Association Between Efficacy of Immune Checkpoint Inhibitors and Sex: An Updated Meta-Analysis on 21 Trials and 12,675 Non-Small Cell Lung Cancer Patients

Abstract

BackgroundMounting randomized clinical trials have proved that immune checkpoint inhibitors (ICIs) achieved better overall survival (OS) and progression-free survival (PFS) than chemotherapy drugs for advanced non-small cell lung cancer (NSCLC) patients. However, some literatures have indicated that different sexes might not have equal immune response. Also, no agreement reached on the issue whether therapeutic benefit of ICIs is related to sex.ObjectivesTo explore the association between efficacy of ICIs for NSCLC patients and their sexes and summarize overall treatment-related adverse events (TRAEs) in an exploratory manner.MethodsWe performed this systematic review and meta-analysis of all potentially relevant studies retrieved from PubMed, EMBASE, and the Cochrane Library until June 2021, for eligible randomized controlled trials (RCTs) comparing immunotherapy with chemotherapy in advanced NSCLC patients. Literature screening, summary data extraction was performed independently and in duplicate. The pooled hazard ratio (HR) and 95% confidence interval (CI) of OS, PFS and TRAEs were calculated, applying STATA software and random-effects models. This study was registered in international prospective register of systematic reviews (PROSPERO), number CRD42020210797.ResultsTwenty-one trials involving 12,675 NSCLC patients were included. For patients with advanced NSCLC, ICIs significantly prolonged the OS (males: HR 0.73, 95%CI 0.67-0.79; females: HR 0.73, 95%CI 0.61-0.85) and PFS (males: HR 0.62, 95%CI 0.55-0.70; females: HR 0.68, 95%CI 0.55-0.81) versus chemotherapy. Overall, there was no statistical difference between their sexes (OS: P = 0.97; PFS: P = 0.43), respectively. Owing to insufficient TRAEs data of different sexes, we only found immunotherapy for NSCLC patients had more all-grades (RR 0.88; 95%CI 0.82-0.95) and 3-5 grades (RR 0.60; 95%CI 0.47-0.75) AEs compared with chemotherapy.ConclusionOur findings indicated that the interaction between immunotherapy efficacy and different sexes was equally evident. Overall, patients with NSCLC could obtain more benefits from ICIs than chemotherapy regimen regardless of their sexes.Systematic Review RegistrationPROSPERO (https://www.crd.york.ac.uk/prospero/), identifier CRD42020210797.

The influence of baseline characteristics on the efficacy of immune checkpoint inhibitors for advanced lung cancer: A systematic review and meta-analysis

“…Therefore, it makes sense to explore appropriate predictors for suitable patients. Previous studies (Yan et al, 2020;Wang et al, 2021;Xue et al, 2021) found that baseline characteristics (i.e., age, gender, and brain metastases, etc.) could influence the efficacy of ICIs on lung cancer.…”

“…Therefore, in order to screen the predictors of efficacy of ICIs for lung cancer, it is necessary to conduct pooled analysis of relative RCTs. Recent research ( Yan et al, 2020 ; Wang et al, 2021 ; Xue et al, 2021 ) has reported the association between unique baseline characteristics and the efficacy of ICIs for lung cancer. To further investigate the potential influence of baseline characteristics on efficacy, we conducted a comprehensive study in this field.…”

Association between sex and outcomes in patients with non-small-cell lung cancer receiving combination chemoimmunotherapy as a first-line therapy: a systematic review and meta-analysis of randomized clinical trials

“…For example, Conforti et al conducted a meta-analysis of randomized and controlled clinical trials evaluating sex-based differences in response to first-line ICI monotherapy in patients with NSCLC expressing high PD-L1 levels and showed that the pooled hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) reported in males vs females was 0.71 (0.64–0.98), indicating a significantly greater effect for males [ 4 ]. However, Xue et al reported that there was no statistical difference in OS and progression-free survival (PFS) between males and females in a meta-analysis [ 30 ]. The meta-analysis by Xue et al included patients treated with ICI monotherapy and ICI combination therapy as a first-line, second-line, or higher line therapy, and the heterogeneity may have contributed to the controversial results.…”

The effect of gender on the clinical outcome of PD-1/PD-L1 inhibitor in advanced lung cancer patients

“…[4] Many clinical trials have demonstrated that PD-1/PD-L1 inhibitors have better survival benefit than chemotherapy in either non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). [5] With the expansion of PD-1/PD-L1 inhibitors in the treatment of malignancies, influence factor of clinical effects have become an area of particular interest. [6] Previous studies have mentioned sex dimorphism in cancer-related immunity and cancer biology.…”

“…Hence, heterogeneity exists, and different varieties of tumors do not have equal outcomes. [5] More clinical trials which explore this problem have been published recently. A comprehensive updated meta-analysis should be made to yield more information.…”