RESUMEN
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively. METHODS: We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed. RESULTS: A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification. CONCLUSIONS: Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).
Asunto(s)
Camptotecina/análogos & derivados , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Receptor ErbB-2/genética , Trastuzumab/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Inmunoconjugados/efectos adversos , Enfermedades Pulmonares Intersticiales/inducido químicamente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Neumonía/inducido químicamente , Supervivencia sin Progresión , Trastuzumab/efectos adversosRESUMEN
BACKGROUND: We examined the impact of race on the maximum tolerated doses (MTD) and final approved doses (FAD) of single-agent molecular-targeted agents (MTA) in North America/Europe (NA/EU) and Asia. METHODS: We searched PubMed and regulatory databases to identify targeted drugs approved globally and compared their FAD and MTD in corresponding phase I/II studies conducted separately in NA/EU and Asia. To evaluate this further, we conducted parallel, prospective, first-in-human studies of DS-7423, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumours in the US and Japan. We pooled and compared the pharmacokinetics (PK), pharmacodynamics (PD), toxicity, and efficacy between these populations. RESULTS: 17 MTA were approved in NA/EU and Asia from 2001 to 2015. Recommended phase 2 doses (RP2D) were identical across races in 14 of 17 (80%) studies and differences were not clinically meaningful. FAD were identical across all regions. 42 and 27 patients from US and Japan, respectively, were enrolled in the phase I studies of DS-7423. Despite differences in race, body weight, and body mass index, the RP2D were 240 mg/day with no differences in toxicities, PK, PD, or efficacy. CONCLUSIONS: Conducting separate clinical trials of single-agent MTA in Caucasian and Asian populations may be redundant.
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Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Aprobación de Drogas , Unión Europea , Femenino , Humanos , Japón , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias/etnología , Neoplasias/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Grupos Raciales , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Estados Unidos , Adulto JovenRESUMEN
Smoking induces a wide range of drug-metabolizing enzymes. Among them, CYP2B6 as well as CYP1A2 is well known to be up-regulated in smokers. Although the induction of CYP1A2 is mediated by the aryl hydrocarbon receptor, the molecular mechanisms of CYP2B6 induction by smoking remain to be fully elucidated. In this study, by preparing cigarette smoke extract (CSE), we addressed the possibility that human constitutive androstane receptor (hCAR) is involved in smoking-mediated induction of CYP2B6. In HepG2 cells, CSE induced CYP1A2 but not CYP2B6, suggesting that CYP2B6 expression is differentially regulated from CYP1A2. Compared with liver in vivo, hCAR expression is dramatically reduced in cultured hepatocytes, such as HepG2. Therefore, to reconstitute hCAR signaling pathways in vitro, we generated adenovirus vector expressing hCAR. Real-time reverse transcription-polymerase chain reaction analyses revealed that the adenoviral transfection of hCAR resulted in the up-regulation of CYP2B6 mRNA, even in the absence of CSE. It is interesting to note that CSE stimulation augmented hCAR-mediated induction of CYP2B6. In contrast, the expression of CYP2B6 was not enhanced by adenovirus vector expressing ß-galactosidase, a control vector, either in the presence or absence of CSE. In summary, hCAR mediated the CYP2B6 induction by CSE in Hep2G cells. These data suggest that smoking up-regulates CYP2B6 through hCAR in vivo.
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Hidrocarburo de Aril Hidroxilasas/genética , Citocromo P-450 CYP1A2/efectos de los fármacos , Nicotiana , Oxidorreductasas N-Desmetilantes/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Humo , Fumar/metabolismo , Células Cultivadas , Receptor de Androstano Constitutivo , Citocromo P-450 CYP2B6 , Sistema Enzimático del Citocromo P-450/metabolismo , Inducción Enzimática , Células HEK293 , Células Hep G2 , Hepatocitos/enzimología , Hepatocitos/metabolismo , Humanos , Hígado/metabolismo , ARN Mensajero/biosíntesis , Receptores de Hidrocarburo de Aril/metabolismo , Regulación hacia ArribaRESUMEN
Oncogenic ROS1 and NTRK fusions were reported in solid tumors, including non-small cell lung cancer (NSCLC). DS-6051b is an oral, potent selective small molecule tyrosine kinase inhibitor. We report the safety, tolerability, efficacy, and pharmacokinetics of DS-6051b in 15 Japanese patients with NSCLC harboring ROS1 fusions. Patients received DS-6051b once daily (400 mg n = 6; 600 mg n = 6; or 800 mg n = 3) for cycles of 3 weeks. Safety, tolerability, maximum-tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. Common treatment-related adverse events were increased: aspartate aminotransferase and alanine aminotransferase (80.0% each), diarrhea (53.3%), and nausea (46.7%). Dose-limiting toxicities (two grade-3 alanine aminotransferase increases) were seen in the 800 mg cohort. The maximum-tolerated dose and recommended phase II dose was 600 mg once daily. Plasma concentrations of free DS-6051b and DS-6051a increased with dose. Compared with a US phase I study, AUC0-24 h on day 15 was higher but narrowed after body weight correction. Objective response rate was 58.3% in patients with target lesions (n = 12) and 66.7% in crizotinib-naïve patients (n = 9). Disease control rate was 100%. DS-6051b is well tolerated and effective in Japanese patients with NSCLC harboring ROS1 fusions and might be a targeted therapy for advanced NSCLC.