Elsevier

Cancer Treatment Reviews

Volume 45, April 2016, Pages 30-37
Cancer Treatment Reviews

Anti-Tumour Treatment
Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A systematic review and meta-analysis

https://doi.org/10.1016/j.ctrv.2016.02.006Get rights and content

Highlights

  • This meta-analysis compared the efficacy of ICIs between younger and older patients.

  • ICIs significantly improved OS in both younger (HR, 0.75) and older (HR, 0.73) groups.

  • An improvement in PFS was observed in younger (HR, 0.58) and older (HR, 0.77) patients.

  • In the PD-1 inhibitor subgroup, a significant benefit was not seen in the patients aged ⩾75 years.

Abstract

Background

Immune checkpoint inhibitors (ICIs) rely on the presence of ongoing immune response to exert their antitumor effect. Little is known whether an age-related decline in immune function negatively influences antitumor response and in so doing diminishes the efficacy of ICIs in elderly subjects. We performed a meta-analysis to compare the efficacy of ICIs between younger and older patients.

Patients and methods

PubMed and the ASCO databases were searched up to September 2015. We included randomized controlled trials (RCTs) of ICIs (ipilimumab, tremelimumab, nivolumab and pembrolizumab) reporting subgroup comparison of overall survival (OS) and/or progression-free survival (PFS) based on age cutoffs. The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated.

Results

A total of 5265 patients from nine RCTs of ICI were included. When patients are dichotomized into younger and older groups with an age cut-off of 65–70 years, ICIs improved OS in both younger (HR, 0.75; 95% CI, 0.68–0.82) and older (HR, 0.73; 95% CI, 0.62–0.87) groups. An improvement in PFS was observed in younger (HR, 0.58; 95% CI, 0.40–0.84) and older (HR, 0.77; 95% CI, 0.58–1.01) patients. Subgroup analyses according to ICI and tumor type showed a consistent survival benefit in both younger and older groups except for the subgroup of older patients treated in 4 trials of anti-programmed cell death protein-1 (PD-1) monoclonal antibody (HR, 0.86; 95% CI, 0.41–1.83).

Conclusions

A benefit in OS with ICIs was significant in both younger and older patients with a cut-off age of 65–70 years.

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.

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