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Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance.
Br J Cancer 2019; 120(8):791-796BJ

Abstract

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.

Authors+Show Affiliations

Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA. ben.creelan@moffitt.org.Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA.Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA.Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA.Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2, Ono-Higashi, Osakasayama, Osaka, 589-8511, Japan.Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA.Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA.Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30880334

Citation

Creelan, Ben C., et al. "Phase 1 Trial of Dasatinib Combined With Afatinib for Epidermal Growth Factor Receptor- (EGFR-) Mutated Lung Cancer With Acquired Tyrosine Kinase Inhibitor (TKI) Resistance." British Journal of Cancer, vol. 120, no. 8, 2019, pp. 791-796.
Creelan BC, Gray JE, Tanvetyanon T, et al. Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance. Br J Cancer. 2019;120(8):791-796.
Creelan, B. C., Gray, J. E., Tanvetyanon, T., Chiappori, A. A., Yoshida, T., Schell, M. J., ... Haura, E. B. (2019). Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance. British Journal of Cancer, 120(8), pp. 791-796. doi:10.1038/s41416-019-0428-3.
Creelan BC, et al. Phase 1 Trial of Dasatinib Combined With Afatinib for Epidermal Growth Factor Receptor- (EGFR-) Mutated Lung Cancer With Acquired Tyrosine Kinase Inhibitor (TKI) Resistance. Br J Cancer. 2019;120(8):791-796. PubMed PMID: 30880334.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance. AU - Creelan,Ben C, AU - Gray,Jhanelle E, AU - Tanvetyanon,Tawee, AU - Chiappori,Alberto A, AU - Yoshida,Takeshi, AU - Schell,Michael J, AU - Antonia,Scott J, AU - Haura,Eric B, Y1 - 2019/03/18/ PY - 2018/11/06/received PY - 2019/02/27/accepted PY - 2019/02/19/revised PY - 2020/03/18/pmc-release PY - 2019/3/19/pubmed PY - 2019/3/19/medline PY - 2019/3/19/entrez SP - 791 EP - 796 JF - British journal of cancer JO - Br. J. Cancer VL - 120 IS - 8 N2 - 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. SN - 1532-1827 UR - https://www.unboundmedicine.com/medline/citation/30880334/Phase_1_trial_of_dasatinib_combined_with_afatinib_for_epidermal_growth_factor_receptor___EGFR___mutated_lung_cancer_with_acquired_tyrosine_kinase_inhibitor__TKI__resistance_ L2 - http://dx.doi.org/10.1038/s41416-019-0428-3 DB - PRIME DP - Unbound Medicine ER -