title: Pharmacologic study (JP28927) of alectinib in Japanese patients with ALK+ non-small-cell lung cancer with or without prior crizotinib therapy.
abstract: We report pharmacokinetics, efficacy and safety data for a new 150-mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (≥20 years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naïve and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300 mg twice daily (comprising different schedules of 20/40-mg and 150-mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40 mg vs 150 mg; food effect with 150 mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1 months (range 1.1-15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUClast± standard deviation 3230 ± 914 h·ng/mL vs 3710 ± 1040 h·ng/mL, respectively, for 150-mg vs 20/40-mg capsules. Food effect with 150 mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2 months (95% CI 1.1-2.1). For the full analysis set (n = 35) and crizotinib-failure subpopulations (n = 23), the overall response rate was 70.0% (95% CI 50.6-85.3) and 65.0% (95% CI 40.8-84.6), and median progression-free survival was 13.9 months (95% CI 11.1-not reached) and 12.9 months (95% CI 3.9-not reached), respectively. The 150-mg capsule had a similar exposure profile to 20/40-mg capsules. Alectinib demonstrated promising efficacy and was well tolerated.
authors: Department of Thoracic Oncology, Aichi Cancer Center, Nagoya, Japan.
authors: Toyoaki
authors: T
authors: Hida
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.
authors: Kazuhiko
authors: K
authors: Nakagawa
authors: Department of Thoracic Oncology, National Kyusyu Cancer Center, Fukuoka, Japan.
authors: Takashi
authors: T
authors: Seto
authors: Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan.
authors: Miyako
authors: M
authors: Satouchi
authors: Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Makoto
authors: M
authors: Nishio
authors: Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors: Katsuyuki
authors: K
authors: Hotta
authors: Department of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
authors: Toshiaki
authors: T
authors: Takahashi
authors: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.|National Cancer Center East, Chiba, Japan.
authors: Yuichiro
authors: Y
authors: Ohe
authors: Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan.
authors: Koji
authors: K
authors: Takeda
authors: Translational Clinical Research Science & Strategy Department, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
authors: Masahiro
authors: M
authors: Tatsuno
authors: Clinical Science & Strategy Department, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
authors: Takashi
authors: T
authors: Asakawa
authors: Clinical Science & Strategy Department, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
authors: Tadashi
authors: T
authors: Shimada
authors: Clinical Science & Strategy Department, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
authors: Tomohiro
authors: T
authors: Tanaka
authors: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.|Thoracic Center, St. Luke's International Hospital, Tokyo, Japan.
authors: Tomohide
authors: T
authors: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002227:Carbazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D000077547:Crizotinib; D018572:Disease-Free Survival; D005215:Fasting; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D013810:Therapeutic Equivalency; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D002227:Carbazoles; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib
keywords: Alectinib; Japanese; anaplastic lymphoma kinase; bioequivalence; non-small-cell lung cancer