Tubulin inhibitors in non-small cell lung cancer: looking back and forward

ABSTRACT

Introduction: Although the advent of target therapy for lung cancer has brought about outstanding results, this benefit is confined to a subgroup of molecularly selected patients, whereas for most non-small cell lung cancer (NSCLC) patients, chemotherapy still represents the milestone of treatment. Since their introduction into clinics, microtubule targeting agents (MTA), including vinca alkaloids and taxanes, have been extensively used for NSCLC in different settings and combinations.

Areas Covered: In this review, MTA are classified according to their mechanism of action, with a focus on the most common mechanisms of resistance. Moreover, an overview of the most remarkable clinical data regarding MTA in adjuvant, neoadjuvant and advanced setting is provided. Finally, the novel mitotic kinases inhibitors are described according to their different mechanism of action and clinical activity compared to MTA.

Expert Opinion: Unfortunately, the awaited benefit deriving from the actually available chemotherapeutic regimens for advanced NSCLC has reached a plateau. In this scenario, the identification of reliable predictive biomarkers represents a major challenge. Moreover, different schedules for MTA administration are currently under investigation, such as the combination of MTA with other drugs able to bypass the resistance derived from the ‘mitotic slippage’ and the use of metronomic administration of spindle poisons with anti-angiogenic or immunomodulatory agents.

KEYWORDS:

• Microtubule target agents
• vinca alkaloids
• taxanes
• mitotic kinase inhibitors
• lung cancer

Article highlights

• In advanced NSCLC, vinorelbine, docetaxel and paclitaxel are commonly used third-generation agents that showed better survival and response rate compared with second-generation drugs (such as vindesine, etoposide, teniposide).

• Unsolved issues remain about the equivalence among different third-generation regimens.

• In first-line treatment, nab-paclitaxel in combination with carboplatin demonstrated a favorable toxicity profile and promising activity, particularly in squamous NSCLC.

• To date, no validated predictive factors for treatment with MTA have been identified, although some candidate biomarkers, as class III β tubulin for taxanes and vinorelbine or SPARC for nab-paclitaxel, are currently under investigation.

• In adjuvant setting, vinorelbine and cisplatin represents the preferred combination regimen; although no randomized trial compared cisplatin and vinorelbine with another third-generation agents in combination with a platinum compound are available.

• Despite MTA have been only marginally investigated in neoadjuvant setting, they seem to have a promising efficacy and favorable toxicity profile in combination with platinum, in the context of different multimodality treatment strategies.

• Although the encouraging preclinical results of new mitotic targeted agents, their clinical activity is not yet been established. In this regard, a deeper understanding of their mechanism of action and targets is necessary to improve the awaited benefit.

• The metronomic administration of MTA or the combination of MTA with new mitotic inhibitors able to target the ‘mitotic slippage’ and revert chemo-resistance to MTA represent promising treatment strategies with these agents.

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Declaration of interest

This work was partially supported by a grant of the Italian Association for Cancer Research (AIRC-MFAG 14282) and a fellowship award of the International Association for Lung Cancer (IASLC). 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.