Tan, Daniel S-W, Leighl, Natasha B., Riely, Gregory J., Yang, James C-H, Sequist, Lecia, V, Wolf, Juergen, Seto, Takashi, Felip, Enriqueta, Aix, Santiago P., Jonnaert, Maud, Pan, Chun, Tan, Eugene Y., Ko, Jinnie, Moody, Susan E. and Kim, Dong-Wan (2020). Safety and efficacy of nazartinib (EGF816) in adults with EGFR-mutant non-small-cell lung carcinoma: a multicentre, open-label, phase 1 study. Lancet Resp. Med., 8 (6). S. 561 - 573. OXFORD: ELSEVIER SCI LTD. ISSN 2213-2600
Full text not available from this repository.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.
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| URN: | urn:nbn:de:hbz:38-331686 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DOI: | 10.1016/S2213-2600(19)30267-X | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Lancet Resp. Med. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Volume: | 8 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Number: | 6 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Page Range: | S. 561 - 573 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Date: | 2020 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Publisher: | ELSEVIER SCI LTD | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Place of Publication: | OXFORD | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ISSN: | 2213-2600 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Language: | English | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Faculty: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Divisions: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | no entry | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| URI: | http://kups.ub.uni-koeln.de/id/eprint/33168 |
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