Navigating resistance to ALK inhibitors in the lorlatinib era: a comprehensive perspective on NSCLC

ABSTRACT

Introduction

The emergence of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) has revolutionized targeted therapy. This dynamic landscape, featuring novel ALK inhibitors and combination therapies, necessitates a profound understanding of resistance mechanisms for effective treatment strategies. Recognizing two primary categories – on-target and off-target resistance – underscores the need for comprehensive assessment.

Areas covered

This review delves into the intricacies of resistance to ALK inhibitors, exploring complexities in identification and management. Molecular testing, pivotal for early detection and accurate diagnosis, forms the foundation for patient stratification and resistance management. The literature search methodology involved comprehensive exploration of Pubmed and Embase. The multifaceted perspective encompasses new therapeutic horizons, ongoing clinical trials, and their clinical implications post the recent approval of lorlatinib.

Expert opinion

Our expert opinion encapsulates the critical importance of understanding resistance mechanisms in the context of ALK inhibitors for shaping successful treatment approaches. With a focus on molecular testing and comprehensive assessment, this review contributes valuable insights to the evolving landscape of NSCLC therapy.

KEYWORDS:

• Non-small cell lung cancer (NSCLC)
• ALK inhibitors
• target therapy
• resistance mechanisms
• lung cancer

Article highlights

• Emergence of ALK rearrangements in NSCLC has revolutionized targeted therapy.

• Dynamic landscape with novel ALK inhibitors and combination therapies.

• Understanding resistance mechanisms is crucial for effective treatment.

• Resistance mechanisms categorized as on-target and off-target.

• Molecular testing’s pivotal role in early detection and patient stratification.

• Exploration of new therapeutic horizons and ongoing clinical trials.

• Consideration of clinical implications after the approval of lorlatinib.

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 was not funded.