Elsevier

Lung Cancer

Volume 102, December 2016, Pages 21-27
Lung Cancer

The addition of anti-angiogenic tyrosine kinase inhibitors to chemotherapy for patients with advanced non-small-cell lung cancers: A meta-analysis of randomized trials

https://doi.org/10.1016/j.lungcan.2016.10.004Get rights and content

Highlights

  • Meta-analysis involving 7997 patients with non-small cell lung cancers.

  • No survival benefit adding antiangiogenic tyrosine kinase inhibitor to chemotherapy.

  • Modest survival benefit seen in patients with lung adenocarcinomas.

  • Significantly increased toxicity and treatment-related deaths.

  • Predictive biomarkers needed for the development of this class of drugs.

Abstract

Objectives

The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy.

Materials and Methods

We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology.

Results

The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P < 0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P < 0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P = 0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P = 0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P = 0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P < 0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI.

Conclusion

The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs.

Introduction

Anti-angiogenesis as a form of cancer therapy has held great promise since the original proposal by Folkman in 1971 [1]. A primary driver of tumor-associated angiogenesis is vascular endothelial growth factor (VEGF). VEGF is produced and secreted by tumor cells in response to hypoxia, and binds to a particularly important cognate receptor, VEGF Receptor 2 (VEGFR2) on endothelial cells, promoting proliferation of those cells and initiating a program of angiogenic growth leading to increased tumor vascularity, supplying solid tumors with glucose, oxygen, and other nutrients required for cancer cell survival and proliferation.

The VEGF:VEGFR2 angiogenic axis has been a focus of intense drug development in oncology over the past 20 years. Almost all agents fall into two general classes: (1) highly specific monoclonal antibodies directed against either the ligand (VEGF) or its receptors (VEGFR) and (2) small molecule tyrosine kinase inhibitors of the kinase domain of the VEGFR. Primary examples of the first class of monoclonal antibodies include bevacizumab, an anti-VEGF antibody, and ramucirumab, an anti-VEGFR2 antibody. Both of these agents have been approved for use in non-small cell lung cancer (NSCLC) patients, with bevacizumab use limited to non-squamous NSCLC due to toxicity concerns including deaths from hemoptysis observed in early phase trials including patients with large, centrally located squamous cell cancers [2]. Ramucirumab is approved in combination with docetaxel for recurrent NSCLC. Both agents have been approved by the U.S. FDA based on studies that have shown modest but statistically significant improvements in overall survival (OS) when combined with chemotherapy, relative to chemotherapy alone [3], [4].

The remarkable early responses observed using molecularly targeted tyrosine kinase inhibitors prompted substantial excitement surrounding the development of multi-target oral anti-angiogenic tyrosine kinase inhibitors (AATKI) directed against VEGFR2, as a potentially more effective means of inhibiting this key signaling axis than the monoclonal antibodies [5], [6], [7]. This excitement has driven development of a large family of anti-VEGFR2 AATKIs, many of which are structurally closely related, and has led to a multitude of clinical trials over the past decade. However, despite the heavy investment from industry, academia and patients, the role of this class of agents in patients with NSCLC remains uncertain.

Earlier meta-analyses have included patients with NSCLC treated with monoclonal antibodies and AATKI, and have attempted to merge datasets involving various combinations with standard agents as well as anti-angiogenic agents given alone [8], [9], [10]. Subgroup analyses suggested potential survival benefit when combining anti-angiogenic agents with chemotherapy in the second line setting, with conflicting data on efficacy according to histology and limited information on toxicity [9], [10]. In order to clearly inform the clinical development of AATKI as a class of agents for patients with NSCLC, we performed a meta-analysis of randomized controlled trials (RCT) to assess the efficacy and toxicity of adding AATKI to chemotherapy, with preplanned analyses of OS according to histology and chemotherapy partner.

Section snippets

Search strategy

In September 2015, we completed a search of PubMed, Medline, EMBASE, Cochrane Library as well as the ASCO, ESMO and WCLC electronic databases for RCT comparing the addition of AATKI to chemotherapy versus chemotherapy alone or plus placebo. Search terms were the combination of “NSCLC” with any of “angiogenesis inhibitors”, “protein kinase inhibitors”, “tyrosine kinase inhibitors”, “axitinib”, “cediranib”, “vandetanib”, “sorafenib”, “linifanib”, “sunitinib”, “motesanib”, “nintedanib” or

Included studies

A total of 517 articles were reviewed and 15 RCTs involving 7997 patients met eligibility criteria (Fig. 1). Eight AATKI agents (axitinib, cediranib, vandetanib, sorafenib, linifanib, sunitinib, motesanib, nintedanib) were studied in 8 phase II and 7 phase III trials (Table 1) [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. Nine trials were conducted in the first line setting involving the addition of AATKI to platinum doublet chemotherapy and 6 trials

Discussion

One theoretical advantage of multi-targeted AATKIs over high-specificity monoclonal antibodies is the ability to inhibit not only tumor angiogenesis, but also closely related receptor tyrosine kinases regulating growth and survival, including the receptors for platelet derived growth factors, fibroblast growth factors and endothelial growth factors [6]. However, after a decade of randomized clinical trials involving close to eight thousand patients, the role of this class of agents for patients

Conflict of Interest Statement

BTL has received consulting fees from Biosceptre International; MGK has received consulting fees from AstraZeneca, Roche; NP has received consulting fees from Boehringer Ingelheim, Roche; all other authors declare no competing interests.

Funding Support and Acknowledgement

This study was supported in part by the Comprehensive Cancer Center Core Grant (P30 CA008748) at Memorial Sloan Kettering Cancer Center from the National Institutes of Health, USA.

Part of this work was originally presented at the IASLC 15th World Conference on Lung Cancer, Sydney, Australia, October 2013.

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