Online citations, reference lists, and bibliographies.
← Back to Search

A Phase Ib Open-Label Multicenter Study Of AZD4547 In Patients With Advanced Squamous Cell Lung Cancers

P. Paik, R. Shen, M. Berger, D. Ferry, J. Soria, Alastair M Mathewson, C. Rooney, N. Smith, M. Cullberg, E. Kilgour, D. Landers, P. Frewer, N. Brooks, F. André
Published 2017 · Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
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.
This paper references
10.1038/nature11404
Comprehensive genomic characterization of squamous cell lung cancers
P. Hammerman (2012)
Efficacy and safety of crizotinib in patients with advanced c-METamplified non-small cell lung cancer (NSCLC)
CamidgeD (2014)
10.1038/sj.onc.1210399
Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer
D. Tomlinson (2007)
10.1158/1078-0432.CCR-13-3060
FGFR1 mRNA and Protein Expression, not Gene Copy Number, Predict FGFR TKI Sensitivity across All Lung Cancer Histologies
M. Wynes (2014)
10.1126/scitranslmed.3001451
Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer
J. Weiss (2010)
Nextgeneration sequencing of stage IV squamous cell lung cancers reveals an
PK Paik (2017)
10.1016/J.JTHO.2015.12.027
Efficacy and safety of dovitinib in pretreated advanced squamous non-small cell lung cancer with FGFR1 amplification: A single-arm, phase II study
M. Ahn (2016)
10.1074/JBC.M300464200
Notch Activation Suppresses Fibroblast Growth Factor-dependent Cellular Transformation*
D. Small (2003)
10.1158/2159-8290.CD-14-1129
Next-Generation Sequencing of Stage IV Squamous Cell Lung Cancers Reveals an Association of PI3K Aberrations and Evidence of Clonal Heterogeneity in Patients with Brain Metastases.
P. Paik (2015)
10.1200/JCO.2013.49.4757
Use of statins and the risk of death in patients with prostate cancer.
O. Yu (2014)
10.1016/S0969-2126(99)80091-4
A dimeric ternary complex of FGFR1, heparin and FGF-1 leads to an 'electrostatic sandwich' model for heparin binding
M. Huhtala (1999)
MSKIMPACT: a hybridization capture-based next generation sequencing clinical assay for solid tumor molecular oncology
D Cheng (2015)
10.1158/0008-5472.CAN-08-2816
Fibroblast growth factor receptor 1 promotes proliferation and survival via activation of the mitogen-activated protein kinase pathway in bladder cancer.
D. Tomlinson (2009)
10.3791/50710
Detecting somatic genetic alterations in tumor specimens by exon capture and massively parallel sequencing.
H. Won (2013)
10.1158/2159-8274.CD-11-0005
Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer.
P. Hammerman (2011)
10.1016/j.jmoldx.2014.12.006
Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology.
Donavan T. Cheng (2015)
Nextgeneration sequencing of stage IV squamous cell lung cancers reveals an Paik et al. Clin Cancer Res
PK Paik (2017)
10.1158/1078-0432.CCR-12-2694
Translating the Therapeutic Potential of AZD4547 in FGFR1-Amplified Non–Small Cell Lung Cancer through the Use of Patient-Derived Tumor Xenograft Models
Jingchuan Zhang (2012)
10.1158/2159-8290.CD-13-0323
Cell-autonomous and non-cell-autonomous mechanisms of transformation by amplified FGFR1 in lung cancer.
F. Malchers (2014)
The Cancer Genome Atlas Network. Comprehensive genomic characterization of squamous cell lung cancers
(2012)
10.1002/cncr.30135
Efficacy and safety of dovitinib in pretreated patients with advanced squamous non‐small cell lung cancer with FGFR1 amplification: A single‐arm, phase 2 study
S. H. Lim (2016)
Nextgeneration sequencing of stage IV squamous cell lung cancers reveals an association of PI3K aberrations and evidence of clonal heterogeneity in patients with brain metastases
P K Paik (2015)
10.1016/0092-8674(93)90423-N
Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor
I. Rebay (1993)
10.1200/JCO.2016.67.2048
Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study.
L. Nogova (2017)
10.1200/JCO.2014.32.15_SUPPL.8001
Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC).
D. Camidge (2014)



This paper is referenced by
10.1007/s10637-019-00783-7
A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma
E. V. van Brummelen (2019)
10.1158/0008-5472.CAN-18-0757
Transcriptomics and Transposon Mutagenesis Identify Multiple Mechanisms of Resistance to the FGFR Inhibitor AZD4547.
S. Kas (2018)
10.1038/s41571-018-0115-y
Fibroblast growth factor receptors as treatment targets in clinical oncology
M. Katoh (2018)
10.1016/j.cllc.2018.06.004
A miRNA Panel Predicts Sensitivity of FGFR Inhibitor in Lung Cancer Cell Lines
S. Ren (2018)
10.1016/S1470-2045(19)30412-7
Rogaratinib in patients with advanced cancers selected by FGFR mRNA expression: a phase 1 dose-escalation and dose-expansion study.
M. Schuler (2019)
10.1177/1933719118802053
Upregulation of Fibroblast Growth Factors Caused by Heart and Neural Crest Derivatives Expressed 2 Suppression in Endometriotic Cells: A Possible Therapeutic Target in Endometriosis
Nao Kato (2019)
10.1101/mcs.a004002
Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy
M. Krook (2019)
10.21149/10115
Squamous cell lung cancer: genomic evolution and personalized therapy.
A. Cardona (2019)
10.1016/j.ebiom.2020.102683
FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their co-expression may predict FGFR-targeted therapy efficacy
Á. Quintanal-Villalonga (2020)
10.1002/cam4.2994
Fibroblast growth factor receptor 1 gene amplification and protein expression in human lung cancer
Omar Elakad (2020)
10.1080/13543784.2020.1838484
Clinical complexity of utilizing FGFR inhibitors in cancer therapeutics
S. Chandana (2020)
10.1158/1078-0432.CCR-17-1172
Comprehensive Pharmacogenomic Profiling of Malignant Pleural Mesothelioma Identifies a Subgroup Sensitive to FGFR Inhibition
J. Quispel-Janssen (2017)
10.3390/ijms19113491
Receptor Tyrosine Kinase-Targeted Cancer Therapy
T. Yamaoka (2018)
10.20517/CDR.2019.42
Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy
David K. Lau (2019)
10.1186/s40164-019-0149-6
Targeted and novel therapy in advanced gastric cancer
Julie H. Selim (2019)
10.1016/j.tranon.2018.11.017
Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC
Kristine Raaby Gammelgaard (2019)
10.1016/j.cllc.2018.09.001
Preselection of Lung Cancer Cases Using FGFR1 mRNA and Gene Copy Number for Treatment With Ponatinib
T. Ng (2019)
10.1016/j.jtho.2018.12.021
FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy
Á. Quintanal-Villalonga (2019)
10.1007/s10637-020-00933-2
Mechanisms of Efficacy of the FGFR1–3 Inhibitor AZD4547 in Pediatric Solid Tumor Models
Nikki Phanhthilath (2020)
10.1038/s41388-018-0311-3
FGFR1-ERK1/2-SOX2 axis promotes cell proliferation, epithelial–mesenchymal transition, and metastasis in FGFR1-amplified lung cancer
K. Wang (2018)
10.1080/14737159.2018.1440210
Bright-field in situ hybridization detects gene alterations and viral infections useful for personalized management of cancer patients
C. C. Volpi (2018)
p-Regulated FGFR 1 Expression s a Mediator of Intrinsic TKI esistance in EGFR-Mutated SCLC
J. Vad-Nielsen (2019)
10.1016/j.lungcan.2019.12.018
A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma.
Wei-Sen Lam (2019)
10.1016/j.semcancer.2019.03.006
Receptor tyrosine kinases in PI3K signaling: The therapeutic targets in cancer.
W. Jiang (2019)
10.3390/cancers12041009
Personalized Medicine: Recent Progress in Cancer Therapy
V. Gambardella (2020)
10.1002/ANGE.201710398
Lektion gelernt? Die molekularen Grundlagen von Kinase-gerichteten Therapien und Wirkstoffresistenz im nicht-kleinzelligen Lungenkrebs
Jonas Lategahn (2018)
10.1371/journal.pone.0231877
INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models
P. Liu (2020)
10.7150/jca.44476
mRNA Expression of FGFR1 as Potential Marker for Predicting Prognosis of Surgical Resection of Small Cell Lung Cancer may be better than Protein Expression and Gene Amplification
J. Qin (2020)
10.1158/0008-5472.CAN-19-2568
Futibatinib Is a Novel Irreversible FGFR 1–4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors
Hiroshi Sootome (2020)
10.1038/s41389-019-0151-1
Reciprocal regulatory mechanism between miR-214-3p and FGFR1 in FGFR1-amplified lung cancer
Y. Yang (2019)
10.1016/j.cllc.2018.03.014
Molecular and Immune Biomarker Testing in Squamous‐Cell Lung Cancer: Effect of Current and Future Therapies and Technologies
F. Hirsch (2018)
10.1200/JCO.19.02630
Phase II Study of AZD4547 in Patients With Tumors Harboring Aberrations in the FGFR Pathway: Results From the NCI-MATCH Trial (EAY131) Subprotocol W.
Y. Chae (2020)
See more
Semantic Scholar Logo Some data provided by SemanticScholar