Novel ALK mutation with durable response to brigatinib—a case report

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors are the preferred initial treatment for ALK rearranged non-small cell lung cancer (NSCLC). While initial responses to next-generation inhibitors are robust, acquired resistance is expected for nearly all patients. Resistance is often mediated by point mutations along the solvent front. Use of the acquired mutational profile to guide therapy is still investigational and largely based on preclinical data demonstrating sensitivity of resistant cell lines to available kinase inhibitors. Here, we describe outcomes after development of an ALK L1196Q mutation. We present a patient with stage IV ALK rearranged lung cancer received who received first line crizotinib at 250 mg twice daily, then at progression, second line alectinib at 600 mg twice daily. When radiographic evidence of progression was noted, a biopsy was performed. Next generation sequencing (NGS) identified an acquired ALK L1196Q mutation. The patient was treated with third line brigatinib, at 90 mg daily and escalating to 180 mg daily, and achieved a partial response that is still ongoing, one year later. We highlight false-negative ALK mutation results when only plasma is used, particularly in early metastatic disease. We also discuss how the use of specific ALK resistance mutations to guide therapy is clinically relevant is being investigated.