Relationship between Patients’ Baseline Characteristics and Survival Benefits in Immunotherapy-Treated Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

Abstract

Background. The difference of patients’ baseline characteristics such as sex, age, Eastern Cooperative Oncology Group performance status (ECOG PS), and smoking status may influence the immune response. However, little is known about whether these factors affect the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small-cell lung cancer (NSCLC). Therefore, we performed this systematic review and meta-analysis to investigate the relationship between patients’ baseline characteristics and survival benefits in immunotherapy-treated NSCLC. Materials and Methods. We performed a systematic search of PubMed, the Cochrane Library, and Embase for randomized controlled trials (RCTs) of NSCLC immunotherapy. We also searched abstracts and presentations from the proceedings of the American Society of Clinical Oncology and the European Society of Medical Oncology to identify unpublished studies. These studies have available data based on patients’ baseline characteristics (such as sex, age, ECOG PS, and smoking status). We take the hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS) as the effect index and use the random effect model to pool the results. Results. We included 18 phase II/III RCTs with a total of 14,189 participants. The benefits of ICIs were found for both male (pooled OS-HR 0.77, 95% CI 0.72-0.82, P < 0.05 ) and female patients (pooled OS-HR 0.77, 95% CI 0.67-0.87, P < 0.05 ); for both younger (<65 y: pooled OS-HR 0.74, 95% CI 0.68-0.81, P < 0.05 ) and older patients (≥65 y: pooled OS-HR 0.80, 95% CI 0.75-0.86, P < 0.05 ); and for both patients with ECOG PS = 0 (pooled OS-HR 0.77, 95% CI 0.71-0.84, P < 0.05 ) and ECOG PS ≥ 1 (pooled OS-HR 0.76, 95% CI 0.70-0.82, P < 0.05 ). Moreover, there was no significant difference in the efficacy of ICIs among different sex ( P value for interaction = 0.955), age ( P value for interaction = 0.17), or ECOG PS ( P value for interaction = 0.765). However, in patients with different smoking status, the application of ICIs significantly prolonged the OS of smokers (pooled OS-HR 0.77, 95% CI 0.71-0.83, P < 0.05 ) but could not significantly improve the OS of never smokers (pooled OS-HR 0.85, 95% CI 0.70-1.03, P > 0.05 ). Conclusions. ICIs could significantly improve prognosis in patients with advanced NSCLC, regardless of sex, age, or ECOG PS. But among patients with different smoking status, the survival benefits of never smokers treated with ICIs were no better than that of controls. The impact of these factors on immunotherapy should be considered in the future clinical practice and guidelines.

Male sex and pretreatment weight loss are associated with poor outcome in patients with advanced non-small cell lung cancer treated with immunotherapy: a retrospective study

“…A seminal meta-analysis of advanced NSCLC randomized controlled trials of PD-(L)1 inhibitors showed that compared to chemotherapy alone, chemoimmunotherapy benefits females more than males whereas ICI monotherapy benefits males more than females 27 . Subsequent meta-analyses could not replicate these findings, reporting no sex difference in response to either treatment group, but may have introduced heterogeneity by including CTLA-4 inhibitor, non-first line therapy and adjuvant trials 30 , 32 . Of note, these studies had no access to patient level data and could not directly compare males to females.…”

“…Better identification of patients likely to benefit from immunotherapy is clearly needed. Recent studies report conflicting findings on the influence of sex and BMI on response to ICIs 5 – 11 , 25 – 30 , 32 – 34 , while emerging evidence suggests a potential link between cachexia status and poor response to ICIs 12 – 15 , 18 . In this retrospective study, we evaluated the effects of sex, BMI and PWL on outcomes in metastatic NSCLC patients treated with ICIs as part of standard of care at our institution.…”

“…These findings are in line with some studies, but not with all. While there is clear sex-based dimorphism in the innate and adaptive immune systems 24 , there are conflicting data regarding sex differences in ICI efficacy in NSCLC 27 – 30 , 32 – 34 . Historically, female sex has been associated with improved outcomes in NSCLC across all stages, even after controlling for variables such as EGFR mutation status 35 , 36 .…”

“…A follow-up study reported that treatment with ICIs alone versus chemotherapy had a greater beneficial effect in males than in females, while females derived a larger benefit from treatment with chemoimmunotherapy 27 . However, these results were not replicated in subsequent retrospective analyses nor in a later meta-analysis that included more recent RCTs 28 – 30 . These findings underscore the complexity of sex-based effects on the immune system and response to ICIs.…”

Immune-related adverse events are associated with therapeutic efficacy of immunotherapy in patients with melanoma brain metastases

“…There have been some evidence from several randomised trials suggesting that immunotherapy was much more efficacious in men than in women [29,30], although other studies did not demonstrate the same distinction [31]. In our small patient cohort, we did not find any gender-specific survival benefit post-immunotherapy treatment, but did observe a trend for men to more likely to experience irAEs, and when they did, their irAEs appeared to be of higher severities than that in women.…”