Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC

Background: The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2–7% of lung adenocarcinomas, with higher incidence (17–20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown. Methods: We report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with ..... READ ARTICLE

Journal of Personalized Medicine DOI:10.3390/jpm10030107

Authors: László Urbán, Róbert Dóczi, Barbara Vodicska, Dóra Kormos, László Tóth, István Takács, Edit Várkondi, Dóra Tihanyi,Dóra Lakatos, Anna Dirner, István Vályi-Nagy, István Peták

Real-World OutcomesKirk SmithAugust 28, 2020NSCLC, ALK rearrangement, TP53 mutation, TKI, personalized treatment

Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC

More than 10 EML4-ALK variants based on the exon breakpoints in EML4 have been identified. Unlike other receptor tyrosine kinase fusion positive NSCLC such as ROS1 or RET fusion, EML4-ALK is the dominant fusion variant in ALK+ NSCLC accounting for approximately 85 % of all fusion variants in ALK+ NSCLC. Currently, eight EML4-ALK variants are generally recognized with a number (1, 2, 3a/b, 4′, 5a/b, 5′, 7, 8) with EML4-ALK variants 1 and 3 being the two most common variants accounting for 75–80 % of the total EML4-ALK variants. Preclinical, retrospective analyses of institutional databases, and global randomized phase 3 trials have demonstrated differential clinical response (overall response rate, progression-free survival) to ALK tyrosine kinase inhibitors (TKIs) between the “short” (v3 and v5) and “long” (v1, v2, v5′, v7, and v8) EML4-ALK variants. We discuss in more details how EML4-ALK variant structure influences protein stability and response to ALK TKIs. Additionally, the most recalcitrant single solvent-front mutation ALK G1202R is more prone to develop among EML4-ALK v3 following sequential use of next-generation ALK TKIs. Furthermore, TP53 mutations being the most common genomic co-alterations in ALK+ NSCLC also contribute to the heterogeneous response to ALK TKIs. Recognizing ALK+ NSCLC is not one homogeneous disease entity but comprised of different ALK fusion variants with different underlying genomic alterations in particular TP53 mutations that modulate treatment response will provide insight into the further optimization of treatment of ALK+ NSCLC patients potentially leading to improvement in survival. READ ARTICLE

Lung cancer DOI: 10.1016/j.lungcan.2021.06.012

Authors: Shannon S. Zhang, Misako Nagasaka, Viola W. Zhu, Sai-Hong Ignatius Ou

Review PaperKirk SmithJune 1, 2020EML4-ALK variant 1, EML4-ALK variant 3, ALK TKI, protein stability, ALK+ NSCLC, TP53 mutation