How to select the best upfront therapy for metastatic disease? Focus on ALK-rearranged non-small cell lung cancer (NSCLC)

Abstract: Anaplastic lymphoma kinase (ALK) inhibitors have demonstrated robust clinical activity in patients with ALK-rearranged lung cancers. The echinoderm microtubule-associated protein-like (EML)-ALK translocation was first discovered in 2007 and 4 years later, crizotinib, a first-generation ALK inhibitor was approved. Since then, subsequent generations of ALK inhibitors have demonstrated superior efficacy and better CNS activity compared to crizotinib. Alectinib and brigatinib, both second-generation ALK inhibitors have been compared directly to crizotinib in the first-line setting and has demonstrated improved progression free survival (PFS) and intracranial response. Ceritinib, another second-generation ALK inhibitor has been shown to be superior to chemotherapy in ALK-rearranged disease with good CNS activity. Initial responses to ALK inhibitors are not always durable and resistance can occur as on-target or off-target alterations. Lorlatinib, a third-generation ALK inhibitor, has demonstrated activity in the treatment naïve setting and in resistance to crizotinib and second-generation ALK inhibitors. Lorlatinib has also shown improved PFS in patients harboring EML4-ALK variant 3, which is associated with the development of ALK resistance mutations, specifically G1202R. Another new ALK inhibitor, ensartinib, has demonstrated efficacy in the first-line setting and in alectinib refractory disease. Additional studies are underway examining mechanisms of resistance and best treatment options post resistance.