The mechanisms of resistance to second- and third-generation ALK inhibitors and strategies to overcome such resistance

ABSTRACT

Introduction

Anaplastic lymphoma kinase (ALK) inhibitors are widely known to contribute to the long-term survival of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Based on clinical trial data, treatment with second- or third-generation ALK inhibitors can be initiated after crizotinib therapy without analyzing resistance mechanisms, and some randomized trials have recently shown the superiority of second- or third-generation ALK inhibitors over crizotinib as the initial treatment; however, the optimal treatment for patients who relapse while on second- or third-generation ALK inhibitors is not well-defined.

Areas covered

This review provides an overview of the mechanisms of resistance to second- or third-generation ALK inhibitors that have been identified in both clinical and pre-clinical settings, and introduces strategies for overcoming resistance and discusses ongoing clinical trials.

Expert opinion

The comprehensive elucidation of both ALK-dependent and ALK-independent resistance mechanisms is necessary to improve the prognosis of patients with ALK-rearranged NSCLC. Liquid biopsy to clarify these mechanisms of resistance might play an important role in the near future.

KEYWORDS:

• ALK
• NSCLC
• ALK-TKI
• resistance
• alectinib
• ceritinib
• brigatinib
• lorlatinib

Article highlights

• Second- and third-generation ALK-TKIs are highly effective for patients with ALK-positive NSCLC; however, all patients eventually progress on these ALK-TKI treatments.

• The mechanisms of resistance to ALK-TKIs are diverse and complex, and are still not well known. An overview of both ALK-dependent and ALK-independent resistance mechanisms is provided in this review.

• Understanding the mechanisms of ALK-TKI resistance will be useful for the selection of optimal treatment strategies, with the prediction and eventual circumvention of disease progression.

• Dynamic plasma monitoring using liquid biopsy might make it possible to identify the emergence of acquired ALK-dependent and -independent resistance at an earlier time-point.

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.

Reviewer disclosures

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

Additional information

Funding

This paper received no funding.