Association between circulating tumor DNA burden and disease burden in patients with ALK-positive lung cancer

Plasma genotyping is an emerging approach for the identification of genetic alterations mediating resistance to ana-plastic lymphoma kinase (ALK)–targeted therapy. The authors reviewed plasma genotyping and imaging findings to assess the correla-tion between circulating tumor DNA (ctDNA) burden and disease burden in patients with ALK-positive lung cancer. The authors analyzed 97 plasma specimens from 75 patients with ALK-positive lung cancer to identify ALK and non-ALK alterations. In patients with ALK-positive lung cancer, the maximum plasma alteration AF and maximum ALK alteration AF correlate with the extrathoracic burden of disease and are more predictive of tumor burden com-pared with the ALK fusion AF alone. READ ARTICLE

Cancer DOI:10.1002/cncr.33118

Authors: Eric W. Zhang , Ibiayi Dagogo-Jack MD, Anderson Kuo MD, PhD, Marguerite M. Rooney BSc, Alice T. Shaw MD, PhD, Subba R. Digumarthy MD

Real-World OutcomesKirk SmithAugust 5, 2021ALK-positive lung cancer, circulating tumor DNA (ctDNA), plasma genotyping, surveillance imaging, tumor burden

Structural and functional analysis of lorlatinib analogs reveals roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

The treatment approach to advanced, ALK-positive non-small cell lung cancer (NSCLC) utilizing sequential ALK tyrosine kinase inhibitors (TKIs) represents a paradigm of precision oncology. Lorlatinib is currently the most advanced, potent and selective ALK tyrosine kinase inhibitor (TKI) in the clinic. However, tumors invariably acquire resistance to lorlatinib, and after sequential ALK TKIs culminating with lorlatinib, diverse refractory compound ALK mutations can emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations identified in patients after treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. By assessing a panel of lorlatinib analogs against compound ALK mutant in vitro and in vivo models, we identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R- versus I1171N/S/T-based compound ALK mutations. Structural analysis revealed that increased potency against compound mut..... READ ARTICLE

BioRxiv DOI:10.1101/2021.07.16.452681

Authors: Aya Shiba-Ishii, Ted W Johnson, Ibiayi Dagogo-Jack, Mari Mino-Kenudson, Theodore R Johnson, Ping Wei, Scott L Weinrich, Michele A McTigue, Makeba A Walcott, Linh Nguyen-Phuong, Kristin Dionne, Adam Acker, Lesli Kiedrowski, Andrew Do, Jennifer L Peterson, Jaimie L Barth, Beow Y Yeap, Justin F Gainor, Jessica J Lin, Satoshi Yoda, Aaron N Hata

Pre-Clinical, group4Kirk SmithJuly 16, 2021Structural and functional analysis, lorlatinib analogs, compound resistance mutations, ALK-positive lung cancer