Treating ALK-positive non-small cell lung cancer

Abstract

Targeting genomic alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements, have radically changed the treatment of patients with non-small cell lung cancer (NSCLC). In the case of ALK-rearranged gene, subsequent rapid development of effective genotype-directed therapies with ALK tyrosine kinase inhibitors (TKIs) triggered major advances in the personalized molecularly based approach of NSCLC. Crizotinib was the first-in-class ALK TKI with proven superiority over standard platinum-based chemotherapy for the 1st-line therapy of ALK-rearranged NSCLC patients. However, the acquired resistance to crizotinib and its diminished efficacy to the central nervous system (CNS) relapse led to the development of several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib. To date, four ALK TKIs, crizotinib, ceritinib, alectinib and brigatinib have received approval from the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) and even more agents are currently under investigation for the treatment of ALK-rearranged NSCLC. However, the optimal frontline approach and the exact sequence of ALK inhibitors are still under consideration. Recently announced results of phase III trials recognized higher efficacy of alectinib compared to crizotinib in first-line setting, even in patients with CNS involvement. In this review, we will discuss the current knowledge regarding the biology of the ALK-positive NSCLC, the available therapeutic inhibitors and we will focus on the raised issues from their use in clinical practise.

Real World Experience of Crizotinib in 104 Patients With ALK Rearrangement Non-small-cell Lung Cancer in a Single Chinese Cancer Center

“…Although a significant benefit can be achieved in the management of ALK -positive NSCLC with crizotinib, it is worth noting that a substantial risk of central nervous system (CNS) progression inevitably exists (13, 29). The patients with ALK -positive NSCLC have a high risk of developing CNS metastasis, as observed in ~30% of cases at the time of tumor diagnosis and in 50–60% of patients during crizotinib treatment (30). Our study analyzed brain metastases and progression pattern and found that brain metastases occurred in 32.7% of patients (34 of 104) with PD at the time of data cutoff during crizotinib therapy.…”

Gingival Metastasis of ALK Rearranged Non-Small Cell Lung Cancer

“…Rearrangements of ALK gene accounts for approximately 3–7% of NSCLC patients with higher rates observed in younger, never or light smokers of adenocarcinoma [4]. Rapid development of targeted therapies for advanced ALK rearranged NSCLCs have shown higher response and longer response duration than cytotoxic chemotherapy.…”

“…Approximately 3–7% of patients with NSCLC have ALK rearrangement [4]. Targeted therapy for advanced ALK rearranged NSCLC have been developed and show a higher response and longer response duration than cytotoxic chemotherapy, by the first-generation ALK inhibitor, crizotinib and the second-generation, alectinib and ceritinib.…”

Molecular findings reveal possible resistance mechanisms in a patient with ALK-rearranged lung cancer: a case report and literature review

“…This particular translocation leads to oncogenic transformation of the cell through a constitutively active ALK kinase and can be effectively targeted through the available tyrosine kinase inhibitors (TKI). Despite a greater efficacy of targeted ALK inhibitorscompared with standard chemotherapy, development of acquired resistance is often a matter of time and disease progression is imminent 4. Therefore, identification of resistance mechanisms after targeted inhibition of the EML4-ALK fusion oncogene is crucial for designing an effective sequential treatment strategy.…”