Modulation of chemoimmunotherapy efficacy in non-small cell lung cancer by sex and histology: a real-world, patient-level analysis

It has been postulated that patient's sex impacts response to immunotherapy. Sex modulation of immunotherapy benefit, however, has not yet been explored using patient-level data, where potential confounders, as well as histologic type, can be accounted for. Here we investigated the association between sex and chemoimmunotherapy efficacy for non-small cell lung cancer (NSCLC) using a large, nation-wide dataset. Stage IV NSCLC patients diagnosed in 2015 were identified in the National Cancer Database (NCDB). Patients were treated with either chemoimmunotherapy or chemotherapy alone. The efficacy of the addition of immunotherapy treatment by sex was investigated using both an adjusted Cox proportional hazards model and propensity-score matching, in both the overall cohort and stratified by histological subtype. 2064 (16%) patients received chemoimmunotherapy and10,733 (84%) received chemotherapy alone. Adjusted survival analysis in the overall cohort showed that both males (hazards ratio (HR) : 0.80, 95% CI: 0.74-0.87) and females (HR : 0.83, 95% CI: 0.76-0.90) had better OS when treated with chemoimmunotherapy than chemotherapy alone, with no statistically significant interaction between sex and receipt of immunotherapy (p = 0.63). Propensity matching confirmed these results. However, for those with squamous cell histology, male patients derived more benefit from chemoimmunotherapy treatment than females (HR : 0.73, 95% CI: 0.58-0.91 vs HR : 1.03, 95% CI: 0.76-1.38; p for interaction = 0.07). Male patients with squamous cell carcinoma may derive more benefit from chemoimmunotherapy treatment. Histology likely plays an important role in how sex modulates immunotherapy efficacy.