The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer

Abstract

The treatment of metastatic non-small cell lung cancer (NSCLC) has undergone a paradigm shift over the last decade. Better molecular characterization of the disease has led to the rapid improvement of personalized medicine and the prompt delivery of targeted therapies to patients with NSCLC. The discovery of the EML4-ALK fusion gene in a limited subset of patients affected by NSCLC and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistances regularly develop, hence disease progression occurs. Afterward, modern tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, and lorlatinib, have been approved by the Food and Drug Administration (FDA) for the management of anaplastic lymphoma kinase (ALK)-positive NSCLCs. Several compounds are currently under investigation to achieve the optimal strategy of therapy. Additionally, the results of ongoing clinical trials with novel-generation TKI will provide more evidence on the best sequence in the treatment of ALK-positive NSCLC patients. In this review, we provide a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized.

Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK-Rearrangement Positive Advanced Non-Small Cell Lung Cancer in Asian and Non-Asian Patients: A Systematic Review and Network Meta-Analysis

“…lorlatinib will be the most beneficial to patients. A better understanding of the molecular biology and clinical aspects of cancers with ALK rearrangement is needed to determine the best treatment strategy [81]. Additional studies, including analysis of accumulated data from future large-scale, direct comparison RCTs, will therefore be required.…”

Novel MRPS9-ALK Fusion Mutation in a Lung Adenocarcinoma Patient: A Case Report

“…Although higher ALK VAF may suggest a better response of ALK-TKI treatment in theory, interestingly, correlation between ALK expression levels and alectinib penetration in the tumor was not observed early after the administration of single dose in neuroblastoma xenografts ( 33 ). Further investigation on revealing the correlation between VAF and high CNS penetrance of alectinib may benefit the better clinical application of alectinib at an individualized level ( 34 ).…”

Multiplexed electrokinetic sensor for detection and therapy monitoring of extracellular vesicles from liquid biopsies of non-small-cell lung cancer patients

“…A key benefit of liquid biopsies is the ability to follow cancer patients during their treatments, thereby guiding the clinician with effective therapy choices such as precision cancer medicine agents or immune checkpoint inhibitors (ICI). This is important also in NSCLC, where EGFR-TKI, ALK-TKI or PD-1/PD-L1 immune therapy have changed the treatment landscape, however responses of patients are often heterogenous (Abdel Karim and Kelly, 2019;Gristina et al, 2020;Lazzari et al, 2020). In clinical settings, circulating/cell-free DNA is partially used as a biomarker (BM) for evaluating treatment response when tumor biopsy is not feasible (Rolfo et al, 2018).…”