Phase II study of dasatinib in patients with advanced non-small-cell lung cancer.
OBJECTIVE
Src family kinases (SFKs) promote cancer progression and are commonly expressed in non-small-cell lung cancer (NSCLC), but the clinical effects of SFK inhibition in NSCLC are unknown. We conducted a phase II trial of the SFK inhibitor dasatinib for advanced NSCLC. We tested the hypotheses that the activation of epidermal growth factor receptor (EGFR) or SFK or modulation of serum cytokines may predict a response to dasatinib.


METHODS
Patients received dasatinib as first-line therapy. Response was measured by tumor size on computed tomography scans and by metabolic activity on positron emission tomography scans. Tissue samples taken before patients received dasatinib were tested for EGFR and Kras mutation and phosphorylated SFK expression.


RESULTS
Thirty-four patients were enrolled. The overall disease control rate (partial responses plus stable disease) for dasatinib was 43%. One patient had a partial response to therapy. Eleven patients (32%) had a metabolic response to dasatinib. SFK activation and EGFR and Kras mutations in tumor tissue did not predict response to dasatinib. Significant toxicities included fatigue and dyspnea. The presence of a pleural effusion before dasatanib therapy predicted the development of a clinically significant effusion during therapy.


CONCLUSIONS
Dasatinib as a single agent had modest clinical activity that was lower than that generally observed in patients with NSCLC who receive chemotherapy. Pleural effusion was an expected and problematic toxicity that was successfully treated with steroids, diuretics, and dose interruptions. Marked activity in one patient and prolonged stable disease in four others suggested a potential subpopulation of patients with dasatinib-sensitive NSCLC.
Johnson
Faye M
FM
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-4009, USA. fmjohns@mdanderson.org
Bekele
B Nebiyou
BN
Feng
Lei
L
Wistuba
Ignacio
I
Tang
Xi Ming
XM
Tran
Hai T
HT
Erasmus
Jeremy J
JJ
Hwang
Li-Ling
LL
Takebe
Naoko
N
Blumenschein
George R
GR
Lippman
Scott M
SM
Stewart
David J
DJ
D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D016207:Cytokines / Q000097:blood; D000069439:Dasatinib; D018572:Disease-Free Survival; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D013781:Texas; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D047368:Tumor Burden; D018631:ras Proteins / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D016207:Cytokines; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D013844:Thiazoles; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000069439:Dasatinib