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Updated: Jun 16, 2026
Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
Phase I/II study of the Src inhibitor dasatinib in combination with erlotinib in advanced non-small-cell lung cancer
Eric B Haura1, Tawee Tanvetyanon, Alberto Chiappori
1Department of Thoracic Oncology and Biostatistics, Clinical Trials and Clinical Pharmacology Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612-9497, USA. Eric.haura@moffitt.org
Purpose:
Src family kinase (SFK) proteins are frequently activated in cancer and can coordinate tumor cell growth, survival, invasion, and angiogenesis. Given the importance of SFK signaling in cancer, known cooperation between SFK and epidermal growth factor receptor (EGFR) signaling, and efficacy of EGFR inhibitors, we performed a phase I trial combining dasatinib, an SFK and multikinase inhibitor, with erlotinib, an EGFR inhibitor, in patients with advanced non-small-cell lung cancer.
Patients And Methods:
Patients received erlotinib for 1 week before addition of dasatinib; pharmacokinetics were performed after weeks 1 and 2. Four cohorts were examined, including twice-daily and daily dasatinib dosing. Responses were assessed after 8 weeks. Plasma levels of angiogenic markers (vascular endothelial growth factor [VEGF], interleukin-8, and basic fibroblast growth factor [bFGF]) were determined before and during treatment.
Results:
Thirty-four patients were enrolled. The average duration of treatment was 73 days. The main adverse events include GI (diarrhea, anorexia, and nausea), skin rash, cytopenias, pleural effusions, and fatigue. No effect of escalating doses of dasatinib was observed on erlotinib pharmacokinetics. Two partial responses and one bone response were observed, and the disease control rate was 63%. Reductions in plasma VEGF and bFGF were observed, and reductions in VEGF correlated with disease control.
Conclusion:
The combination of erlotinib and dasatinib is tolerable, with adverse effects consistent with the two agents. Disease control and inhibition of plasma angiogenesis markers were observed. Personalized strategies for deployment of SFK should receive further attention.
Insights
Combining dasatinib and erlotinib showed tolerable safety and disease control in advanced non-small-cell lung cancer. This combination also inhibited angiogenesis markers, suggesting potential for targeted therapies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Src family kinases (SFKs) are crucial in cancer progression, influencing growth, survival, and invasion.
- SFK signaling pathways often cooperate with epidermal growth factor receptor (EGFR) signaling in cancer.
- EGFR inhibitors have demonstrated efficacy, highlighting the therapeutic potential of targeting this pathway.
Purpose of the Study:
- To evaluate the safety and tolerability of combining dasatinib (an SFK and multikinase inhibitor) with erlotinib (an EGFR inhibitor).
- To assess the preliminary efficacy of this combination therapy in patients with advanced non-small-cell lung cancer (NSCLC).
- To investigate the pharmacokinetic interactions and effects on angiogenic markers during combination treatment.
Main Methods:
- A Phase I clinical trial was conducted, enrolling 34 patients with advanced NSCLC.
- Patients received erlotinib for one week, followed by the addition of dasatinib in a dose-escalation design.
- Pharmacokinetic assessments, response evaluations after 8 weeks, and measurements of plasma angiogenic markers (VEGF, IL-8, bFGF) were performed.
Main Results:
- The combination therapy was generally tolerable, with adverse events consistent with known side effects of erlotinib and dasatinib.
- Two partial responses and one bone response were observed, achieving a disease control rate of 63%.
- Reductions in plasma VEGF and bFGF levels were noted, with VEGF reduction correlating with disease control.
Conclusions:
- The combination of erlotinib and dasatinib is a tolerable treatment option for advanced NSCLC.
- The observed disease control and inhibition of angiogenesis markers warrant further investigation.
- Personalized strategies for utilizing SFK inhibitors in cancer treatment require further attention.
