Next-Generation Sequencing Reveals a Novel NSCLC ALK F1174V Mutation and Confirms ALK G1202R Mutation Confers High-Level Resistance to Alectinib (CH5424802/RO5424802) in ALK-Rearranged NSCLC Patients Who Progressed on Crizotinib

Abstract

Acquired secondary mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients who developed disease progression while on crizotinib treatment. Here, we identified a novel secondary acquired NSCLC ALK F1174V mutation by comprehensive next-generation sequencing in one ALK+ NSCLC patient who progressed on crizotinib after a prolonged partial response to crizotinib. In a second case, we identified a secondary acquired ALK G1202R, which also confers resistance to alectinib (CH5424802/RO5424802), a second-generation ALK inhibitor that can inhibit ALK gatekeeper L1196M mutation in vitro. ALK G1202R is located at the solvent front of the ALK kinase domain and exhibits a high level of resistance to all other ALK inhibitors currently in clinical development in vitro. Comprehensive genomic profiling of resistant tumor is increasingly important in tailoring treatment decisions after disease progression on crizotinib in ALK+ NSCLC given the promise of second-generation ALK inhibitors and other therapeutic strategies.

ALK inhibitors in non-small cell lung cancer: the latest evidence and developments

“…Many other resistance mutations have been described [Sasaki et al 2011;Katayama et al 2012;Doebele et al 2012;Ignatius Ou et al 2014]. Moreover, copy number gains of the ALK fusion gene [Katayama et al 2011] and bypass track activation involving NSCLC drivers such as EGFR, c-KIT and KRAS [Sasaki et al 2011;Doebele et al 2012;Katayama et al 2012] have been reported.…”

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

“…However, ceritinib inhibits I1171T [136]. G1202R is an acquired mutation that drives crizotinib resistance but has also been demonstrated to confer high-level in vitro and in vivo resistance to alectinib and ceritinib [137]. A case of MET amplification has been reported in an alectinib-resistant tumor.…”

“…Other acquired ALK kinase mutations that confer resistance to crizotinib include C1156Y, L1152R, I1171T, S1206Y, F1174L and G1269A [131,[133][134][135][136]. The G1202R crizotinib-resistance mutation also confers resistance to second generation ALK TKIs [137]. Increase in ALK copy number has also been demonstrated in patients who develop crizotinib resistance [132].…”

Identification of a novel inherited ALK variant M1199L in the WNT type of medulloblastoma

“…This variant may be linked to the ALK inhibitors resistance since the contact maintained by methionine residue M-1199 is most important for the effective binding and stability of the ALK-crizotinib complex [19]. The neighbouring region includes also the sites of secondary acquired ALK alterations L1996M and L1998P in EML4-ALK fusion positive lung cancers which confer resistance to crizotinib, and G1202R, which confers resistance to a second-generation ALK inhibitor alectinib and other ALK inhibitors [4,7,14,15]. Therefore, a precise character of the detected variant is critical for further therapeutic considerations.…”