Cox Proportional Hazard Ratios Overestimate Survival Benefit of Immune Checkpoint Inhibitors: Cox-TEL Adjustment and Meta-Analyses of Programmed Death-Ligand 1 Expression and Immune Checkpoint Inhibitor Survival Benefit

Abstract

Introduction: Survival benefit of immune checkpoint inhibitor (ICI) therapy in lung cancer is not fully understood.

Methods: PubMed-cataloged publications through February 14, 2022, were queried for randomized controlled trials of ICI in lung cancer, and identified publications were reviewed for inclusion. Reported Cox hazard ratios (HRs) for overall survival were transformed to Cox-TEL HR for ICI short-term survivors (ST-HR) and difference in proportions for patients with long-term survival (LT-DP). Meta-analyses were performed using a frequentist random-effect model. Outcomes of interest were pooled overall survival Cox HR, ST-HR, and LT-DP in NSCLC, stratified by programmed death-ligand 1 (PD-L1) level (primary outcome) and ICI treatment line (secondary).

Results: A total of nine publications representing eight clinical trials were selected for meta-analysis. Primary analysis yielded the following metrics for patients with PD-L1 expression less than 1%, more than or equal to 1%, and more than or equal to 50%, respectively: pooled Cox HR, 0.71 (95% confidence interval [CI]: 0.62-0.82), 0.74 (95% CI: 0.68-0.82), and 0.62 (95% CI: 0.54-0.70); pooled ST-HR, 0.91 (95% CI: 0.79-1.05), 0.88 (95% CI: 0.82-0.94), and 0.70 (95% CI: 0.60-0.83); and pooled LT-DP, 0.10 (95% CI: 0.00-0.20), 0.09 (95% CI: 0.06-0.12), and 0.11 (95% CI: 0.05-0.17). Results of secondary analysis revealed LT-DP of approximately 10% across treatment lines.

Conclusions: This study reveals an approximately 10% long-term survival probability increment in ICI long-term survivors across PD-L1-positive subpopulations in both ICI treatment lines. Furthermore, ST-HR was consistently poorer than Cox HR. For patients with PD-L1 less than 1%, neither LT-DP nor ST-HR achieved statistical significance. The analysis provides greater insight into the treatment effect of ICI in published trials.

Keywords: Cox HR; Cox-TEL; Immune checkpoint inhibitor; Long-term survival; PD-L1.

Figure 1.

Study selection flowchart. CI, confidence interval; HR, hazard ratio; ICI, immune checkpoint inhibitor; ITT, intention-to-treat; KM, Kaplan-Meier; OS, overall survival.

Figure 2.

Associations of immune checkpoint inhibitors with overall survival benefit in NSCLC stratified by PD-L1 expression levels. (A) PD-L1 greater than or equal to 1%, (B) PD-L1 greater than or equal to 50%, (C) PD-L1 less than 1%. Forest plots of Cox HRs (HR), Cox-TEL HRs (ST-HR), and LT-DPs illustrate overall survival end points of included studies before and after Cox-TEL adjustment. Individual and pooled HRs, ST-HRs, and LT-DPs are illustrated with 95% CI. Pooled end points are meta-analysis results. Atezo, atezolizumab; CI, confidence interval; HR, hazard ratio; ipi, ipilimumab; JCO, Journal of Clinical Oncology; JTO, Journal of Thoracic Oncology; LT-DP, difference in proportions for long-term survival; NEJM, The New England Journal of Medicine; nivo, nivolumab; PD-L1, programmed death-ligand 1; pembro, pembrolizumab; ST-HR, hazard ratio for short-term survivors.

Figure 3.

Association of immune checkpoint inhibitors with overall survival benefit in NSCLC stratified by treatment line and PD-L1 expression level. (A) First-line and intention-to-treat population, (B) first-line and PD-L1 greater than or equal to 1%, (C) first-line and PD-L1 greater than or equal to 50%, (D) second-line and intention-to-treat population, (E) second-line and PD-L1 greater than or equal to 1%, (F) second-line and PD-L1 greater than or equal to 50%. Forest plots of Cox HRs (HR), Cox-TEL HRs (ST-HR), and LT-DPs illustrate overall survival end points of included studies before and after Cox-TEL adjustment. Individual and pooled HRs, ST-HRs, and LT-DPs are illustrated with 95% CI. Pooled end points are meta-analysis results. Atezo, atezolizumab; CI, confidence interval; HR, hazard ratio; ipi, ipilimumab; JCO, Journal of Clinical Oncology; JTO, Journal of Thoracic Oncology; LT-DP, difference in proportions for long-term survival; NEJM, The New England Journal of Medicine; nivo, nivolumab; PD-L1, programmed death-ligand 1; pembro, pembrolizumab; ST-HR, hazard ratio for short-term survivors.