Abstract and Introduction
Abstract
Background and Objective: Anaplastic lymphoma kinase (ALK) rearrangements are detected in 3–7% of advanced non-small cell lung cancer (NSCLC). There are currently 5 U.S Food and Drug Administration (FDA)-approved ALK tyrosine kinase inhibitors (TKIs) for the treatment of patients with ALK-positive lung cancer in the advanced/metastatic disease setting. Despite these advances, most patients with ALK-positive lung cancer who are treated with ALK TKI therapy ultimately experience disease progression due to various mechanisms of drug resistance. In this review, we discuss strategies to address acquired therapeutic resistance to ALK inhibition, novel agents and combinatorial strategies in development for both on and off-target resistance, and some emerging approaches to prolong response to ALK inhibitors.
Methods: We performed a search of peer-reviewed literature in the English language, conference abstracts, and trial registrations from the MEDLINE (Ovid), Embase (Elsevier), and CENTRAL (Cochrane Library) databases and major international oncology meetings up to August 2022. We then screened for studies describing interventions to overcome ALK resistance based on review of each title and abstract.
Key Content and Findings: For patients with oligo-progression, treatment may include maintaining the same systemic treatment beyond progression while adding local therapies to progressing lesions. Strategies to combat ALK TKI resistance mediated by on-target resistance mechanisms include 4th generation TKIs (TPX-0131, NVL-655) and proteolysis-targeting chimeras (PROTACs) currently in development. While for those patients who develop tumor progression due to off-target (ALK independent) resistance, options may include combination therapies targeting ALK and other downstream or parallel pathways, novel antibody drug conjugates, or combinations of ALK inhibitors with chemotherapy and immunotherapy. Lastly, other potential strategies being explored in the clinic include circulating tumor DNA (ctDNA) surveillance to monitor for molecular mediators of drug resistance prior to frank progression on imaging studies and utilization of ALK TKIs in the adjuvant and neoadjuvant settings.
Conclusions: Strategies to overcome resistance to currently available ALK inhibitors are urgently needed. Given the variety of resistance mechanisms, tailormade approaches are required for disease control.
Introduction
Background
Anaplastic lymphoma kinase (ALK), a member of insulin receptor protein tyrosine kinase superfamily, has been shown to play a role in development of central and peripheral nervous systems.[1] Rearrangements involving the ALK gene on chromosome 2p have been reported in a variety of human tumors, both solid organ tumors as well as hematologic malignancies.[1,2] These rearrangements result in hybrid mutant oncoproteins which contain the amino-terminal portion of a fusion partner in frame with the entire tyrosine kinase domain of ALK. Multiple ALK fusions have been described, with EML4–ALK being the most prevalent in non-small cell lung cancer (NSCLC). The resultant oncoprotein drives activation of the ALK signaling pathways, promoting cell proliferation, survival, and evasion of programmed cell death. ALK fusions are validated therapeutic targets across multiple types of tumors.[3–5]
ALK rearrangements are detected in 3–7% of advanced NSCLC and are typically—albeit not exclusively—associated with young age, non-smoking and adenocarcinoma histology.[6] The treatment landscape for and prognosis of patients whose tumors harbor ALK rearrangements (hereafter called ALK-positive lung cancer) has significantly improved with the advent of small molecule tyrosine kinase inhibitors (TKIs) targeting ALK.[7]
Rationale and Knowledge gap
Since the approval of the first ALK TKI, crizotinib, in 2011, a plethora of basic science and clinical studies have rapidly advanced the field through the development of "next-generation" ALK TKIs, which have increased on-target potency and improved central nervous system (CNS) efficacy. As of the timing of the writing of this narrative, there are currently 5 TKIs approved by the U.S Food and Drug Administration (FDA) and European Medicines Agency for the treatment of patients with ALK-positive lung cancer in the advanced/metastatic disease setting, including crizotinib[8] [1st generation]; ceritinib,[9] alectinib,[10] brigatinib[11] [all 2nd generation]; and lorlatinib [3rd generation][12] (described in detail by Drs. Meador and Piotrowska in this issue). Ensartinib [a 2nd generation ALK TKI] is also currently approved in China.[13]
Despite these advances, most patients with ALK-positive lung cancer who are treated with ALK TKI therapy ultimately experience disease progression due to various mechanisms of drug resistance (described in detail by Drs. Meador and Piotrowska in this issue).
Objective
In this review, we first discuss strategies to address acquired therapeutic resistance to ALK inhibition, broken down by the type of progression observed (oligoprogression vs. systemic progression). We then describe the novel agents and combinatorial strategies in development for both on and off-target resistance. Lastly, we summarize some potential approaches to prolong response to ALK inhibitors. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-708/rc).
Transl Lung Cancer Res. 2023;12(3):615-628. © 2023 AME Publishing Company
