Anti-Tumour TreatmentComparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A systematic review and meta-analysis
Introduction
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) are the two most well studied immunoregulatory checkpoint pathways in cancer [1]. They exert their function by restricting immune cell activation in distinct phases and anatomic locations of host antitumor response [2]. Various clinical-grade monoclonal antibody therapies have been developed to target these and other immune checkpoint proteins to enhance antitumor immune responses. The monoclonal antibodies (mAbs) against CTLA-4 and PD-1 have been the best studied immunotherapies so far and shown to improve survival outcomes in various randomized controlled trials [3], [4], [5]. The mechanism of action of CTLA-4 inhibitors involves abrogation of immune tolerance leading to increases in the number and repertoire of activated T cells. PD-1 inhibitors, on the other hand, re-stimulate previously primed T cells that have lost effector and proliferative function during the course of an immune response. Underlying host anti-tumor immune response is fundamental for clinical benefit from these agents [6]. Currently, the United States Food and Drug Administration (FDA) has approved ipilimumab, nivolumab, and pembrolizumab for patients with unresectable or distant metastatic melanoma. Nivolumab and pembrolizumab have been approved as a second-line treatment of patients with advanced non-small-cell lung cancer. Recently, the FDA approved has approved nivolumab as a treatment for patients with metastatic renal cell carcinoma following prior treatment with an anti-angiogenic therapy [7], [8], [9]. Additionally, tremelimumab, an anti-CTLA-4 mAb, has been granted orphan drug designation by the FDA for the treatment of patients with malignant mesothelioma [10].
The age-related decline in the immune system has been termed immunosenescence. Of note, immunosenescence may be, at least in part, associated with higher propensity to react to self-antigens (autoimmunity), reduced ability of the host to defend microbes and cancer (immunodeficiency), and dysregulation between different immune system components [11], [12], [13]. T cells, the primary effectors of antitumor response, undergo significant changes with age: their absolute numbers, in particular the naïve, CD8+ T cells decline with age in part due to thymic involution and contraction of lymphopoietic stem cells [14]. In addition to numeric defects, functional defects have been described, such deficiency in CD28 co-stimulation, upregulation of co-inhibitory immune checkpoints PD-1 and Tim-3 [15], diminution of intracellular signaling important for T-cell activation, decreased cytokine production and IL-2 signaling [16]. Since ICIs exert their anti-tumor effects through effector T-cells, immunosenescence may have a negative impact on the efficacy of ICIs in elderly cancer patients. The clinical efficacy of immune checkpoint inhibitors in elderly cancer patients has not been fully elucidated in previous clinical trials [3], [4], [5]. Therefore, we conducted a systemic review and study-level meta-analysis of randomized controlled trials to compare the efficacy of ICIs between younger and older patients.
Section snippets
Data source
This analysis was performed in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement [17]. We conducted an independent review of PubMed from January 1966 to September 2015. Search terms included “ipilimumab”, “tremelimumab”, “nivolumab”, “pembrolizumab”. The search was limited to randomized controlled trial. We searched abstracts and virtual meeting presentations utilizing the same search terms from the American Society of Clinical Oncology
Search results and patient characteristics
Our search strategy yielded 199 potentially relevant publications in the PubMed and ASCO databases. 190 publications were excluded. Our selection process and reasons for study exclusion are shown in Fig. 1. A total of eight phase III and one phase II randomized clinical trials were considered eligible for the meta-analysis. A total of 5265 patients (ICIs: 2925; controls: 2340) were included in the analysis from three ipilimumab trials, one tremelimumab trial, four nivolumab trials and one
Discussion
Our meta-analysis of nine RCTs that included 5265 patients investigated the efficacy of immune checkpoint inhibitors in elderly patients with advanced cancer as compared with younger patients. Though the randomized controlled studies performed subgroup analyses based on age, these analyses were not designed to have sufficient statistical power. Meta-analysis is a statistical method to summarize these data and estimate the effect size. This study showed that ICIs significantly improved overall
Role of the funding source
This study was not funded by any sponsors.
Authorship
T.F.N. designed research, collected data, analyzed and interpreted data, and wrote the manuscript. S.S.S. contributed to collection of data and revision of the manuscript. H.B.M. and S.J.M. participated in the elaboration of the research design and revision of the manuscript.
Funding
None.
Conflict of interest
The authors declare no competing financial interests. Hyman B. Muss: Consultant Pfizer. Stergios J. Moschos: Consultant Genentech, Amgen, Merck, Prometheus Laboratories.
References (40)
- et al.
Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study
Lancet Respir Med
(2015) - et al.
Ageing and infection
Lancet Infect Dis
(2002) - et al.
Immunosenescence and cancer
Crit Rev Oncol/Hematol
(2010) - et al.
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
J Clin Epidemiol
(2009) - et al.
Assessing the quality of reports of randomized clinical trials: is blinding necessary?
Control Clin Trials
(1996) - et al.
Meta-analysis in clinical trials
Control Clin Trials
(1986) - et al.
Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial
Lancet Oncol
(2014) - et al.
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial
Lancet Oncol
(2015) - et al.
The immune response of aged mice to influenza: diminished T-cell proliferation, interleukin 2 production and cytotoxicity
Cell Immunol
(1983) - et al.
Age-related increase of tumor susceptibility is associated with myeloid-derived suppressor cell mediated suppression of T cell cytotoxicity in recombinant inbred BXD12 mice
Mech Ageing Dev
(2007)