Treatment of advanced ALK-rearranged NSCLC following second-generation ALK–TKI failure

ABSTRACT

Introduction

Anaplastic lymphoma kinase (ALK) gene rearrangement is detected in approximately 3–5% of non-small cell lung cancer (NSCLC) cases. Tyrosine kinase inhibitors (TKIs) targeting ALK rearrangement (ALK–TKIs) have shown significant efficacy and improved the survival of patients with NSCLC exhibiting ALK rearrangement. However, almost all patients exhibit disease progression during TKI therapy owing to resistance acquired through various molecular mechanisms, including both ALK-dependent and ALK-independent.

Areas covered

Here, we review the mechanisms underlying resistance to second-generation ALK–TKIs, and the clinical management strategies following resistance in patients with ALK rearrangement-positive NSCLC.

Expert opinion

Treatment strategies following the failure of second-generation ALK–TKIs failure should be based on resistant mechanisms. For patients with ALK mutations who exhibit resistance to second-generation ALK–TKIs, lorlatinib is the primary treatment option. However, the identification of resistance profiles of second-generation ALK–TKIs can aid in the selection of an appropriate treatment strategy. In cases of ALK-dependent resistance mutations, lorlatinib could be the first choice as it exhibits the broadest coverage of mutations that lead to resistance against second-generation ALK–TKIs, such as G1202R, and L1196M. In cases of no resistance mutations, atezolizumab, bevacizumab, and platinum-based chemotherapy could be the alternative treatment options.

KEYWORDS:

• ALK
• NSCLC
• second-generation ALK–TKI
• alectinib
• brigatinib
• ceritinib
• lorlatinib

Article highlights

• Mechanisms of resistance to ALK–TKIs can be categorized as follows: ALK-dependent and ALK-independent.

• Lorlatinib is the main treatment option for patients exhibiting resistance to second-generation ALK–TKIs.

• In cases of ALK-dependent resistance mutations, lorlatinib could be the first therapeutic choice.

• In cases of no resistance mutations, atezolizumab and platinum-based chemotherapy could be the alternative treatment option.

• Several clinical trials evaluating next-generation ALK–TKIs monotherapy or combination therapies of ALK–TKIs and other target agents are currently ongoing.

• Further investigation is needed to establish treatment strategies based on the resistance mechanisms.

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.