An advanced NSCLC patient with and fusions treated with -TKI combination therapy: a case report.

Background: Anaplastic lymphoma kinase () rearrangement is one of the most important drivers in non-small cell lung cancer (NSCLC). Despite the effectiveness to canonical 3'- fusions, the clinical efficacy of ALK inhibitors in patients with complex fusions, such as nonreciprocal/reciprocal translocation remains uncertain. Exploring the optimal therapeutic regimens for this subset of patients is of crucial clinical significance.

Case Description: We reported a female patient diagnosed with stage IVB lung adenocarcinoma (LUAD) harboring a novel fusion, concurrent with a Huntingtin-interacting protein 1 ()-ALK fusion and a loss-of-function variant. The patient sequentially received multiple lines of treatment with -tyrosine kinase inhibitor (TKI), chemotherapy, radiotherapy and -TKI combined with anti-angiogenesis. Disease progression accompanied by a squamous cell carcinoma transformation was indicated after -TKI combined with anti-angiogenesis and both and fusions were retained in the tumor. The patient was subsequently treated with a third generation -TKI, lorlatinib, in combination with albumin-bound paclitaxel and anlotinib, and then achieved stable disease. The patient remained on the treatment as of the last follow-up resulting in an overall survival (OS) of more than 18 months.

Conclusions: We have reported an advanced NSCLC patient with a complex nonreciprocal/reciprocal translocation containing a novel fusion, concurrent with a loss-of-function mutation, who subsequently experienced pathological squamous cell carcinoma transformation. The combined treatment with -TKI, chemotherapy, and anti-angiogenesis demonstrates clinical efficacy and may provide optional therapeutic strategies for this phenotype.