Dual inhibition of SRC and EGFR -dependent pathways may overcome acquired resistance to EGFR-TKIs for patients with lung adenocarcinoma with EGFR mutations. The SRC-inhibitor dasatinib demonstrates anti-tumor activity in gefitinib-resistant cells lines and xenografts. Dasatinib is tolerable for patients with advanced non-small cell lung cancer, and in combination with erlotinib.
We conducted this phase II study of dasatinib 70 mg twice daily in patients with EGFR-mutant lung adenocarcinoma and acquired resistance to EGFR-TKIs. After a protocol amendment based upon evolving data about both drugs, patients received dasatinib at a dose of 100 mg daily with continued erlotinib after developing acquired resistance. Enrolled patients either harbored an activating mutation in EGFR or experienced clinical benefit with single-agent erlotinib or gefitinib, followed by RECIST documented progression while being treated with an EGFR-TKI.
Twenty-one patients were enrolled, nine under the original trial design and 12 after the protocol amendments. We observed no complete or partial responses (0% observed rate, 95% CI 0–18%). The median time to progression was 0.5 months (range 0.2–1.8 months) in patients treated with dasatinib, and 0.9 months (range 0.4–5 months) for patients treated with dasatinib and erlotinib in combination. Pleural effusions and dyspnea were frequent toxicities.
Dasatinib has no activity in patients with EGFR-mutant lung adenocarcinoma with acquired resistance to erlotinib and gefitinib.