Vascular endothelial growth factor receptor tyrosine kinase inhibitors for the treatment of advanced non-small cell lung cancer

ABSTRACT

Introduction: Angiogenesis is the process by which the tumor develops its potential for growth and distant metastasis. The main proangiogenic switch is vascular endothelial growth factor (VEGF), which, along with its receptor VEGFR, is a target for biological drugs such as multi-targeted tyrosine kinase inhibitors used for many neoplasms, including non-small cell lung cancer (NSCLC).

Areas covered: The fact that angiokinase inhibitors act on several signaling molecules simultaneously means that the use of alternative transmission pathways, which nullifies the effect of drugs directed against a single target, is avoided. Nevertheless, most of these drugs have failed to improve any outcome in NSCLC patients. The authors discuss these points and provide their expert perspectives.

Expert opinion: Multikinase inhibitors are the fruit of research which regards cancer as a complex system of interacting processes. However, the lack of predictive biomarkers of response has limited the development of this class of drugs in NSCLC. Combination trials with chemotherapy, immunotherapy or other targeted drugs are ongoing, and while some have already confirmed the role of antiangiogenic small molecules in integrated regimes, others are still evaluating the efficacy of these drugs and raising questions about their cost and tolerability.

KEYWORDS:

• Angiogenesis
• anlotinib
• antiangiogenic therapy
• molecular targeted drugs
• nintedanib
• NSCLC
• second-line treatment
• TKIs
• VEGF
• VEGFR tyrosine kinase inhibitors

Article Highlights

• The inhibition of angiogenesis and, above all, of VEGFR, represent an important therapeutic strategy for NSCLC patients.

• Many redundant pathways are involved in angiogenesis and are the targets for small molecules that inhibit the receptor tyrosine kinase activity. These inhibitors produced some interesting results in NSCLC treatment and antiangiogenic drugs are available in clinical practice.

• Nintedanib and anlotinib are currently approved for advanced NSCLC in some countries. Phase II and III studies were completed and many are ongoing to test the efficacy of several TKIs in different clinical contexts.

• Overall, the outcomes improvements are modest and must be balanced against the costs and toxicities of these treatments. Predictive biomarkers to address selected patients to antiangiogenic therapies are missing.

• Investigation on antiangiogenic agents, integrated with targeted TKIs and immunotherapy for NSCLC, represents the future of combination therapies that aim to substantial improvements in response and survival.

This box summarizes key points contained in the article.

Declaration of interest

C Gridelli received honoraria as speaker bureau and advisory board member from Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Roche and Boehringer Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.