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Peer-reviewedCC BY 4.0PLOS One

Sex difference in survival benefits of immune checkpoint inhibitors in advanced non-small cell lung cancer: A meta-analysis

  • Tingting Liu1,2
  • Dandan Song3
  • Jun Chen4
  • Jiacheng Yao1
  • Jiehao Liao5
  • Jun Dang1
5 affiliations
  1. 1Department of Radiation Oncology, The First Hospital of China Medical University, Shenyang, China
  2. 2Department of Radiation Oncology, Anshan Cancer Hospital, Anshan, China
  3. 3Department of Radiation Oncology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
  4. 4Department of Radiation Oncology, Shenyang Tenth People’s Hospital, Shenyang, China
  5. 5Department of Oncology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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Abstract

Background: Whether sex influences the survival benefit of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) remains uncertain. Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus up to April 1, 2026, for randomized controlled trials (RCTs) comparing ICIs with chemotherapy and reporting overall survival (OS) or progression-free survival (PFS) stratified by sex. A random-effects model was used for meta-analysis. Results: Sixty-three publications (reporting 42 phase 3 RCTs) involving 25,827 patients (18,772 male; 7,055 female) were included. Compared with chemotherapy, ICIs significantly improved both OS and PFS in males (OS: HR 0.74 [95% CI 0.71–0.78]; PFS: HR 0.59 [95% CI 0.54–0.64]) and females (OS: HR 0.83 [95% CI 0.77–0.90]; PFS: HR 0.76 [95% CI 0.66–0.86]). Pooled treatment-by-sex interaction analyses demonstrated significantly greater OS (interaction HR = 0.90 [95% CI 0.84–0.97]; P = 0.01) and PFS (interaction HR = 0.82 [95% CI 0.73–0.92]; P = 0.0006) benefits in males than in females. In subgroup analyses, sex‑based differences in OS reached statistical significance in patients receiving ICI monotherapy (P = 0.02), including those treated with anti‑PD‑1 monotherapy (P = 0.04) and those with PD‑L1 expression ≥50% (P = 0.02). However, these differences did not persist after the False Discovery Rate (FDR) correction (adjusted P = 0.07, 0.10, and 0.07, respectively). In contrast, sex‑based differences in PFS remained statistically significant after FDR correction in the ICI monotherapy (adjusted P = 0.001), anti‑PD‑1 monotherapy (adjusted P = 0.001), and PD‑L1 ≥ 50% (adjusted P = 0.004) subgroups. No significant sex‑based differences in either OS or PFS were observed among patients treated with ICI plus chemotherapy. Conclusions: Although ICIs are superior to chemotherapy in both sexes, the PFS benefit of ICI monotherapy appears to be attenuated in females relative to males. Given the imbalances in baseline confounders coupled with the underrepresentation of females in the included trials, these findings should be interpreted with caution and warrant confirmation in future RCTs designed specifically to investigate sex‑based differences.

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Cite

BibTeXRIS
BibTeX
@article{liu2026difference,
  title = {{Sex difference in survival benefits of immune checkpoint inhibitors in advanced non-small cell lung cancer: A meta-analysis}},
  author = {Tingting Liu and Dandan Song and Jun Chen and Jiacheng Yao and Jiehao Liao and Jun Dang},
  journal = {PLOS One},
  year = {2026},
  month = nov,
  doi = {10.1371/journal.pone.0361953},
  url = {https://doi.org/10.1371/journal.pone.0361953},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Sex difference in survival benefits of immune checkpoint inhibitors in advanced non-small cell lung cancer: A meta-analysis
AU  - Tingting Liu
AU  - Dandan Song
AU  - Jun Chen
AU  - Jiacheng Yao
AU  - Jiehao Liao
AU  - Jun Dang
PY  - 2026
DA  - 2026/11/03
JO  - PLOS One
DO  - 10.1371/journal.pone.0361953
UR  - https://doi.org/10.1371/journal.pone.0361953
AB  - Background: Whether sex influences the survival benefit of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) remains uncertain. Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus up to April 1, 2026, for randomized controlled trials (RCTs) comparing ICIs with chemotherapy and reporting overall survival (OS) or progression-free survival (PFS) stratified by sex. A random-effects model was used for meta-analysis. Results: Sixty-three publications (reporting 42 phase 3 RCTs) involving 25,827 patients (18,772 male; 7,055 female) were included. Compared with chemotherapy, ICIs significantly improved both OS and PFS in males (OS: HR 0.74 [95% CI 0.71–0.78]; PFS: HR 0.59 [95% CI 0.54–0.64]) and females (OS: HR 0.83 [95% CI 0.77–0.90]; PFS: HR 0.76 [95% CI 0.66–0.86]). Pooled treatment-by-sex interaction analyses demonstrated significantly greater OS (interaction HR = 0.90 [95% CI 0.84–0.97]; P = 0.01) and PFS (interaction HR = 0.82 [95% CI 0.73–0.92]; P = 0.0006) benefits in males than in females. In subgroup analyses, sex‑based differences in OS reached statistical significance in patients receiving ICI monotherapy (P = 0.02), including those treated with anti‑PD‑1 monotherapy (P = 0.04) and those with PD‑L1 expression ≥50% (P = 0.02). However, these differences did not persist after the False Discovery Rate (FDR) correction (adjusted P = 0.07, 0.10, and 0.07, respectively). In contrast, sex‑based differences in PFS remained statistically significant after FDR correction in the ICI monotherapy (adjusted P = 0.001), anti‑PD‑1 monotherapy (adjusted P = 0.001), and PD‑L1 ≥ 50% (adjusted P = 0.004) subgroups. No significant sex‑based differences in either OS or PFS were observed among patients treated with ICI plus chemotherapy. Conclusions: Although ICIs are superior to chemotherapy in both sexes, the PFS benefit of ICI monotherapy appears to be attenuated in females relative to males. Given the imbalances in baseline confounders coupled with the underrepresentation of females in the included trials, these findings should be interpreted with caution and warrant confirmation in future RCTs designed specifically to investigate sex‑based differences.
SN  - 1932-6203
ER  -