Sex, Timing, and Outcomes of Curative-Intent Immunotherapy: A Systematic Review and Meta-Analysis.

TL;DR

A systematic review of 38 randomized trials found immune checkpoint inhibitors (ICIs) improved survival in curative-intent solid tumor treatment, with no significant sex-based differences in efficacy, though female patients were underrepresented in the data. Neoadjuvant or perioperative ICI approaches showed superior outcomes compared to adjuvant-only strategies .

What the Study Found

Immune checkpoint inhibitors have transformed cancer treatment by unleashing the immune system to recognize and attack tumor cells. Yet critical gaps remained about whether their efficacy differs by sex and whether timing relative to surgery matters. This meta-analysis, published in JAMA Network Open, pooled data from 62 reports spanning 38 randomized phase 3 trials involving 31,721 patients to answer those questions directly.

The headline finding: ICIs delivered in curative-intent settings (alongside surgery and local therapies like radiotherapy) improved overall survival by approximately 17 percent compared to standard treatment alone. Specifically, patients receiving ICIs had a hazard ratio of 0.83 for death (95% CI, 0.79-0.89), meaning a roughly 17 percent lower risk. For disease-free and recurrence-free survival combined, the benefit was even larger: a hazard ratio of 0.73, translating to a 27 percent reduction in the risk of disease recurrence or progression. These improvements held across multiple cancer types, including melanoma, non-small-cell lung cancer, gastric cancer, and colorectal cancer.

On the sex question, the analysis found no statistically significant differences in how males and females responded to ICIs. Female patients showed a hazard ratio of 0.76 for overall survival, while males showed 0.78. For the combined recurrence-free endpoints, females had a hazard ratio of 0.74 versus 0.73 for males. The confidence intervals overlapped substantially, indicating the differences were consistent with random variation rather than true biological sex differences. However, a critical caveat: only 29.7 percent of trial participants were female, meaning the analysis was underpowered to detect potential sex-specific effects if they exist. The authors explicitly noted female underrepresentation as a limitation.

Where timing showed a clear signal: ICIs given before surgery (neoadjuvant) or around the time of surgery (perioperative) outperformed ICIs given only after surgery (adjuvant). The neoadjuvant/perioperative approach achieved a hazard ratio of 0.77 for overall survival and 0.64 for recurrence-free survival. Adjuvant-only strategies yielded hazard ratios of 0.84 and 0.74 respectively. While both approaches reduced risk compared to no ICI, the pre-surgical window appeared to capture additional benefit, possibly because ICIs can prime immune responses before tumor removal and address micrometastatic disease earlier in the treatment trajectory.

What This Means for You

This analysis provides three actionable takeaways for patients and clinicians considering immunotherapy in curative cancer settings:

First, sex should not drive immunotherapy decisions. The data show no evidence that females or males metabolize or respond to ICIs differently in these curative treatment contexts. Treatment recommendations should rest on tumor characteristics, stage, and individual medical history rather than sex-based assumptions about efficacy.

Second, timing of immunotherapy relative to surgery appears clinically important. If you or a loved one is considering ICI therapy as part of curative cancer treatment, the evidence now supports advocating for neoadjuvant or perioperative approaches when feasible. These strategies delivered superior recurrence-free survival and overall survival in the pooled data. This supports the authors' conclusion that broader adoption of neoadjuvant ICI approaches is warranted, a shift already underway in oncology practice but now reinforced by this large evidence synthesis.

Third, recognize the female data gap. Although the analysis found no sex difference, the underrepresentation of women (under 30 percent) means subtle differences could have been missed. Ensure that female-specific concerns and side effects are carefully monitored during ICI therapy, and advocate for inclusion in future immunotherapy trials.

Study Details

Sources

Eggermont, A.M.M., et al. (2025). Sex, Timing, and Outcomes of Curative-Intent Immunotherapy: A Systematic Review and Meta-Analysis. JAMA Network Open.

PubMed: https://pubmed.ncbi.nlm.nih.gov/42709437/