Lung adenocarcinoma harboring complex EML4-ALK fusion and BRAF V600E co-mutation responded to alectinib

The echinoderm microtubule-associated protein-like 4 gene and anaplastic lymphoma kinase gene (EML4-ALK) is the most frequent fusion variant of ALK rearrangements in non-small cell lung cancer (NSCLC). With the widespread application of next-generation sequencing (NGS), more fusions and co-mutations of EML4-ALK have been discovered. Complex co-mutation of EML4-ALK fusions together with BRAF V600E, though rarely occurred, also deserves attention to determine the standard of caring these patients. Herein, we report a case of lung adenocarcinoma harboring a complex ALK fusion that coexisted with a BRAF mutation, as tested by DNA-NGS prior to treatment.A 51-year-old non-smoking man, without any symptoms, was admitted to hospital due to small pulmonary nodules and enlarged supraclavicu larlymph nodes found in health checkup.He was diagnosed with stage IVB (T4N3M1c) lung adenocarcinoma. BRAF V600E (abundance 3.75%) mutation and a novel thus little-understood EML4-ALK (E13, A5; abundance 2.16%) fusion were identified by DNA-NGS analysis of lymph node biopsy tissue in December 2019.Darafenib plus trametinib targeted therapy and chemotherapy were given firstly, but tumor progression was not inhibited. The ALK inhibitor alectinib was prescribed then.The patient exhibited a rapid disease response to ALK tyrosine kinase inhibitors alectinib with a complete remission of widespread metastatic disease and progression-free survival of more than 26 months, but not to darafenib plus trametinib targeted BRAF V600E therapy. Re-analyzed the patient's DNA-NGS original data, showed it is a rare and complex EML4-ALK (E13, A5, A20) fusion in fact. Additional RNA-NGS analysis showed it verified to be a canonical EML4-ALK (E13, A20) fusion transcript and coexisting with a BRAF V600E mutation.This case suggests that for patients with rare or complex EML4-ALK fusions at DNA level, additional RNA-NGS is necessary to verify its functionality as early as possible. Targeting EML4-ALK firstly may be more preferable despite the coexisting of BRAF V600E.