Journal Article

Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance

Haura, Eric B., Creelan, Ben C., Gray, Jhanelle E., Tanvetyanon, Tawee, Yoshida, Takeshi, Antonia, Scott J., Chiappori, Alberto A., Schell, Michael J.

2019

Overview

Background Bypass activation of Src family kinases can confer resistance to EGFR tyrosine kinase inhibitors (TKIs) based on preclinical models. We prospectively assessed the safety and clinical activity of dasatinib and afatinib in combination for patients with resistant EGFR-mutant lung cancer. Methods An open-label, dose-escalation phase 1/2 trial (NCT01999985) with 2-stage expansion was conducted with 25 lung cancer patients. Dose expansion required activating EGFR mutations and progression following prior EGFR TKI. Results Patients were 72% Caucasian and received median of 2 prior lines of therapy. Maximum-tolerated dose was 30 mg afatinib with 100 mg dasatinib. New or increased pleural effusions were observed in 56% of patients. No radiologic responses were observed, although several EGFR-mutant TKI-resistant patients (26%) had prolonged stable disease over 6 months. The combination reduced the EGFR mutation and T790M variant allele frequency in cell-free DNA ( p  < .05). Nonetheless, the threshold for futility was met, based on 6-month progression-free survival. For EGFR TKI-resistant patients, median progression-free survival was 3.7 months (95% confidence interval (CI), 2.3–5.0) and overall survival was 14.7 months (95% CI, 8.5–20.9). Conclusions The combination had a manageable toxicity profile and in vivo T790M modulation, but no objective clinical responses were observed.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/1438 / 631/67/1612/1350 / 631/67/69 / 692/308/153 / 692/4028/67/1612/1350 / Adult / Afatinib - administration & dosage / Afatinib - adverse effects / Aged / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Biomedical and Life Sciences / Biomedicine / c-Met protein / Cancer Research / Cell-Free Nucleic Acids - drug effects / Dasatinib - administration & dosage / Dasatinib - adverse effects / Deoxyribonucleic acid / Disease Progression / DNA / Dose-Response Relationship, Drug / Drug Resistance / Drug-Related Side Effects and Adverse Reactions - classification / Drug-Related Side Effects and Adverse Reactions - pathology / Enzyme inhibitors / Epidemiology / Epidermal growth factor / Epidermal growth factor receptors / ErbB Receptors - genetics / Female / Gene Frequency / Humans / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Male / Middle Aged / Molecular Medicine / Mutation / Oncology / Progression-Free Survival / Protein Kinase Inhibitors - administration & dosage / src-Family Kinases - antagonists & inhibitors / Toxicity / Tyrosine kinase inhibitors