After their seminal discovery of EML4-ALK variant 1 (v1) (E13:A20) and v2 (E20:A20) as a transforming driver mutation in NSCLC in 2007,1 Choi et al.2 went on to identify EML4-ALK v3 (E6:A20) in 2008 using reverse transcriptase-polymerase chain reaction. Two EML4-ALK v3 isoforms, v3a and v3b, which differs by an inclusion of a cryptic (exon EML4 6b) exon of 33 DNA base pairs into v3b, were identified together in two patients' samples... Currently, no combination therapy has been approved for the treatment of advanced ALK+ NSCLC despite our tremendous understanding of both on-target,17 and off-target resistances.18 The clinical approval of “double mutant active” ALK TKIs is at best years away with no guarantee that they will be developed to address the current unmet need of acquired double ALK mutations given that double mutations are only part of the spectrum of acquired resistances to ALK TKIs.19 The successful clinical development of six ALK TKIs globally leading to long-term surviva..... READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.11.010
Authors: Misako Nagasaka, Sai-Hong Ignatius Ou