Sex-Based Heterogeneity in Response to Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis
Open accessAbstract
Background: We previously showed that therapy with anti–checkpoints T-lymphocyte-associated protein 4 (anti–CTLA-4) or antiprogrammed cell death protein 1 (anti–PD-1) agents was more effective for men as compared with women. However, because the sex-dimorphism of the immune system is complex, involving multiple elements of immune responses, it is possible that women could derive larger benefit than men from strategies other than therapy with immune checkpoint inhibitors (ICIs) alone. Here we investigated whether women could derive larger benefit than men from the combination of chemotherapy and anti-PD-1 or anti-PD-L1. Methods: We performed two meta-analyses. The first included all randomized controlled trials (RCTs) testing anti-PD1 and anti–PD-L1 plus chemotherapy vs chemotherapy to assess different efficacy between men and women. The second included all RCTs of first-line systemic treatment in advanced non-small cell lung cancer testing anti–PD-1/PD-L1 given either alone or combined with chemotherapy to assess the different efficacy of these two immunotherapeutic strategies according to patients’ sex. For each RCT included in the two meta-analyses, first, a trial-specific ratio of hazard ratios (HRs) was calculated from the ratio of the reported hazard ratios in men and in women; second, these trial-specific ratios of hazard ratios were combined across trials using a random-effects model to obtain a pooled hazard ratios ratio. A pooled HRs ratio estimate lower than 1 indicates a greater treatment effect in men, and higher than 1 a greater effect in women. Results: Eight RCTs were included in the first meta-analysis. The pooled overall survival hazard ratios (OS-HRs) comparing anti–PD-1/PD-L1 plus chemotherapy vs chemotherapy was 0.76 (95% confidence interval [CI] = 0.66 to 0.87) for men and 0.48 (95% CI = 0.35 to 0.67) for women. The pooled ratio of the overall survival hazard ratios reported in men vs women was 1.56 (95% CI = 1.21 to 2.01), indicating a statistically significant greater effect for women. Six RCTs were included in the second meta-analysis: three tested an anti-PD-1 alone, whereas three RCTs tested anti-PD-1/PD-L1 plus chemotherapy. The pooled overall survival hazard ratios were 0.78 (95% CI = 0.60 to 1.00) in men and 0.97 (95% CI = 0.79 to 1.19) in women for anti–PD-1 alone, compared with 0.76 (95% CI = 0.64 to 0.91) in men and 0.44 (95% CI = 0.25 to 0.76) in women for anti–PD-1/PD-L1 plus chemotherapy. The pooled ratio of overall survival hazard ratios was 0.83 (95% CI = 0.65 to 1.06) for anti–PD-1 alone, indicating a greater effect in men, and 1.70 (95% CI = 1.16 to 2.49) for anti–PD-1/PD-L1 plus chemotherapy, indicating a greater effect in women. Conclusion: Women with advanced lung cancer derived a statistically significantly larger benefit from the addition of chemotherapy to anti–PD-1/PD-L1 as compared with men.
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Two meta-analyses of 20 and 14 randomized clinical trials, involving more than 15,000 patients, found that although ICIs enhance anti-cancer responses in both men and women, men appear to experience a modestly greater benefit.
“Two meta-analyses of 20 and 14 randomized clinical trials, involving more than 15,000 patients diagnosed with different indications, found that although ICIs enhance anti-cancer responses in both men and women, men appear to experience a modestly greater benefit.51,52”
From Gut dysbiosis in oncology: a risk factor for immunoresistance (2026) · cites this paper as [51]
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- Authors
- Conforti, F., Pala, L., Bagnardi, V., Viale, G., De Pas, T., Pagan, E., Pennacchioli, E., Cocorocchio, E., Ferrucci, P. F., De Marinis, F., Gelber, R. D., & Goldhirsch, A.
- Affiliations
- See the Notes section for the full list of authors’ affiliations
- Corresponding author
- Conforti, Fabio
- ORCID
- Venue
- JNCI: Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-05-20
- Volume
- 111
- Issue
- 8
- Pages
- 772-781
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- PMC
- PMC6695312
- OpenAlex
- W2946644285
- Cited by
- 262
- References
- 34
- Citations by year
- 2026: 23 · 2025: 39 · 2024: 56 · 2023: 36 · 2022: 36 · 2021: 39 · 2020: 28 · 2019: 4
- FWCI
- 2.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- sex differences, lung cancer immunotherapy, immune checkpoint inhibitors, anti-PD-1, PD-L1 inhibitors, anti-CTLA-4, non-small cell lung cancer, combination chemotherapy, overall survival, first-line systemic treatment
- MeSH terms
- Female, Humans, Immunotherapy, Lung Neoplasms, Male, Sex Characteristics, Disease-Free Survival, B7-H1 Antigen, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
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