Clinical Study

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

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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.

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Acknowledgements

Trial was designed at the AACR/ASCO 2011 Methods in Cancer Research workshop, including assistance from mentors Patricia LoRusso, Gary Clark, and Miguel Villalona. Angela Reagan and Sonya J. Smyk provided editorial assistance. Angela Reagan and Sonya J. Smyk was not compensated beyond her regular salary. This study was partially funded by the Moffitt Cancer Center National Cancer Institute support grant, P30-CA076292. Afatinib drug supply and funding for the conduct of the clinical trial was provided by Boehringer Ingelheim GmbH. Dasatinib drug supply was provided by E.R. Squibb & Sons, L.L.C. Support for the performance of digital droplet PCR was provided by Biodesix, Inc. The support sources had no role in the design, analysis or interpretation of the results in this study. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to BIPI substances, as well as intellectual property considerations.

Author contributions

The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). B.C.C. was the principal investigator who helped to design, conducted the trial, analysis of results, and wrote the primary manuscript. J.E.G. helped by reviewing trial design, contributing patients, and review of the manuscript. T.T. helped by contributing patients and manuscript review. A.A.C. helped by reviewing trial design, contributing patients, and review of the manuscript. T.Y. helped by writing the protocol rationale, and review of the manuscript. M.J.S. provided statistical justification for the study design, analysis, and review of the manuscript. S.J.A. helped by contributing patients and review of the manuscript. E.B.B. provided the study rationale, supervised the study design, contributed patients, and contributed to the analysis and manuscript review.

Author information

Correspondence to Ben C. Creelan.

Ethics declarations

Competing interests

B.C.C. discloses the following: Speaker’s Bureau: Hoffman-LaRoche AG, E.R. Squibb & Sons LLC, AstraZeneca LLC, Takeda Pharmaceutical Company Ltd, Foundation Medicine Inc. Advisory Board: E.R. Squibb & Sons LLC, AbbVie Inc., GlaxoSmithKline plc, Celgene. Contracted/Support Research Grant: Prometheus Inc., Iovance Biotherapeutics Inc., Boehringer Ingelheim GmbH. J.E.G. discloses research support from Boehringer Ingelheim GmbH and Bristol-Myers Squibb. S.J.A. has research funding from Boehringer Ingelheim. E.B.H. serves on the advisory board of Janssen Pharmaceuticals and receives research support from Forma Therapeutics and Incyte Pharmaceuticals. The other authors declare no competing interests.

Ethics approval and consent to participate

The study was institutional review board approved, Federal wide assurance number IRB00003411, Liberty Institutional Review Board, Inc. All patients provided written informed consent. The study was performed in accordance with the Declaration of Helsinki.

Data availability:

Raw data and materials generated during the study are available upon request to the author study team, thoraciccro@moffitt.org.

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

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