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Safety and efficacy of nazartinib (EGF816) in adults with EGFR-mutant non-small-cell lung carcinoma: a multicentre, open-label, phase 1 study
DC Field | Value | Language |
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dc.contributor.author | Tan, Daniel S-W | - |
dc.contributor.author | Leighl, Natasha B. | - |
dc.contributor.author | Riely, Gregory J. | - |
dc.contributor.author | Yang, James C-H | - |
dc.contributor.author | Sequist, Lecia, V | - |
dc.contributor.author | Wolf, Juergen | - |
dc.contributor.author | Seto, Takashi | - |
dc.contributor.author | Felip, Enriqueta | - |
dc.contributor.author | Aix, Santiago P. | - |
dc.contributor.author | Jonnaert, Maud | - |
dc.contributor.author | Pan, Chun | - |
dc.contributor.author | Tan, Eugene Y. | - |
dc.contributor.author | Ko, Jinnie | - |
dc.contributor.author | Moody, Susan E. | - |
dc.contributor.author | Kim, Dong-Wan | - |
dc.date.accessioned | 2021-01-31T08:06:56Z | - |
dc.date.available | 2021-01-31T08:06:56Z | - |
dc.date.created | 2020-07-06 | - |
dc.date.created | 2020-07-06 | - |
dc.date.issued | 2020-06 | - |
dc.identifier.citation | The Lancet Respiratory Medicine, Vol.8 No.6, pp.561-572 | - |
dc.identifier.issn | 2213-2600 | - |
dc.identifier.other | 105119 | - |
dc.identifier.uri | https://hdl.handle.net/10371/171817 | - |
dc.description.abstract | Background Resistance to first-generation and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is mediated by the emergence of the Thr790Met mutation in 50-60% of treated patients with non-small-cell lung cancer (NSCLC). We aimed to assess the safety and activity of nazartinib (EGF816), a third-generation EGFR TKI that selectively inhibits EGFR with Thr790Met or activating mutations (or both), while sparing wild-type EGFR, in patients with advanced EGFR-mutant NSCLC. Methods This phase 1 dose-escalation part of an open-label, multicentre, phase 1/2 study was conducted at nine academic medical centres located in Europe, Asia, and North America. Patients were included if they were aged 18 years or older and had stage IIIB-IV EGFR-mutant NSCLC (with varying statuses of EGFR mutation and previous therapy allowed), at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Nazartinib (at seven dose levels between 75 mg and 350 mg, in capsule or tablet form) was administered orally, once daily, on a continuous 28-day dosing schedule. A two-parameter Bayesian logistic regression model, guided by the escalation with overdose control principle, was implemented to make dose recommendations and estimate the maximum tolerated dose or recommended phase 2 dose of nazartinib (the primary outcome). This study is registered with ClinicalTrials.gov (NCT02108964); enrolment to phase 1 is complete and the study is ongoing. Findings By Aug 31, 2017, 180 patients (116 [64%] women; median age 60 years (52-69); 116 [64%] with ECOG performance status 1) received nazartinib across seven dose levels: 75 mg (n=17), 100 mg (n=38), 150 mg (n=73), 200 mg (n=8), 225 mg (n=28), 300 mg (n=5), and 350 mg (n=11). Seven dose-limiting toxicities were observed in six (3%) patients who received 150 mg, 225 mg, or 350 mg nazartinib once daily. Although the maximum tolerated dose was not met, the recommended phase 2 dose was declared as 150 mg once daily (tablet). The most common adverse events, regardless of cause, were rash (all subcategories 111 [62%] patients, maculopapular rash 72 [40%], dermatitis acneiform 22 [12%]), diarrhoea (81 [45%]), pruritus (70 [39%]), fatigue (54 [30%]), and stomatitis (54 [30%]), and were mostly grades 1-2. Any-cause grade 3-4 adverse events were reported in 99 (55%) patients across all doses, the most common being rash (all subcategories grouped 27 [15%]), pneumonia (12 [7%]), anaemia (ten [6%]), and dyspnoea (nine [5%]). Serious adverse events suspected to be drug-related occurred in 16 (9%) patients. Interpretation Nazartinib has a favourable safety profile, with low-grade skin toxicity characterised by a predominantly maculopapular rash that required minimal dose reductions. Copyright (C) 2020 Elsevier Ltd. All rights reserved. | - |
dc.language | 영어 | - |
dc.publisher | Elsevier Limited | - |
dc.title | Safety and efficacy of nazartinib (EGF816) in adults with EGFR-mutant non-small-cell lung carcinoma: a multicentre, open-label, phase 1 study | - |
dc.type | Article | - |
dc.contributor.AlternativeAuthor | 김동완 | - |
dc.identifier.doi | 10.1016/S2213-2600(19)30267-X | - |
dc.citation.journaltitle | The Lancet Respiratory Medicine | - |
dc.identifier.wosid | 000540618400029 | - |
dc.identifier.scopusid | 2-s2.0-85085950394 | - |
dc.citation.endpage | 572 | - |
dc.citation.number | 6 | - |
dc.citation.startpage | 561 | - |
dc.citation.volume | 8 | - |
dc.identifier.sci | 000540618400029 | - |
dc.description.isOpenAccess | Y | - |
dc.contributor.affiliatedAuthor | Kim, Dong-Wan | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.subject.keywordPlus | CANCER | - |
dc.subject.keywordPlus | RESISTANCE | - |
dc.subject.keywordPlus | MUTATIONS | - |
dc.subject.keywordPlus | OSIMERTINIB | - |
dc.subject.keywordPlus | ROCILETINIB | - |
dc.subject.keywordPlus | INHIBITORS | - |
dc.subject.keywordPlus | AZD9291 | - |
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