BACKGROUND

To investigate the sex-based heterogeneity of immune microenvironmental feature and its impact on the response to first-line PD-1 blockade plus chemotherapy in patients with driver-negative advanced or metastatic non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS

A total of 439 patients with advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy or chemotherapy were identified. Differences in clinical outcomes between female and male patients were determined using Kaplan-Meier curves. Neoantigen burden and five immune microenvironmental markers expression including PD-L1, CD4, CD8, FOXP3, and CD68 were compared between two groups.

RESULTS

Of 175 eligible patients, 89 received PD-1 blockade plus chemotherapy and 86 received first-line chemotherapy. Forty five were women (25.7%) and 130 were men (74.3%). Female patients received first-line PD-1 blockade in combination with chemotherapy had dramatically better ORR (85.2% vs. 53.2%; p = 0.009), PFS (23.7 vs. 7.3 months; p = 0.013), and OS (46.2 vs. 20.0 months; p = 0.004) than males. Treatment outcomes were similar between females and males in chemotherapy group. Multivariate analyses showed that sex was the independent prognostic factor for patients received PD-1 blockade combined with chemotherapy. Although female patients had significantly lower tumor mutational and neoantigen burden than males, pretreatment tumor tissues of female patients had markedly higher CD4, CD4/FOXP3, and CD4/FOXP3/PD-L1 expression level than male patients.

CONCLUSIONS

Female patients with untreated advanced or metastatic NSCLC would derive a larger benefit from PD-1 blockade in combination with chemotherapy than males. The biological significances of heterogeneity of tumor immune microenvironmental features between them need further investigation.