Emerging treatment using tubulin inhibitors in advanced non-small cell lung cancer

ABSTRACT

Introduction: Tubulin inhibitors including taxanes and vinca alkaloids are important components of chemotherapy regimens used in advanced non-small cell lung cancer (NSCLC). Despite a treatment paradigm shift due to molecularly-targeted therapies and immunotherapy, a majority of patients will receive chemotherapy during their treatment course. Either used alone or in combination, tubulin inhibitors have demonstrated clinical benefits in different settings of lung cancer management.

Areas covered: This review first discusses FDA-approved tubulin inhibitors for NSCLC, such as paclitaxel, docetaxel, vinorelbine, and nab-paclitaxel. The article then provides a summary of novel tubulin inhibitors, including cabazitaxel, eribulin, ixabepilone, patupilone, plinabulin, new colchicine analogues and others. It also discusses new tubulin inhibitor combinations with immunotherapy (PD-1/PD-L1 inhibitors) and molecularly-targeted therapies (e.g. anti-angiogenic agents, mTOR inhibitors, heat shock protein 90 inhibitors, MEK inhibitors, and anti-HER3 agents). Lastly, emerging data on potential resistance mechanisms and predictive biomarkers for tubulin inhibitors are explored.

Expert opinion: Tubulin inhibitors will likely continue to play important roles in NSCLC management due to the advent of novel agents and combinations. Through further understanding of tumor biology, investigation of drug resistance, and development of predictive biomarkers, we will be better positioned to incorporate microtubule inhibition into patient specific treatment strategies.

KEYWORDS:

• Adenocarcinoma
• docetaxel
• microtubule
• tubulin
• tubulin inhibitor
• novel
• NSCLC
• paclitaxel
• squamous cell
• vinorelbine

Article highlights

• Microtubule inhibitors including paclitaxel, docetaxel, vinorelbine and nab-paclitaxel are commonly used in advanced NSCLC either in combinations with platinum-based agents or as monotherapy.

• Nab-paclitaxel plus carboplatin has demonstrated a superior toxicity profile and overall response rate compared to paclitaxel. In squamous cell NSCLC, this combination has become an acceptable and preferred first-line regimen.

• Multiple novel MTAs are being evaluated including plinabulin, which may partially abrogate the toxicities associated with docetaxel.

• MTAs have demonstrated efficacy when combined with platinum agents plus immunotherapy; the results of multiple trials are awaited and may provide practice-changing results.

• The addition of MTAs with targeted therapy has been evaluated in multiple settings. This includes the VEGF targeted inhibitors bevacizumab and ramucirumab, which are both FDA-approved in combination with standard chemotherapy.

• Resistance to MTAs is mediated by multiple mechanisms including increased presence of drug efflux pumps such as P-glycoprotein, as well as variable tubulin isotype expression and microtubule dynamics. Mitotic centromere-associated kinesin can promote paclitaxel resistance by facilitating microtubule detachment from centrosomes. Varying expression of important miRNAs have also been implicated as a mechanism of resistance to MTAs.

• There are currently no available predictive biomarkers for MTA activity. Beta-III tubulin overexpression may correlate to MTA resistance, while caveolin-1 levels may correspond to improved survival; however, both markers require further validation. Meanwhile, microtubule-binding proteins have demonstrated early evidence of future roles as biomarkers.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.