Letter to the Editor High-dose, weekly erlotinib is not an effective treatment in EGFR-mutated non-small cell lung cancer-patients with acquired extracranial progressive disease on standard dose erlotinib J.L. Kuiper a,⇑ , D.A.M. Heideman b , E. Thunnissen b , A.W. van Wijk a , P.E. Postmus a , E.F. Smit a a Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands b Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands Dear Editor, Resistance to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC)-patients with an epidermal growth factor (EGFR) mutation is a major clinical problem. Several mechanisms of resistance have been detected, the most prevalent being the T790M mutation [1]. At present, there is no consensus on the optimal treatment strategy at time of acquired TKI- resistance. Although the recommended dose for erlotinib in phase II single agent and combination trials is 150 mg once daily, doses up to 2000 mg weekly were evaluated in phase I trials and were found tolerable, with an acceptable toxicity profile [2]. This higher dose of erloti- nib administered in a weekly schedule (hereafter called ‘pulsatile erlotinib’) is thought to achieve higher concen- trations in the cerebrospinal fluid and has several times been described as a salvage option for patients with lep- tomeningeal metastases [3–7]. Interestingly, a single patient refractory to standard dose erlotinib who was treated with high-dose, weekly erlotinib (‘pulsatile erl- otinib’) for leptomeningeal metastases, showed a response of thoracic lesions as well [8]. Also, in imati- nib-treatment of Chronic myeloid leukemia (CML)- and gastrointestinal stromal tumour (GIST)-patients (which bears close resemblance to erlotinib-treatment of EGFR-mutated NSCLC-patients), dose escalation of imatinib has been proven effective in patients who had developed progressive disease to standard dose imatinib [9,10]. Since erlotinib is a competitive inhibitor of EGF signalling, we hypothesised that a higher dose of the drug might theoretically restore sensitivity for the drug. If this relatively simple, higher dosing schedule was indeed effective, it would provide an easy therapeu- tic option for advanced, EGFR-mutated NSCLC- patients with acquired resistance to TKIs. We therefore evaluated pulsatile erlotinib in advanced EGFR-mutated NSCLC-patients with extra- cranial progressive disease on standard dose EGFR– TKIs. Patients were treated with 1500 mg erlotinib once weekly until disease progression, intolerable toxicity or withdrawal of consent. Objective response rate (ORR) and disease control rate at 8 weeks (DCR; rate of no http://dx.doi.org/10.1016/j.ejca.2014.02.005 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author: Address: Department of Pulmonary Dis- eases, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: +31 20 444 2214; fax: +31 20 444 4328. E-mail address: jl.kuiper@vumc.nl (J.L. Kuiper). European Journal of Cancer (2014) xxx, xxx– xxx Available at www.sciencedirect.com ScienceDirect journal homepage: www.ejcancer.com Please cite this article in press as: Kuiper J.L. et al., High-dose, weekly erlotinib is not an effective treatment in EGFR-mutated non-small cell lung cancer-patients with acquired extracranial progressive disease on standard dose erlotinib, Eur J Cancer (2014), http://dx.doi.org/10.1016/j.ejca.2014.02.005