Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review

Background and Objective: Anaplastic lymphoma kinase (ALK) rearrangements are observed in approximately 3-7% of advanced non-small cell lung cancer (NSCLC) cases. Presently, there are five ALK tyrosine kinase inhibitors (TKIs) approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with ALK-positive lung cancer in the advanced or metastatic stages. Despite these therapeutic advancements, most patients with ALK-positive lung cancer undergoing ALK TKI therapy eventually experience disease progression due to multiple mechanisms of drug resistance. This review aims to explore strategies to combat acquired therapeutic resistance to ALK inhibition, including novel agents and combinatorial strategies under development for both on-target and off-target resistance, along with emerging methods to extend the efficacy of ALK inhibitors.

Methods: We conducted a comprehensive search of English-language peer-reviewed literature, conference abstracts, and trial registrations in the MEDLINE (Ovid), Embase (Elsevier), and CENTRAL (Cochrane Library) databases, as well as from major international oncology meetings up to August 2022. Studies focusing on interventions to overcome ALK resistance were selected after reviewing each title and abstract.

Key Content and Findings: In cases of oligo-progression, treatment strategies may involve continuing the current systemic treatment beyond progression and supplementing it with local therapies targeting the progressing lesions. Approaches to address ALK TKI resistance driven by on-target mechanisms include the development of 4th generation TKIs such as TPX-0131 and NVL-655, and proteolysis-targeting chimeras (PROTACs). For patients experiencing tumor progression due to off-target (ALK-independent) resistance, combination therapies targeting ALK and other downstream or parallel pathways, novel antibody-drug conjugates, or combinations of ALK inhibitors with chemotherapy and immunotherapy may be effective. Additionally, other potential strategies being investigated include the use of circulating tumor DNA (ctDNA) surveillance to identify molecular mediators of drug resistance before significant progression is detected on imaging, and the application of ALK TKIs in adjuvant and neoadjuvant settings.

Conclusions: There is an urgent need for strategies to overcome resistance to current ALK inhibitors. Due to the diverse mechanisms of resistance, customized approaches are essential for effective disease management.