The efficacy of lorlatinib in a lung adenocarcinoma patient with a novel ALK G1202L mutation: a case report

Report reveals the efficacy of lorlatinib in targeting ALK G1202L and can serve as an option for the clinical management of patients with ALK-rearranged lung adenocarcinoma after acquiring G1202L-mediated resistance from prior ALK inhibitor therapy. Furthermore, it demonstrates the sequential use of crizotinib, brigatinib, and lorlatinib in a patient with advanced ALK-rearranged lung adenocarcinoma with an overall progression-free survival of 33.3 months for the sequential ALK inhibitor regimens. His overall survival was 41.5 months inclusive of all regimens. READ ARTICLE

Cancer Biology & Therapy DOI: 10.1080/15384047.2020.1836947

Authors: Zhaoting Meng, Ting Li, Pei Wang, Analyn Lizaso, Dingzhi Huang

Case StudyKirk SmithDecember 30, 2020TKI Resistance, Lorlatinib, ALK-rearranged NSCLC, ALK G1202L, sequential, ALK inhibitor

A Novel Sequentially Evolved EML4-ALK Variant 3 G1202R/S1206Y Double Mutation In Cis 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 ALK resistance mutations, including the solvent-front mutation G1202R. Here, we report, for the first time, a novel, sequentially-evolved EML4-ALK variant 3 G1202R/S1206Y double mutation in cis detected in a patient with ALK-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 (ALK G1202R/L1196M, ALK G1202R/F1174C, ALK G1202R/l1198F, ALK 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 ALK mutations that are resistant to lorlatinib from both patient samples and in vitro mutagenesis experiments. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtocrr.2020.100116

Authors: Viola W. Zhu, Misako Nagasaka, Russell Madison, Alexa B. Schrock, Jean Cui, Sai-Hong Ignatius Ou

Review PaperKirk SmithNovember 1, 2020TKI Resistance, Resistance mutation