Therapeutic Sequencing in ALK+ NSCLC

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.

Keywords: ALK+ non-small-cell lung cancer; EML4-ALK fusion variant 3, chemotherapy; sequential therapies; tyrosine kinase inhibitors.

Figure 2

Current algorithm for sequential use of systemic pharmaceuticals in ALK⁺ NSCLC. Details and the rationale are given in Section 2.1, Section 2.2, Section 2.3, Section 2.4 and Section 2.5. Footnotes: ¹ if no ALK mutation is detectable by molecular analysis of tissue or liquid rebiopsies, close monitoring with short-term restaging after ≤ 6 weeks is warranted, in order to ensure timely switch to chemotherapy if there is no response; ² a trial of brigatinib after lorlatinib for patients who did not receive brigatinib as first-line treatment in order to prolong chemotherapy-free time, based on the results of the international EAP, with a median duration of treatment 7.5 months for the lorlatinib-pretreated cohort [70]. EAP: extended access program.

Figure 1

(a) Molecular pathogenesis of ALK⁺ NSCLC: In approximately 90% of cases, a paracentric inversion in the short arm of chromosome 2 [inv(2)(p21p23)] creates the fusion oncogene EML4-ALK, which facilitates overexpression of the ALK exons 20–29 under the influence of the EML4 promoter, and their autophosphorylation due to the trimerization domain (TD) of EML4 [6]. In the remaining 10% of cases, a different partner gene is fused with ALK and triggers similar pathophysiologic effects. (b) The length of the EML4 component can differ between patients, with 90% harboring EML4-ALK fusion variant 1, 2 or 3. Shorter variants (mainly variant 3, aka V3, E6:A20, present in 30–35% of cases) have higher stability, accumulate more and interact better with the cytoskeleton, causing stronger oncogenic signaling, reduced sensitivity to ALK inhibitors, enhanced migration and metastasis [20,21,22,23,24]. (c) Approval timeline of currently available ALK inhibitors, along with their respective first-line phase 3 trials. 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].