title: Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
abstract: BACKGROUND
  Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8-11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib.
  
  
  METHODS
  We enrolled patients with ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib. We administered various oral doses of alectinib (300-900 mg twice a day) during the dose-escalation portion of the study (phase 1), to ascertain the recommended dose for phase 2. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan (CT or MRI), with central radiological review of individuals with brain metastases. We assessed safety in all patients who received at least one dose of alectinib. Here, we present data for the phase 1 portion of the study, the primary objective of which was to establish the recommended phase 2 dose; phase 2 is ongoing. This trial is registered at ClinicalTrials.gov, number NCT01588028.
  
  
  RESULTS
  47 patients were enrolled. Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1-2), myalgia (eight [17%]; all grade 1-2), and peripheral oedema (seven [15%] grade 1-2, one [2%] grade 3). Dose-limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3-4 adverse events were increased levels of γ-glutamyl transpeptidase (two [4%]), a reduction in the number of neutrophils (two [4%]), and hypophosphataemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural effusion and pericardial effusion; and brain metastasis. At data cut-off (median follow-up 126 days [IQR 84-217]), 44 patients could be assessed for activity. Investigator-assessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. Pharmacokinetic data indicated that mean exposure (AUC0-10) after multiple doses of alectinib (300-600 mg twice a day) was dose-dependent.
  
  
  CONCLUSIONS
  Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2.
  
  
  BACKGROUND
  Chugai Pharmaceuticals, F Hoffmann La-Roche.
authors.affiliation: Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Shirish M
authors.initials: SM
authors.lastname: Gadgeel
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Leena
authors.initials: L
authors.lastname: Gandhi
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.affiliation: H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Alberto A
authors.initials: AA
authors.lastname: Chiappori
authors.affiliation: Swedish Medical Center, Seattle, WA, USA.
authors.forename: Howard L
authors.initials: HL
authors.lastname: West
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA USA.
authors.forename: Michele C
authors.initials: MC
authors.lastname: Azada
authors.affiliation: Roche Pharmaceutical Research and Early Development Center, Roche Innovation Center New York, F Hoffmann-La Roche, New York, NY, USA.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.affiliation: Roche Pharmaceutical Research and Early Development Center, Roche Innovation Center New York, F Hoffmann-La Roche, New York, NY, USA.
authors.forename: Ruey-Min
authors.initials: RM
authors.lastname: Lee
authors.affiliation: Chugai Pharma USA, Berkeley Heights, NJ, USA.
authors.forename: Linta
authors.initials: L
authors.lastname: Garcia
authors.affiliation: Roche Pharmaceutical Research and Early Development Center, Roche Innovation Center New York, F Hoffmann-La Roche, New York, NY, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.affiliation: Roche Pharmaceutical Research and Early Development Center, Roche Innovation Center New York, F Hoffmann-La Roche, New York, NY, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Boisserie
authors.affiliation: Roche Pharmaceutical Research and Early Development Center, Roche Innovation Center New York, F Hoffmann-La Roche, New York, NY, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Di Laurenzio
authors.affiliation: Roche Pharmaceutical Research and Early Development Center, Roche Innovation Center New York, F Hoffmann-La Roche, New York, NY, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Golding
authors.affiliation: Chugai Pharmaceuticals, Tokyo, Japan.
authors.forename: Jotaro
authors.initials: J
authors.lastname: Sato
authors.affiliation: Chugai Pharmaceuticals, Tokyo, Japan.
authors.forename: Shumpei
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: Chugai Pharmaceuticals, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA USA. Electronic address: ignatius.ou@uci.edu.
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D002227:Carbazoles / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D000077547:Crizotinib; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018579:Patient Selection; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib