Durable clinical response to ALK tyrosine kinase inhibitors in ALK-rearranged non-small cell lung cancer: a case report

Background: Anaplastic lymphoma kinase (ALK) rearrangement is a key oncogenic driver promoting the expression of ALK protein in non-small-cell lung cancer (NSCLC). ALK tyrosine kinase inhibitors (TKIs) have significantly improved survival benefits. However, the emergence of drug resistance limits their clinical benefits.Case Description: We herein report a patient benefited from the sequential use of ALK TKIs (crizotinib, brigatinib, and lorlatinib) based on liquid biopsy testing. A female patient with stage IIIB NSCLC had a progression after chemotherapy and sequential radiotherapy. DNA-based next-generation sequencing (NGS) assay was performed in bronchoscopic biopsy tissue sample, demonstrating EML4-ALK (E13:A20) rearrangement. Crizotinib was administered, and partial response (PR) was achieved with a progression free survival (PFS) of 8 months. Brigatinib was used when NGS simultaneously identified the six mutations ALKE1129V, F1174C, F1174L, F1174V, I1171T, and G1269A, with the retention of EML4-ALK. The best overall response of brigatinib was a stable disease, and the PFS was 10 months. Lorlatinib was prescribed at brigatinib progression with five out of the six ALK mutations undetected. The patient took alectinib after lorlatinib resistance with ALKL1196M. The overall survival was four years.Conclusions: EML4-ALK rearrangement was detected after chemotherapy treatment in an NSCLC patient with a remarkable therapeutic response with ALK TKIs based on liquid biopsy testing. We also revealed crizotinib acquired resistance mediated by multiple mutations ALK E1129V, F1174C, F1174L, F1174V, I1171T, and G1269A, while five mutations were undetected after brigatinib treatment. ALK F1174C may be the resistant mutation of brigatinib.