Abstract: ALK rearrangements account for ∼ 5% of non-small-cell lung cancer (NSCLC). Numerous rearrangement partners have been discovered. Here, we describe a 53-year-old nonsmoker with NSCLC, in whom we identified four novel rearrangements. The patient was diagnosed as adenocarcinoma in the right middle lobe of lung, with metastases in subcarinal lymph node, ipsilateral lung, pleura and contralateral rib (cT4N2M1, stage IV). Next-generation sequencing (NGS) identified three baseline ALK  fusions: COX7A2L–ALK  (C[intragenic]:A20), LINC01210–ALK  (L[intergenic]:A20) and ATP13A4–ALK  (A9:A19). The patient exhibited 12 months of progression-free survival (PFS) and a partial response (PR) to first-line crizotinib therapy. We then discovered a new SLCO2A1–ALK  fusion (S[intergenic]:A18) and a missense mutation C1156Y after resistance developed. Sequential ceritinib resulted in further 8 months of PFS, after which NGS results demonstrated the loss of ATP13A4–ALK  and SLCO2A1–ALK . This is the first description a NSCLC patient harbors four ALK  fusions and was sensitive to tyrosine kinase inhibitors (TKIs). Acquisition and loss of ALK  fusions after ALK  inhibitors may account for resistance.
Keywords: NSCLC, intergenic ALK , intragenic ALK , non-EML4–ALK , target therapy