title: Durable brain response with pulse-dose crizotinib and ceritinib in ALK-positive non-small cell lung cancer compared with brain radiotherapy.
abstract: Crizotinib achieves excellent systemic control in anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC); however, central nervous system (CNS) metastases frequently occur as an early event. Whole brain irradiation, the standard treatment, results in neurocognitive impairment. We present a case series of three ALK+ NSCLC patients with progressing CNS metastases who were treated with pulse-dose crizotinib followed by ceritinib. Three ALK+ NSCLC patients treated between 2011 and 2014 (two males, two never smokers, age range 20-54years, all echinoderm microtubule-associated protein-like 4/ALK rearrangement), were diagnosed with progressing cerebral disease while receiving crizotinib. Clinico-pathological characteristics, treatments, and outcomes were analyzed. In two patients the progression was limited to the CNS, and radiological evidence of leptomeningeal spread was present in one patient. Sequential use of crizotinib 500mg administered once daily (pulse-dose) followed by ceritinib on progression achieved control of the disease in the CNS for over 18 months and over 7 months in Patient 1 and Patient 2, respectively. This strategy provided durable CNS control after whole-brain radiotherapy failure in Patient 1, and allowed the whole-brain radiotherapy to be deferred in Patient 2. Limited CNS progression was documented in Patient 3 while he was on standard-dose/pulse-dose crizotinib for 15months; durable (over 7 months) complete remission was achieved with stereotactic radiotherapy and ceritinib. Manipulating the crizotinib schedule in ALK+ NSCLC patients with CNS metastases and using a novel ALK-inhibitor at the time of further progression may provide durable CNS control and allow brain radiotherapy to be deferred.
authors.affiliation: Thoracic Cancer Unit, Davidoff Cancer Center, Rabin Medical Center, Kaplan Street, Petah Tikva 49100, Israel.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dudnik
authors.affiliation: Center for Neuro-Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Siegal
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel; Radiation Institute, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Leor
authors.initials: L
authors.lastname: Zach
authors.affiliation: Thoracic Cancer Unit, Davidoff Cancer Center, Rabin Medical Center, Kaplan Street, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Allen
authors.affiliation: Thoracic Cancer Unit, Davidoff Cancer Center, Rabin Medical Center, Kaplan Street, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: Dov
authors.initials: D
authors.lastname: Flex
authors.affiliation: Center for Neuro-Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: Shlomit
authors.initials: S
authors.lastname: Yust-Katz
authors.affiliation: Center for Neuro-Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Limon
authors.affiliation: University of Colorado Cancer Center, Division of Medical Oncology, University of Colorado, Denver, Aurora, CO, USA.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.affiliation: Thoracic Cancer Unit, Davidoff Cancer Center, Rabin Medical Center, Kaplan Street, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel. Electronic address: nirp@post.tau.ac.il.
authors.forename: Nir
authors.initials: N
authors.lastname: Peled
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D016371:Cranial Irradiation; D000077547:Crizotinib; D018450:Disease Progression; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D013450:Sulfones / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib
keywords: ALK rearrangement; Brain metastases; Ceritinib; Crizotinib; NSCLC