What is a bad ALK? A scoping review of molecular markers of poor prognosis.

e20530 Background: Patients with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase ( ALK) rearrangements derive a significant and durable clinical benefit from tyrosine kinase inhibitors (TKI). However, a portion of patients have progressive disease as their best response and progress to death much earlier than expected which is termed primary resistance. This scoping review aims to summarize the known molecular mechanisms that underlie this lethal ALK phenotype. Methods: We performed a systematic scoping review from scientific databases such as Ovid Medline, Ovid Embase, and Cochrane Central Register of Controlled Trials. Data was extracted from the database inception to March 13, 2023. Studies included molecular markers of poor prognosis, with a focus on TP53, variant 3 re-arrangements, and reports of poor clinical response to TKIs (defined as progression-free survival less than 3 months on 1 st line TKI or overall survival less than 2 years from exposure to 1 st line TKI). 2 nd generation and 3 rd generation ALK TKI clinical trial data were also included. Results: A total of 4360 studies were screened and 136 studies were included. Numerous studies implicated the negative prognostic role of variant 3 likely mediated through the acquisition of on-target resistance mutations compared to other variants. TP53 mutations were also associated with a worse prognosis and implicated with greater chromosomal instability and mutational burden. Furthermore, reports of both variant 3 and TP53 mutations together were associated with even worse survival suggesting both molecular mechanisms combined can confer primary resistance phenotype. Other mediators of primary resistance included aberrations in cell cycle regulators such as CDKN2A/B loss, mutations in cell signalling pathways such as the PI3K/ AKT/mTOR pathway, deficiencies in DNA repair mechanisms, and uncommon fusion partners. Consistent with these prior studies, comprehensive genomic analysis from clinical trial data of 2 nd generation and 3 rd generation TKIs was unable to identify a singular genomic signature that underlies this lethal phenotype. However, a general trend from the literature suggested that the combination of multiple aberrations is likely necessary to confer a primary resistance phenotype, though the relative contribution of each somatic mutation likely will vary. Conclusions: This scoping review highlights that in NSCLC, the lethal ALK phenotype is likely composed of a heterogeneous population of various combinations of poor prognostic factors including variant 3, mutations in cell cycle regulators and other aberrations in cell signalling pathways. There remains an unmet need for a genomic assay to integrate all these various molecular markers to predict the lethal ALK phenotype.