PMID- 31106827 OWN - NLM STAT- MEDLINE DCOM- 20200609 LR - 20200609 IS - 1460-2105 (Electronic) IS - 0027-8874 (Print) IS - 0027-8874 (Linking) VI - 111 IP - 8 DP - 2019 Aug 1 TI - Sex-Based Heterogeneity in Response to Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis. PG - 772-781 LID - 10.1093/jnci/djz094 [doi] AB - 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. CI - (c) The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Conforti, Fabio AU - Conforti F AD - See the Notes section for the full list of authors' affiliations. FAU - Pala, Laura AU - Pala L AD - See the Notes section for the full list of authors' affiliations. FAU - Bagnardi, Vincenzo AU - Bagnardi V AD - See the Notes section for the full list of authors' affiliations. FAU - Viale, Giuseppe AU - Viale G AD - See the Notes section for the full list of authors' affiliations. FAU - De Pas, Tommaso AU - De Pas T AD - See the Notes section for the full list of authors' affiliations. FAU - Pagan, Eleonora AU - Pagan E AD - See the Notes section for the full list of authors' affiliations. FAU - Pennacchioli, Elisabetta AU - Pennacchioli E AD - See the Notes section for the full list of authors' affiliations. FAU - Cocorocchio, Emilia AU - Cocorocchio E AD - See the Notes section for the full list of authors' affiliations. FAU - Ferrucci, Pier Francesco AU - Ferrucci PF AD - See the Notes section for the full list of authors' affiliations. FAU - De Marinis, Filippo AU - De Marinis F AD - See the Notes section for the full list of authors' affiliations. FAU - Gelber, Richard D AU - Gelber RD AD - See the Notes section for the full list of authors' affiliations. FAU - Goldhirsch, Aron AU - Goldhirsch A AD - See the Notes section for the full list of authors' affiliations. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review PL - United States TA - J Natl Cancer Inst JT - Journal of the National Cancer Institute JID - 7503089 RN - 0 (B7-H1 Antigen) RN - 0 (CD274 protein, human) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) SB - IM CIN - J Natl Cancer Inst. 2019 Aug 1;111(8):749-750. PMID: 31106816 MH - B7-H1 Antigen/antagonists & inhibitors/immunology MH - CTLA-4 Antigen/antagonists & inhibitors/immunology MH - Disease-Free Survival MH - Female MH - Humans MH - *Immunotherapy MH - Lung Neoplasms/epidemiology/immunology/*therapy MH - Male MH - Programmed Cell Death 1 Receptor/antagonists & inhibitors/immunology MH - *Sex Characteristics PMC - PMC6695312 EDAT- 2019/05/21 06:00 MHDA- 2020/06/10 06:00 PMCR- 2020/05/20 CRDT- 2019/05/21 06:00 PHST- 2018/12/11 00:00 [received] PHST- 2019/02/27 00:00 [revised] PHST- 2019/05/09 00:00 [accepted] PHST- 2019/05/21 06:00 [pubmed] PHST- 2020/06/10 06:00 [medline] PHST- 2019/05/21 06:00 [entrez] PHST- 2020/05/20 00:00 [pmc-release] AID - 5491832 [pii] AID - djz094 [pii] AID - 10.1093/jnci/djz094 [doi] PST - ppublish SO - J Natl Cancer Inst. 2019 Aug 1;111(8):772-781. doi: 10.1093/jnci/djz094.