or anti–PD-L1 administered as monotherapy vs standard chemotherapy. The analysis comprised data from 9,291 patients with advanced solid tumors. Two of the studies were performed in patients with melanoma; eight in NSCLC; two in head and neck squamous cell carcinoma; two in gastric cancer; and one trial each was conducted in patients with renal and urothelial cancers.

Findings

The researchers found that in 15 of the 16 trials evaluated, men derived greater overall survival benefit from immunotherapy alone than women. The pooled overall survival HR was 0.73 (95% CI = 0.69–0.78) in men vs 0.86 (95% CI = 0.78–0.94 in women (heterogeneity P = .0079).

Five phase III randomized clinical trials testing the combination of chemotherapy plus anti–PD-1 or anti–PD-L1 treatment vs chemotherapy in 2,979 patients were included in their analysis. Four randomized trials were performed in NSCLC and one was performed in small cell lung cancer. All five randomized trials showed a larger overall survival benefit in women. The pooled overall survival HR was 0.50 (95% CI = 0.41–0.60) in women vs 0.76 (95% CI = 0.66–0.87) in men (heterogeneity P = .0003).

Clinical Significance

“We confirmed a large and significant interaction between patients’ sex and the efficacy of anti–PD-1/PD-L1 drugs given [as] monotherapy or combined with chemotherapy. The direction of such interaction was the opposite for the two immunotherapeutic strategies: women derived impressively larger benefit from the addition of chemotherapy to anti–PD-1/PD-L1 as compared with men,” concluded the study authors.

Disclosure: For full disclosures of the study authors, visit esmo.org.