Abstract
Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. Of particular interest are cases with off-target resistance, for example MET, HER2 or KRAS alterations, which require special therapeutic maneuvers, e.g., inclusion in early clinical trials or off-label administration of respectively targeted drugs. On the other hand, up to approximately half of the patients failing TKI, develop anatomically restricted progression, which can be initially tackled with local ablative measures without switch of systemic therapy. Among the overall biologically favorable ALK+ tumors, with a mean tumor mutational burden uniquely below 3 mutations per Mb and the longest survival among NSCLC currently, presence of the EML4-ALK fusion variant 3 and/or TP53 mutations identify high-risk cases with earlier treatment failure and a need for more aggressive surveillance and treatment strategies. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a currently a matter of intense investigation. Major pharmaceutical challenges for the field are the development of more potent, fourth-generation TKI and effective immuno-oncological interventions, especially ALK-directed cell therapies, which will be essential for further improving survival and achieving cure of ALK+ tumors.
Highlights
0.5 (Table 1), as well as an even larger advantage regarding intracranial disease control, with a rate of brain progression 20% annually for crizotinib (Table 2) [1,5]. If these drugs are given after crizotinib, they lose most of their systemic efficacy, with a PFS drop of 17 months for alectinib [13,14] and >12 months of brigatinib [15,16], which is longer than the entire first-line PFS of crizotinib (Table 1)
Even though the FLAURA, ALEX and ALTA-1L studies had included only patients with asymptomatic brain lesions (Table 2), real-world data suggest that the same principles probably hold true for large (>1 cm) or symptomatic brain metastases, as well: a retrospective analysis of such tumors treated with alectinib in the routine setting showed an efficacy comparable to that observed with
It is remarkable that longitudinal changes of the tMAD reflect the tumor remission status similar to longitudinal single-nucleotide variants (SNV) changes, and can be used for non-invasive disease monitoring in patients without detectable point mutations in circulating tumor DNA (ctDNA) [72,91]
Summary
The positive results of the ALEX study marked the begin of a new era in the treatment of anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC). Pharmaceuticals 2021, 14, 80 to crizotinib, second-generation TKI are more selective and have lower half-maximal inhibitory concentrations (IC50) for the native ALK kinase, cover more ALK resistance mutations, and show better central nervous system (CNS) penetration (Figure 1c) [7,8,9]. PFS of sequential treatment with first-line crizotinib followed by alectinibTKI or brigatinib [12,13,14,15,16,17], upfront osimerthe approval status of next-line is not tied tosomething specificwhich molecular results, like presence of tinib cannot demonstrate vs the sequence afatinib-osimertinib [11,18]; and second, the EGFR T790M in patients failing EGFR inhibitors. Next-generation ALK inhibitors show higher potency against the native ALK oncoprotein, broader coverage against ALK resistance mutations, and improved CNS penetration [7,8,9]
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