A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers
| Autor: | Elaine Kilgour, Marie Cullberg, Jean-Charles Soria, Michael F. Berger, David Ferry, Fabrice Andre, A. Nigel Brooks, Ronglai Shen, Paul K. Paik, Claire Rooney, Neil R. Smith, Donal Landers, Alastair Mathewson, Paul Frewer |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology Male Cancer Research Pathology Lung Neoplasms Piperazines 0302 clinical medicine Carcinoma Squamous Cell/drug therapy Gene duplication Clinical endpoint Medicine Neoplasm Metastasis Manchester Cancer Research Centre Middle Aged Antineoplastic Agents/administration & dosage Treatment Outcome Tolerability 030220 oncology & carcinogenesis Benzamides Carcinoma Squamous Cell Female Chromosomes Human Pair 8 medicine.medical_specialty Antineoplastic Agents Article 03 medical and health sciences Genetic Heterogeneity Internal medicine Carcinoma Benzamides/administration & dosage Humans Receptor Fibroblast Growth Factor Type 1 Adverse effect Lung Neoplasms/drug therapy Aged Neoplasm Staging business.industry Receptor Fibroblast Growth Factor Type 1/genetics Gene Expression Profiling ResearchInstitutes_Networks_Beacons/mcrc Gene Amplification Cancer Piperazines/administration & dosage Sequence Analysis DNA medicine.disease Pyrazoles/administration & dosage Gene expression profiling stomatognathic diseases 030104 developmental biology Pharmacodynamics Pyrazoles Neoplasm Grading business |
| Zdroj: | Paik, P K, Shen, R, Berger, M F, Ferry, D, Soria, J-C, Mathewson, A, Rooney, C, Smith, N R, Cullberg, M, Kilgour, E, Landers, D, Frewer, P, Brooks, N & André, F 2017, ' A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers ', Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 23, no. 18, pp. 5366-5373 . https://doi.org/10.1158/1078-0432.CCR-17-0645 |
| DOI: | 10.1158/1078-0432.CCR-17-0645 |
| Popis: | Purpose: Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in approximately 20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with antitumor activity in FGFR1-amplified SQCLC cell lines and patient-derived xenografts. Experimental Design: On the basis of these data, we performed a phase I study of AZD4547 in patients with previously treated stage IV FGFR1-amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses. Results: Fifteen FGFR1-amplified patients were treated. The most common related adverse events (AE) were gastrointestinal and dermatologic. Grade ≥3–related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). Two of 15 patients (13.3%) were progression-free at 12 weeks, and the median overall survival was 4.9 months. Molecular tests, including next-generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry, showed poor correlation between gene amplification and expression, potential genomic modifiers of efficacy, and heterogeneity in 8p11 amplicon. Conclusions: AZD4547 was tolerable at a dosage of 80 mg oral twice a day, with modest antitumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational covariates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease. Clin Cancer Res; 23(18); 5366–73. ©2017 AACR. |
| Databáze: | OpenAIRE |
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