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How might treatment of ALK-positive non-small cell lung cancer change in the near future?

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (TK) encoded by the ALK gene on chromosome 2p23. In 2007, an oncogenic fusion protein deriving from a rearrangement between the echinoderm microtubule-associated protein-like 4 (EML-4) gene and the ALK gene was first identified in nonsmall cell lung cancer (NSCLC) by Soda et al. [1]. Ever since, it became evident that ALK rearrangements are present in 4–5% of patients with NSCLC and consist of either inversions or translocations of exon 20 to 29 of ALK fused to a varying proportion of EML-4 [2]. On this basis, highly effective small molecules ALK-TK inhibitors (-TKIs) have been developed, with crizotinib being the first approved agent by both FDA and EMA for the treatment of ALK-rearranged (ALK-positive), advanced NSCLC [2]. More recently, next-generation ALK-TKIs such as ceritinib and alectinib have demonstrated efficacy in ALK-positive NSCLCs pretreated with crizotinib, which has led to their approval by FDA (ceritinib and alectinib) and EMA (ceritinib) for patients who are resistant or intolerant to crizotinib [3–5]. Therefore, at the present time, crizotinib followed by either ceritinib or alectinib appears to be the optimal treatment of ALK-positive advanced NSCLC. Importantly, phase III randomized studies are ongoing in order to evaluate whether a next-generation ALK-TKI could replace crizotinib in the up-front setting. This approach might overcome some of the limitations associated with crizotinib, among which the onset of resistance, either primary or acquired, as well as the modest activity shown by crizotinib on central nervous system (CNS) metastases. Here, we will briefly discuss these topics, focusing on how ceritinib, alectinib, and other novel ALK-TKIs represent an advance in therapeutic armamentarium of ALKpositive NSCLC, also suggesting how treatment landscape may change in the near future. Primary resistance to crizotinib is an important issue in ALKpositive NSCLCs. From the PROFILE 1014 trial, in which untreated ALK-positive NSCLCs were randomized to crizotinib or platinum-pemetrexed chemotherapy, we know that the overall response rate (ORR) to up-front crizotinib is 74% [6]. Importantly, all patients enrolled into this trial had central confirmation of ALK rearrangement by fluorescence in situ hybridization (FISH) analysis. Therefore, the reason why not all of them responded to crizotinib in PROFILE 1014 could be partly due to problems of false-positivity, as FISH analysis requires great expertise (ALK-negative cells can appear FISH positive owing to stochastic and isolated genomic alterations or artifact and/or because of difficulties in the correct identification of tumor cells in dark-field microscopy among a stroma of normal/inflammatory cells) [7]. For this reason, FISH test should be integrated with other techniques such as immunohistochemistry and/or reverse transcription polymerase chain reaction (RT-PCR) in order to better identify ALKpositive patients candidate to crizotinib. On the other hand, primary resistance to crizotinib can be also due to inadequate inhibition of the target by crizotinib, With regard to this, nextgeneration ALK-TKIs such as ceritinib and alectinib may represent a way to overcome this problem, as they have been shown preclinically to be far more potent than crizotinib against ALK kinase, with IC50 of 0.2 and 1.9 nM in cell-free assays, respectively [8,9]. Therefore, their up-front use instead of crizotinib could reduce the occurrence of primary resistance to ALK-targeted therapy, and clinical reports in which patients responded to ceritinib despite primary resistance to crizotinib have already been reported [10,11]. However, understanding primary resistance to crizotinib requires an extensive study of each peculiar ALK gene alteration. Recently, a study conducted on a small sample series of crizotinib-treated patients suggested that some rarer ALK fusion variants (as assessed by RTPCR) could be less prone to respond to treatment, which implies that the type of ALK variant should be more thoroughly investigated in relation to sensitivity to ALK-TKIs [12]. As for acquired resistance, median progression-free survival to first-line crizotinib has been reported to be 10.9 months in the PROFILE 1014 trial [6], which means that most patients will eventually progress within 1 year of treatment initiation. Biologically acquired resistance is mediated by a variety of different mechanisms, including secondary mutations within the ALK-TK domain, copy number gains of the ALK fusion gene, and activation of alternative bypass pathways [2]. Importantly, next-generation ALK-TKIs have the potential to