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    • An important observation is that this patient has

    2023-02-13

    An important observation is that this patient has been on ALK inhibitor for more than 4 years (51 months: 27 months on crizotinib+24 months on alectinib and on-going) and there was no evidence of disease progression in the central nervous system. The other potential driver mutation in this patient’s tumor sample is the truncation of beta-catenin at amino 1568 acid residue 45 (CTNBB1 S45del). Whether CTNBB1 S45del may eventually turn out to suppress brain metastasis remained to be determined. Hence while CGP is being performed on CNS metastasis from NSCLC patients to identify factors that predispose CNS metastasis, it may be equally important to perform CGP to identify long-term NSCLC survivors who did not have CNS metastasis/progression. In summary, this is the first report that F1174V is sensitive to alectinib and confirmed that I1171 missense mutation is resistant to alectinib [10]. This is the converse of what has been reported for ceritnib [5]. Hence identifying acquired ALK resistance mutations will likely help guide the use of second generation ALK inhibitors. It also illustrates the importance of continual development of structurally distinct ALK inhibitors to overcome various acquired resistance.
    Conflict of interest
    Introduction The chromosomal rearrangements of ALK gene encoding the continuously activated anaplastic lymphoma kinase (ALK) fusion protein occur in a variety of human malignancies, including non-small cell lung cancers (NSCLCs) [1], anaplastic large cell lymphoma (ALCL) [2], and inflammatory myofibroblastic tumor (IMT) [3]. As to NSCLCs, the fusion of ALK with echinoderm microtubule-associated protein-like 4 (EML4) represents one of the most frequent fusion oncogenes, accounting for 3–5% NSCLC patient populations [1,4]. The oncogenic driving character of this fusion protein was essentially recognized by the FDA's approval of the first-generation ALK inhibitor crizotinib (1) in 2011 as a standard first-line therapy for advanced ALK-positive NSCLCs [5]. This compound has demonstrated clear clinical benefit, with responses observed in 60–74% of ALK positive NSCLCs, although the majority of patients develop disease relapse within one year of post-treatment due to occurrence of the acquired drug resistance [6]. ALK gene amplification, secondary mutations and bypass pathways activation are the primary mechanisms of acquired resistance to crizotinib [7]. Clinically, over a dozen of on-target secondary ALK mutations have been identified in crizotinib resistant patients, including L1196M (gatekeeper mutation), G1269A, F1174L, S1206Y, 1151T-ins, L1152R, C1156Y, G1202R, and among others [[8], [9], [10]]. Shortly after, several structurally distinct small molecules have been developed as the new-generation ALK inhibitors to overcome the acquired resistance, including the early launched alectinib (2) [11,12] and ceritinib (3) [13], the recently launched brigatinib (4) [14,15], and the phase III investigational drug lorlatinib (5) [16] (Fig. 1). All these new inhibitors showed promising in vitro, in vivo and clinical efficacy against many crizotinib resistant mutants, but their capability to overcome the recalcitrant G1202R mutation was distinctively different. The ALK G1202R mutation appeared in 2% of crizotinib resistant patients, and was invalid to respond to the two already launched second-generation inhibitors alectinib (2) and ceritinib (3) [[17], [18], [19]]. It was found that the frequency of G1202R mutation was significantly increased to 21–43% in patients who experienced progression during treatment with these two second-generation ALK inhibitors [8,19]. The recently launched inhibitor brigatinib and the clinical investigational candidate lorlatinib are characterized as the third-generation ALK inhibitors since they are active against the G1202R mutant, however their potency against this mutant was substantially less potent than that against the native ALK kinase [15,16]. Therefore, development of novel ALK inhibitors, in particular with enhanced potency against the challenging G1202R mutation is highly needed.