Targeting ALK Rearrangements in NSCLC: Current State of the Art

Abstract

Anaplastic lymphoma kinase (ALK) alterations in non-small cell lung cancer (NSCLC) can be effectively treated with a variety of ALK-targeted drugs. After the approval of the first-generation ALK inhibitor crizotinib which achieved better results in prolonging the progression-free survival (PFS) compared with chemotherapy, a number of next-generation ALK inhibitors have been developed including ceritinib, alectinib, brigatinib, and ensartinib. Recently, a potent, third-generation ALK inhibitor, lorlatinib, has been approved by the Food and Drug Administration (FDA) for the first-line treatment of ALK-positive (ALK+) NSCLC. These drugs have manageable toxicity profiles. Responses to ALK inhibitors are however often not durable, and acquired resistance can occur as on-target or off-target alterations. Studies are underway to explore the mechanisms of resistance and optimal treatment options beyond progression. Efforts have also been undertaken to develop further generations of ALK inhibitors. This review will summarize the current situation of targeting the ALK signaling pathway.

New update to the guidelines on testing predictive biomarkers in non-small-cell lung cancer: a National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

“…Outcomes, including survival, are dramatically improved with specific ALK TKIs and, at present, median overall survival for stage IV patients frequently exceeds 5 years. Crizotinib was the first drug approved in this context and, since then, second-(ceritinib, alectinib and brigatinib) and third-generation (lorlatinib) TKIs are available in the European Union for the treatment of untreated patients and for those following progression on prior inhibitors [13]. The benefit of individual drugs in these pretreated patients depends on the mechanism of resistance, which frequently involves acquired mutations in the ALK kinase [14].…”

Novel therapeutic strategies for rare mutations in non-small cell lung cancer

“…For example, the anaplastic lymphoma kinase ( ALK ) receptor gene is located on chromosome 2p23 and encodes a tyrosine kinase receptor. ALK fusions have been identified in approximately 5% of NSCLC patients, with the most common fusion partner being echinoderm microtubule-associated protein-like 4 ( EML4 ) 164 . Crizotinib, the first-generation ALK inhibitor, was approved by the FDA in 2011 for the treatment of ALK -positive NSCLC 165 .…”

Silibinin Suppresses the Hyperlipidemic Effects of the ALK-Tyrosine Kinase Inhibitor Lorlatinib in Hepatic Cells

“…The small macrocyclic compound lorlatinib (product name PF-06463922) is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) originally developed to inhibit ALK mutant forms causing resistance to first- and second-generation ALK-TKIs (e.g., crizotinib, ceritinib, alectinib or brigatinib) in patients with advanced non-small-cell lung cancer (NSCLC) [ 1 , 2 , 3 , 4 , 5 , 6 ]. Consistent with its broad ALK mutational coverage and optimized central nervous system penetration through the blood–brain barrier, lorlatinib has shown substantial systemic and intracranial activity both in treatment-naïve patients and in patients with relapse after first- and second-generation ALK TKIs [ 7 , 8 , 9 , 10 , 11 , 12 ].…”