Effective Crizotinib Schedule for Brain Metastases in ALK Rearrangement Metastatic Non–Small-Cell Lung Cancer

Abstract

T he echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene fusion occurs in 2% to 7% of non-small-cell lung cancer cases. 1 Tumors expressing this fusion respond to treatment with crizotinib, an ALK tyrosine kinase inhibitor. However, brain metastases frequently occur, even in the presence of systemic response to therapy. 2

Targeted Therapy for Brain Metastases in EGFR-Mutated and ALK-Rearranged Non-Small-Cell Lung Cancer

“…49,84 Combination of crizotinib and elacridar (inhibitor of ABCB1/ABCG2 efflux transporters) was shown to increase plasma and brain concentrations of crizotinib in mice, 28 and this may be a promising approach in patients with ALK-positive NSCLC. Other approaches include use of high-dose crizotinib with WBRT 85 and use of high-dose crizotinib with chemotherapy, 86 but these approaches remain investigational and need further evaluation in clinical trial settings. Ceritinib.…”

Alectinib Induces a Durable (>15 Months) Complete Response in an ALK-Positive Non-Small Cell Lung Cancer Patient Who Progressed on Crizotinib With Diffuse Leptomeningeal Carcinomatosis

“…Another second-generation ALK inhibitor, AP26113, has also shown consistent CNS activity in crizotinib-resistant ALK-rearranged patients [11], but to date there is no report of single-agent AP26113 activity against leptomeningeal carcinomatosis arising in crizotinib-resistant patients with ALK-rearranged NSCLC. Other strategies that have been used to treat brain metastasis in patients with ALK-rearranged NSCLC, such as crizotinib with highdose systemic chemotherapy [12], once-daily dosing instead of twice daily [13], or high-dose cirizotinib [14], have not been reported in patients with leptomeningeal carcinomatosis.…”

Anaplastic lymphoma kinase rearrangement in lung Cancer: Its biological and clinical significance

“…With regard to CNG of the fusion gene, two of 11 ALK-positive lung cancer patients who acquired resistance to crizotinib were reported to exhibit new onset ALK CNG, which may occur in combination with resistance mutations [72]. The CNS lesions are currently considered to be a 'sanctuary' for crizotinib due to the inadequate penetration of the drug into the CNS system [73][74][75][76]. The ALK non-dominant mechanisms of resistance to crizotinib include mutations of other oncogenes, such as the EGFR and KRAS genes [72], amplification of the KIT gene [77], increased autophosphorylation of EGFR [77] and transformation to sarcomatoid carcinoma [78].…”