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Published on: August 11, 2017
Phase II study of dasatinib in patients with advanced non-small-cell lung cancer
Faye M Johnson1, B Nebiyou Bekele, Lei Feng
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-4009, USA. fmjohns@mdanderson.org
Purpose:
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.
Patients And 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.
Conclusion:
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.
Insights
Dasatinib showed modest clinical activity in advanced non-small-cell lung cancer (NSCLC). Pleural effusion was a common toxicity, but specific mutations did not predict response in this phase II trial.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Src family kinases (SFKs) are implicated in cancer progression and are prevalent in non-small-cell lung cancer (NSCLC).
- The clinical efficacy of SFK inhibition, specifically with dasatinib, in NSCLC remains largely uncharacterized.
Purpose of the Study:
- To evaluate the clinical activity of dasatinib, an SFK inhibitor, as first-line therapy for advanced NSCLC.
- To investigate whether epidermal growth factor receptor (EGFR) or SFK activation, or serum cytokine modulation, could predict response to dasatinib.
Main Methods:
- A phase II clinical trial was conducted involving 34 patients with advanced NSCLC receiving dasatinib as first-line treatment.
- Tumor response was assessed using computed tomography (CT) scans and positron emission tomography (PET) scans.
- Pre-treatment tumor tissue was analyzed for EGFR and Kras mutations, and phosphorylated SFK expression.
Main Results:
- The overall disease control rate (partial response + stable disease) for dasatinib was 43%, with one partial response and 11 metabolic responses (32%).
- SFK activation, EGFR, and Kras mutations in tumor tissue did not correlate with response to dasatinib.
- Fatigue and dyspnea were significant toxicities; pre-existing pleural effusion predicted its development during therapy.
Conclusions:
- Dasatinib demonstrated modest clinical activity as a single agent in advanced NSCLC, with activity lower than typical chemotherapy regimens.
- Pleural effusion was a notable toxicity, manageable with standard treatments.
- The study suggests a potential subset of patients with dasatinib-sensitive NSCLC, indicated by one notable response and prolonged stable disease in a few patients.
