A Novel Sequentially Evolved Variant 3 G1202R/S1206Y Double Mutation In Confers Resistance to Lorlatinib: A Brief Report and Literature Review.

Lorlatinib is a third-generation ALK inhibitor that can overcome the largest number of acquired resistance mutations, including the solvent-front mutation G1202R. Here, we report, for the first time, a novel, sequentially-evolved variant 3 G1202R/S1206Y double mutation in detected in a patient with -positive NSCLC after disease progression on sequential crizotinib, alectinib, and then lorlatinib. Three-dimensional computer modeling of this double mutation and other G1202R-based double mutations with lorlatinib ( G1202R/L1196M, G1202R/F1174C, G1202R/l1198F, G1202R/G1269A) were provided to reveal how these double mutations may confer resistance to lorlatinib through diverse steric hindrances in the ALK kinase domain. In addition, we performed a comprehensive literature review on published acquired double or triple mutations that are resistant to lorlatinib from both patient samples and in vitro mutagenesis experiments.