Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer

Jakob Schöttle; Sampurna Chatterjee; Caroline Volz; Maike Siobal; Alexandra Florin; Dennis Rokitta; Yvonne Hinze; Felix Dietlein; Dennis Plenker; Katharina König; Kerstin Albus; Johannes M Heuckmann; Daniel Rauh; Thomas Franz; Bernd Neumaier; Uwe Fuhr; Lukas C Heukamp; Roland T Ullrich

doi:10.18632/oncotarget.6276

Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer

Oncotarget. 2015 Nov 17;6(36):38458-68. doi: 10.18632/oncotarget.6276.

Authors

Jakob Schöttle^{1

2

3}, Sampurna Chatterjee^{1

2

4}, Caroline Volz^{1

2}, Maike Siobal², Alexandra Florin⁵, Dennis Rokitta⁶, Yvonne Hinze⁷, Felix Dietlein³, Dennis Plenker³, Katharina König⁵, Kerstin Albus⁵, Johannes M Heuckmann⁸, Daniel Rauh⁹, Thomas Franz⁷, Bernd Neumaier^{2

10}, Uwe Fuhr⁶, Lukas C Heukamp^{5

8}, Roland T Ullrich^{1

2}

Affiliations

¹ Department I of Internal Medicine, Center of Integrated Oncology Köln-Bonn, University of Cologne, Germany and Center of Molecular Medicine Cologne (ZMMK), University of Cologne, Cologne, Germany.
² Max-Planck-Institute for Metabolism, with Klaus-Joachim-Zülch Laboratories of The Max Planck Society and The Medical Faculty of The University of Cologne, Cologne, Germany.
³ Department of Translational Genomics, University of Cologne, Medical Faculty, Weyertal, Cologne, Germany.
⁴ Department of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
⁵ Department of Pathology, University Hospital Medical Center, University of Cologne, Cologne, Germany.
⁶ Department of Pharmacology, University Hospital Medical Center, University of Cologne, Cologne, Germany.
⁷ Max-Planck-Institute for Ageing, Cologne, Germany.
⁸ NEO New Oncology AG, Cologne, Germany.
⁹ Technical University Dortmund, Dortmund, Germany.
¹⁰ Institut für Radiochemie und Experimentelle Molekulare Bildgebung (IREMB), University Hospital Medical Center, University of Cologne, Cologne, Germany.

Abstract

Treatment with EGFR kinase inhibitors improves progression-free survival of patients with EGFR-mutant lung cancer. However, all patients with initial response will eventually acquire resistance and die from tumor recurrence. We found that intermittent high-dose treatment with erlotinib induced apoptosis more potently and improved tumor shrinkage significantly than the established low doses. In mice carrying EGFR-mutant xenografts intermittent high-dose treatment (200 mg/kg every other day) was tolerable and prolonged progression-free survival and reduced the frequency of acquired resistance. Intermittent EGFR-targeted high-dose schedules induce more profound as well as sustained target inhibition and may afford enhanced therapeutic efficacy.

Keywords: EGFR; NSCLC; PET; erlotinib; high-dose scheduling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / administration & dosage*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / enzymology
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Disease-Free Survival
Dose-Response Relationship, Drug
Drug Administration Schedule
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / genetics
ErbB Receptors / metabolism
Erlotinib Hydrochloride / administration & dosage*
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Male
Mice
Mice, Nude
Protein Kinase Inhibitors / administration & dosage*
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Erlotinib Hydrochloride
EGFR protein, human
EGFR protein, mouse
ErbB Receptors