Early-stage anaplastic lymphoma kinase (ALK)-positive lung cancer: a narrative review

Background and Objective: While anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard of care treatment for metastatic ALK-positive non-small cell lung cancer (NSCLC), the benefit of moving ALK inhibitors to earlier disease stages is unclear. The objective of this review is to summarize the literature regarding the prevalence and prognosis of early-stage ALK-positive NSCLC and the utility of targeted therapies, immunotherapy, and chemotherapy in the neoadjuvant and adjuvant settings. Methods: We identified the references for this narrative review through a literature search of papers about early stage ALK-positive NSCLC using PubMed and clinicaltrials.gov. Last search was run on July 3, 2022. There were no language or time frame restrictions. Key Content and Findings: The incidence of oncogenic ALK alterations in early-stage NSCLC ranges from 2-7%, and ALK-positive NSCLC patients are more likely to be younger and never or light smokers. Studies on the prognostic impact of ALK in early-stage disease have had conflicting results. ALK TKIs are not approved in the neoadjuvant or adjuvant setting and there is a lack of large, randomized trial results. Several trials are currently accruing but results are not expected for several years. Conclusions: Attempts at large, randomized trials to evaluate the benefit of ALK TKIs in the adjuvant and neoadjuvant has been hampered by slow recruitment given the rarity of ALK alterations, lack of universal genetic testing, and the rapid pace of drug development. Expanded lung cancer screening recommendations, liberalization of surrogate endpoints (i.e., pathological complete response and major pathological response), growth of multicenter national clinical trials, and new diagnostic technologies (i.e., cell- free DNA liquid biopsies) provide hope of generating much needed data to definitively answer the question of the utility of ALK-directed therapies in the early-stage setting.