Outcome of two patients harboring EML4-ALK fusion gene with brain metastasis treated with crizotinib

Abstract

Background: Although ALK inhibitors have shown high efficacy for lung cancer with EML4-ALK fusion gene, it is unknown whether they have equivalent efficacy for carcinomatous meningitis or brain metastasis. We report 2 patients with EML4-ALK fusion gene positive lung cancer treated by crizotinib. Patient 1: 61-year-old male. In June 2012, he underwent right lower lobe resection and adjuvant chemotherapy for stage IIA lung adenocarcinoma. In December, his cancer recurred with brain metastases and carcinomatous meningitis. In January 2013, he underwent whole brain radiation therapy. Despite the treatment, his symptoms such as diplopia and incontinence gradually got worse. Crizotinib was prescribed on late February, which lead to improve his symptoms and reduce brain metastasis. Cytology of spinal fluid on day15 turned to negative. However, laboratory data on day 39 showed grade 3 liver enzyme elevation and crizotinib was discontinued. Although crizotinib was readministered after improvement of laboratory data, cytology returnd to positive and he died in May. The concentration of crizotinib in his blood was 158 ng/ml, and that in spinal fluid was 4.32 ng/ml on day 15. Patient 2: 71-year-old female. In October 2012, she was diagnosed stage IV lung cancer. After 4 cycles of chemotherapy (carboplatin + paclitaxel + bevacizumab), in May 2013 the disease progressed and crizotinib was initiated. Although pulmonary lesion got smaller, brain lesion did not. In February 2014, brain lesion increased and she underwent whole brain radiation therapy. After improvement of performance status, she started to take alectinib in September. Brain MRI in October showed response of brain lesion. Conclusion: Crizotinib concentration in spinal fluid was lower than that in blood. We need to investigate whether a novel ALK inhibitors can overcome acquired ALK resistance, can cross the blood-brain barrier, and are well tolerated.