Emergence of KRAS mosaicism with multiple variants during treatment with alectinib in ALK-positive metastatic non-small cell lung cancer: A case report.

ALK fusions occur in 3-6% of lung cancers and confer sensitivity to ALK-tyrosine kinase inhibitors. However, acquired resistance inevitably develops through multiple mechanisms, limiting the durability of the treatment response. The present report describes the case of a 36-year-old man with ALK-rearranged lung adenocarcinoma treated with the second-generation ALK-tyrosine kinase inhibitor alectinib. At the time of disease progression, molecular analysis revealed the emergence of a KRAS mosaicism. The present report details the molecular evolution of the tumor, from the initial diagnosis to treatment failure. The current report illustrates a compelling mechanism of resistance to ALK inhibition driven by the synchronous emergence of multiple KRAS variants. While previous case reports have documented an isolated KRAS mutation as a potential resistance mechanism to ALK-tyrosine kinase inhibitor therapy, to the best of our knowledge, this is the first report describing such extensive KRAS mosaicism upon failure of alectinib treatment. The present report highlights the importance of reevaluating the molecular profile of the cancer at the time of progression to accurately define the resistance pathway and develop rational therapeutic strategies capable of overcoming this resistance.