First-line treatment of advanced non-small cell lung cancer with ALK rearrangement: state of the art and future development

ABSTRACT

Introduction: Approximately 5% of all diagnosed non-small cell lung cancer (NSCLC) patients harbor a genetic rearrangement between the ALK and EML4 genes, representing a specific molecular, histological and clinical subgroup (ALK+ NSCLC). To date, upfront treatment with ALK-tyrosine-kinase inhibitors (ALK-TKIs) has replaced chemotherapy in the first line setting for this subset of patients with excellent results. However, all treated patients eventually develop acquired resistance mechanisms to these agents (mainly resistance mutations) and experience progression of the disease.

Areas covered: This paper provides a comprehensive state-of-the-art review about first-line approved ALK-TKIs, furthermore, it discusses the most promising ALK-TKIs under development designed to overcome resistance mutations and their implications.

Expert opinion: Alectinib should currently be regarded as the standard of care for the first-line treatment of ALK+ NSCLC, considering its superior efficacy and safety profile. Regarding developing agents, lorlatinib and ensartinib appear to be the most promising ones, even though the data from their trials are still immature.

KEYWORDS:

• ALK
• ALK-TKI
• EML4
• EML4-ALK RTK
• first-line treatment
• NSCLC
• resistance mechanisms
• G1202R

Key points

• A small subgroup of patients affected by non-small cell lung cancer (about 4%-6% of all NSCLC patients), typically younger light or never smokers affected by adenocarcinoma harbor ALK gene rearrangements.

• ALK rearrangements consist mainly of an inversion between the ALK gene and the EML4 gene, resulting in a pathologically dysregulated ALK-RTK overexpression in the form of a chimeric RTK (EML4-ALK RTK), that shows constitutive tyrosine kinase activity, eventually leading to oncogenesis.

• We are currently able to target the chimeric EML4-ALK RTK using first (crizotinib) or second (ceritinib, alectinib, brigatinib) generation ALK-TKI, a class of drugs that are able to specifically inhibit its tyrosine kinase activity, presently representing the standard of care in the first-line setting for this subset of patients.

• Following an ALK-TKI treatment, however, all treated patients eventually develop acquired resistance to these agents through different mechanisms, secondary resistance mutations in the tyrosine kinase domain being the most frequent one, stopping to respond to therapy and experiencing progression of disease.

• Taking into account the acquired resistance mechanisms adopted by progressing ALK+ NSCLC cells, next-generation ALK-TKI have been developed and are currently under clinical investigation, lorlatinib and ensartinib being the most promising ones.

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.

Reviewers disclosure

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

Additional information

Funding

This paper was not funded.