Background: Immune checkpoint inhibitors (ICIs) that block inhibitory receptors such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death-1 (PD-1) and its ligand PD-L1 have been a cornerstone of immunotherapy in oncology. Four ICIs are currently approved by the United States Food and Drug Administration (FDA): anti-CTLA-4 monoclonal antibodies (ipilimumab and tremelimumab) and anti-PD1 monoclonal antibodies (nivolumab and pembrolizumab). Immunosenescence, a phenomenon of decreased immune function as a result of age-associated alterations to the immune system, has been described. However, it is still unclear to what extent immunosenescence may affect efficacy of ICIs. We performed a systematic review and meta-analysis to compare efficacy of ICIs between younger and older patients.
Methods: We conducted a review of PubMed from January 1966 to May 2015. We limited our search to ICIs approved by the FDA. Search keywords were: ‘‘ipilimumab’’, ‘‘tremelimumab’’, ‘‘nivolumab’’,‘‘pembrolizumab’’. The search was limited to randomized clinical trials (RCTs) published in English. We also searched abstracts and virtual meeting presentations utilizing the same search terms from the American Society of Clinical Oncology (ASCO) conferences held up to May 2015 to identify relevant trials. Clinical trials that met the following criteria were included: (1) phase II and III trials in patients with cancers; (2) random assignment of participants to treatment with ICIs or control (chemotherapy, placebo or best supportive care); and (3) subgroup comparison of overall survival based on age using hazard ratio (HR). A general variance-based method was used to estimate the summary HRs, and their 95% confidence intervals. Statistical heterogeneity in results between trials included in the meta-analysis was examined using Cochrane's Q statistic, and inconsistency was quantified with I2 statistic. The assumption of homogeneity was considered invalid for P values less than 0.10. Summary HRs were calculated using random-effects or fixed-effects models depending on the heterogeneity of included studies. Statistical analyses were performed by using Comprehensive Meta-Analysis software, version 2 (Biostat, Englewood, NJ, USA).
Results: A total of 3,322 patients from six phase III RCTs of ICI were included in the analysis with three ipilimumab trials, two nivolumab trials and one tremelimumab trial. The underlying malignancies included were melanoma (4 trials), prostate cancer (1 trial) and non–small-cell lung cancer (1 trial). Five trials used 65 years and one trial used 70 years as an age cut-off to conduct subgroup analyses. For 2,078 younger patients, the pooled HR for OS showed significant difference between ICIs and controls (HR, 0.73; 95% CI, 0.66–0.81; P <0.001). The fixed-effects model was used because there was no significant heterogeneity (Q = 9.86; P = 0.13; I2 = 39.17). For 1,244 older patients, ICIs also significantly improved OS (HR, 0.72; 95% CI, 0.58–0.90; P = 0.004) in comparison with controls. The test for heterogeneity was significant and a random-effects model was used (Q = 18.43; P = 0.02; I2 = 56.59). There was no statistically significant difference between subgroups of younger and older patients concerning the pooled HR for OS (P = 0.93).
Conclusions: In this meta-analysis, immune checkpoint inhibitors significantly improved overall survival compared with controls in both younger and older patients. Our data suggest the survival benefit conferred by ICIs is independent of chronological age if patients are dichotomized into younger and older groups with an age cut-off of 65-70 years. Further research is needed to examine the association between efficacy of ICIs and functional changes in immune system with aging.
Citation Format: Tomohiro Funakoshi, Hyman Muss, Stergios Moschos. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A meta-analysis of randomized controlled trials. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A159.