Gender and outcomes in non-small cell lung cancer: an old prognostic variable comes back for targeted therapy and immunotherapy?

Abstract

Background: There are well-known differences in gender outcome in non-small cell lung cancer (NSCLC) and other cancers. In this work, we evaluated several randomised clinical trials to explore the gender influence in the outcome of patients with NSCLC treated with targeted therapy and immunotherapy.

Methods: We performed a series of meta-analysis to compare the gender outcome in the routine setting for overall survival and progression-free survival (PFS) in phase III randomised clinical trials comparing EGFR inhibitors versus chemotherapy (OPTIMAL, LUX-lung 3, LUX-lung 6, EURTAC, ENSURE and WTJOG); ALK inhibitors versus chemotherapy (ASCEND 4, ASCEND 5, PROFILE 1014 and NCT009323893) and anti-PD1 checkpoint inhibitors versus chemotherapy (CheckMate 017, CheckMate 026, CheckMate 057, KEYNOTE 010 and KEYNOTE 024).

Results: Female patients with NSCLC have a reduced risk of death compared with men (HR=0.73; 95% CI 0.67 to 0.79; p<0.00001). Women had a better benefit from EGFR inhibitors than men (HR=0.34; 95% CI 0.28 to 0.40; p<0.00001 vs HR=0.44; 95% CI 0.34 to 0.56; p<0.00001, respectively). The benefit from ALK inhibitors was similar for both genders (HR=0.51; 95% CI 0.42 to 0.61; p<0.00001 vs HR=0.48; 95% CI 0.39 to 0.59; p<0.00001, for women and men, respectively). Anti-PD1 inhibitors significantly improved the PFS in male patients when compared with chemotherapy (HR=0.76; 95% CI 0.68 to 0.86; p<0.00001); in contrast, women showed no benefit in 5/5 randomised trials (HR=1.03; 95% CI 0.89 to 1.20; p=0.69).

Conclusions: In this exploratory study, some targeted treatments were influenced by gender. Despite differences in outcomes that could be attributed to different histology, EGFR and smoking status, gender should be evaluated more deeply as prognostic variable in patients with NSCLC.

Keywords: gender; non-small cell lung cancer; prognostic factors; targeted therapy.

Figure 1

Meta-analysis of the effect of gender in the overall survival, comparing HRs and 95% CI obtained from multivariate analysis in hospital databases. Results show that gender is a prognostic factor favouring female patients (A). The funnel plot shows no publication bias among studies included in the analysis (B).

Figure 2

Meta-analysis of randomised phase III clinical trials comparing EGFR tyrosine kinase inhibitor (TKI) shows that male patients with non-small cell lung cancer (NSCLC) have a minor benefit from these drugs (A) compared with female patients who have a 10% additional reduction in progression risk (B). Funnel plots for the detection of publication bias in the meta-analysis of men (C) and women (D).

Figure 3

Meta-analysis of randomised phase III clinical trials with ALK inhibitors in non-small cell lung cancer (NSCLC) showing similar benefit in male patients (A) and female patients (B). There was no observed publication bias in the analysis of men (C) or women (D).

Figure 4

Male patients with non-small cell lung cancer (NSCLC) have a 24% reduction in the risk of disease progression (A). Women have a decreased benefit from anti-PD1 inhibitors nivolumab and pembrolizumab (B). Funnel plots showing publication bias in meta-analysis of male (C) or female patients (D).