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 to 6% of lung cancers and confer sensitivity to ALK inhibitors (ALK-Tyrosine Kinase Inhibitors). However, acquired resistance inevitably develops through multiple mechanisms, limiting the durability of treatment response. We present 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. This report details the molecular evolution of the tumor, from the initial diagnosis to treatment failure. It 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 TKI therapy, this is the first documented case describing such extensive KRAS mosaicism upon failure of alectinib treatment. It 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.