Safety and efficacy of nazartinib (EGF816) in adults with EGFR-mutant non-small-cell lung carcinoma: a multicentre, open-label, phase 1 study
| Autor: | Dong Wan Kim, Santiago Ponce Aix, Takashi Seto, Chun Pan, Gregory J. Riely, Lecia V. Sequist, Maud Jonnaert, Enriqueta Felip, Juergen Wolf, Jinnie Ko, Susan Moody, James Chih-Hsin Yang, Eugene Y. Tan, Natasha B. Leighl, Daniel Shao-Weng Tan |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Pulmonary and Respiratory Medicine
Male medicine.medical_specialty Nicotine Lung Neoplasms Antineoplastic Agents Gastroenterology 03 medical and health sciences 0302 clinical medicine Internal medicine Carcinoma Non-Small-Cell Lung Maculopapular rash medicine Carcinoma Humans 030212 general & internal medicine Dosing Lung cancer Adverse effect Stomatitis Aged Performance status business.industry Middle Aged medicine.disease Rash ErbB Receptors Treatment Outcome 030228 respiratory system Benzimidazoles Female medicine.symptom business |
| Zdroj: | The Lancet. Respiratory medicine. 8(6) |
| ISSN: | 2213-2619 |
| Popis: | Summary 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. Funding Novartis Pharmaceuticals Corporation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|