The Landscape of ALK-Rearranged Non-Small Cell Lung Cancer: A Comprehensive Review of Clinicopathologic, Genomic Characteristics, and Therapeutic Perspectives

Abstract

During the last decade, the identification of oncogenic driver mutations and the introduction of tyrosine kinase inhibitors (TKIs) in daily clinical practice have substantially revamped the therapeutic approach of oncogene-addicted, non-small cell lung cancer (NSCLC). Rearrangements in the anaplastic lymphoma kinase (ALK) gene are detected in around 3–5% of all NSCLC patients. Following the promising results of Crizotinib, a first-generation ALK inhibitor (ALK-i), other second-generation and more recently third-generation TKIs have been developed and are currently a landmark in NSCLC treatment, leading to a significant improvement in patients prognosis. As clinical trials have already demonstrated high efficacy of each ALK-i, both in terms of systemic and intracranial disease control, comparative studies between second and third generation ALK-i are still lacking, and primary or secondary ALK-i resistance inevitably limit their efficacy. Resistance to ALK-i can be due to ALK-dependent or ALK-independent mechanisms, including the activation of bypass signaling pathways and histological transformation: these findings may play an important role in the future to select patients’ subsequent therapy. This review aims to provide an overview of underlying molecular alterations of ALK-i resistance and point out promising role of liquid biopsy in predicting tumor response and monitoring resistance mutations. The purpose of this review is also to summarize current approval for ALK-rearranged NSCLC patients, to help clinicians in making decisions on therapeutic sequence, and to deepen the role of clinicopathological and genomic characteristics influencing patients’ prognosis during treatment with ALK-i.

Multicenter evaluation of an automated, multiplex, RNA-based molecular assay for detection of ALK, ROS1, RET fusions and MET exon 14 skipping in NSCLC

“…To determine eligibility to therapy targeting ALK, ROS1, RET, or MET alterations [10][11][12][13], NSCLC treatment guidelines recommend testing for ALK, ROS1, RET fusions and MET exon 14 skipping [14,15]. Kinase fusions are usually detected using single-test methods like immunohistochemistry (IHC) for ALK fusions [15][16][17], and fluorescence in situ hybridization (FISH), which is the gold standard for detection of ALK and ROS1 fusions and to a lesser extent RET fusions [18,19], or multiplex test methods like Extended author information available on the last page of the article reverse-transcription polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) [20] as valuable alternatives to ALK, ROS1, and RET FISH and as the most effective detection methods for MET exon 14 skipping.…”

Spectrum of Resistance Mechanisms to ALK TKIs in NSCLC: Largest Single-Center Experience from India

“…While G1202 mutations have been reported to be common after second-generation ALK TKIs, in our study, this was not encountered as most cases were post-crizotinib. Secondary ALK mutations like L1196M and I1171T 20,21 have been shown to be sensitive to ceritinib and not alectinib. One patient subsequent to treatment with first-line alectinib, developed I1171T mutation, which has been reported to be sensitive to ceritinib.…”

Targeting ErbB and tankyrase1/2 prevent the emergence of drug tolerant persister cells in ALK fusion positive lung cancer

“…In ALK+ NSCLC, acquired resistance is an unmet need, and early and effective combination therapy in a first-line setting might prevent the occurrence of DTP state and treat the acquired resistance. Combination therapies of TKI with mitogen-activated protein kinase (MEK) inhibitors, angiogenesis inhibitors, and chemotherapy are being evaluated in Phase 1/1b/2 trials mostly in the second-line and beyond treatment settings for the treatment of ALK+ NSCLC; a few trials are also evaluating combination therapy in treatment-naive patients 33 .…”