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Meta-Analysis
. 2022 Aug 1;5(8):e2227211.
doi: 10.1001/jamanetworkopen.2022.27211.

Analysis of Cancer Survival Associated With Immune Checkpoint Inhibitors After Statistical Adjustment: A Systematic Review and Meta-analyses

Emily Pei-Ying Lin  1   2   3   4   5 , Chih-Yuan Hsu  1   2 , Lynne Berry  1   2 , Paul Bunn  6 , Yu Shyr  1   2   7
Affiliations
Meta-Analysis

Analysis of Cancer Survival Associated With Immune Checkpoint Inhibitors After Statistical Adjustment: A Systematic Review and Meta-analyses

Emily Pei-Ying Lin et al. JAMA Netw Open. .

Abstract

Importance: Appropriate clinical decision-making relies on accurate data interpretation, which in turn relies on the use of suitable statistical models. Long tails and early crossover-2 features commonly observed in immune checkpoint inhibitor (ICI) survival curves-raise questions as to the suitability of Cox proportional hazards regression for ICI survival analysis. Cox proportional hazards-Taylor expansion adjustment for long-term survival data (Cox-TEL) adjustment may provide possible solutions in this setting.

Objective: To estimate overall survival and progression-free survival benefits of ICI therapy vs chemotherapy using Cox-TEL adjustment.

Data sources: A PubMed search was performed for all cataloged publications through May 22, 2022.

Study selection: The search was restricted to randomized clinical trials with search terms for ICIs and lung cancer, melanoma, or urothelial carcinoma. The publications identified were further reviewed for inclusion.

Data extraction and synthesis: Cox proportional hazards ratios (HRs) were transformed to Cox-TEL HRs for patients with short-term treatment response (ie, short-term survivor) (ST-HR) and difference in proportions for patients with long-term survival (LT-DP) by Cox-TEL. Meta-analyses were performed using a frequentist random-effects model.

Main outcomes and measures: Outcomes of interest were pooled overall survival (primary outcome) and progression-free survival (secondary outcome) HRs, ST-HRs, and LT-DPs. Subgroup analyses stratified by cancer type also were performed.

Results: A total of 1036 publications was identified. After 3 levels of review against inclusion criteria, 13 clinical trials (7 in non-small cell lung cancer, 3 in melanoma, and 3 in urothelial carcinoma) were selected for the meta-analysis. In the primary analysis, pooled findings were 0.75 (95% CI, 0.70-0.81) for HR, 0.86 (95% CI, 0.81-0.92) for ST-HR, and 0.08 (95% CI, 0.06-0.10) for LT-DP. In the secondary analysis, the pooled values for progression-free survival were 0.77 (95% CI, 0.64-0.91) for HR, 1.02 (95% CI, 0.84-1.24) for ST-HR, and 0.10 (95% CI, 0.06-0.14) for LT-DP.

Conclusions and relevance: This systematic review and meta-analysis of ICI clinical trial results noted consistently larger ST-HRs vs Cox HRs for ICI therapy, with an LT-DP of approximately 10%. These results suggest that Cox HRs may not provide a full picture of survival outcomes when the risk reduction from treatment is not constant, which may aid in the decision-making process of oncologists and patients.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Lin reported receiving grants from the Ministry of Science and Technology Taiwan, National Health Research Institute Taiwan, Taipei Medical University, and Taipei Medical University Hospital during the conduct of the study, and grants from the Ministry of Science and Technology Taiwan, National Health Research Institute Taiwan, Taipei Medical University, and Taipei Medical University Hospital outside the submitted work. Dr Berry reported receiving grants from the National Institutes of Health National Cancer Institute (NIH/NCI) during the conduct of the study. Dr Bunn reported receiving personal fees from AstraZeneca, Eli Lilly, Verastem Oncology BOD, CStone, Ascentage, Viecure, BMS DMC, and Merck DMC outside the submitted work. Dr Shyr reported receiving grants from the NIH/NCI during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Cox Proportional Hazards–Taylor Expansion Adjustment for Long-term Survival Data (Cox-TEL) Adjustment Method Schema
Cox hazard ratios (HRs) are transformed to Cox-TEL HRs (ST-HRs, for patients with short-term treatment response) and difference in proportions (LT-DPs, for responders with long-term survival) by Cox-TEL. The only data required to perform the adjustment are Cox HRs with 95% CIs and survival probabilities excerpted from Kaplan-Meier survival curves.
Figure 2.
Figure 2.. Study Selection Flowchart
FDA indicates Food and Drug Administration; HRs, hazard ratios; ICI, immune checkpoint inhibitor; ITT, intention-to-treat; KM, Kaplan-Meier; LC, lung cancer; NSCLC, non–small cell lung cancer; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; and UC, urothelial carcinoma.
Figure 3.
Figure 3.. Association of Immune Checkpoint Inhibitors With Overall Survival and Progression-Free Survival
Cox hazard ratios (HRs), Cox-Taylor expansion adjustment for short-term survival data (Cox-TEL) HRs (ST-HR), and difference in proportions of survival probability for long-term survivors (LT-DP) illustrate survival end points of included studies before and after Cox-TEL adjustment for overall survival (A) and progression-free survival (B). Pooled end points are meta-analysis results. The weight for each study is inversely proportional to the within-study variance of log(HR) plus the between-studies variance. NSCLC indicates non–small cell lung cancer; UC, urothelial carcinoma.
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References

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