Lung Cancer 83 (2014) 305–307
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Letter to the Editor Dramatic response to high-dose icotinib in a lung adenocarcinoma patient after erlotinib failure
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Keywords: Epidermal growth factor receptor High dose Icotinib Mutation Non-small cell lung cancer Tyrosine kinase inhibitor
a b s t r a c t Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) retreatment is rarely administered for non-small cell lung cancer (NSCLC) patients who did not respond to previous TKI treatment. A high dose of TKI may overcome resistance to the standard dose of TKI and have different effectiveness toward cancer compared with the standard dose of TKI. This manuscript describes a dramatic and durable response to high-dose icotinib in a NSCLC patient who did not respond to a previous standard dose of erlotinib. The treatment extended the life of the patient for one additional year. A higher dose of icotinib deserves further study not only for patients whose therapy failed with the standard dose of TKI but also for newly diagnosed NSCLC patients with a sensitive mutation. Serial mutation testing during disease development is necessary for analysis and evaluation of EGFR TKI treatment. © 2013 Elsevier Ireland Ltd. All rights reserved.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) retreatment is one of the therapeutic options for non-small cell lung cancer (NSCLC) patients who previously beneﬁted from TKI treatment . For patients who did not respond to previous TKI treatment, however, it is rarely administered subsequent to TKI therapy. High-dose imatinib has been an alternative for patients with chronic myelogenous leukemia (CML) that is resistant to a standard-dose of imatinib . Icotinib has a dose-dependent steady-state concentration without the maximum tolerated dose (MTD) being reached, its recommended dose (125 mg, 3 times daily) is far from its tolerated dose, and adverse events are well tolerated [3–7]. Here, we report a dramatic and durable response to high-dose icotinib in a NSCLC patient who did not respond to a previous standard dose of erlotinib. A 46-year-old non-smoking man who was diagnosed with stage IV lung adenocarcinoma by core needle biopsy of the supraclavicular lymphadenopathy in July 2009 became bedridden with severe dyspnea in April 2010 after failing ﬁrst-line chemotherapy with docetaxel 75 mg/m2 and cisplatin 75 mg/m2 (every 3 weeks for 2 cycles), second-line treatment with erlotinib for 4 months with a best response of “stable disease” and third-line therapy with pemetrexed 500 mg/m2 and carboplatin (area under the curve (AUC) = 5) (every 3 weeks for 2 cycles). Chest computed tomography (CT) revealed a mass at the middle lobe of the right lung, obvious diffuse lesions of the bilateral lungs and moderate intra-cavity effusion (Fig. 1a). An exploratory study was carried out using high-dose icotinib (375 mg, 3 times daily) as salvage therapy for this patient after ethics committee approval and complete informed consent. Surprisingly, within 1 week of the initiation, his dyspnea improved signiﬁcantly. The side effect was limited to a grade II rash. A follow-up chest CT in May 2010 demonstrated improvement of the bilateral lung disease and hydropericardium (Fig. 1b). His remission was maintained for more than 6 months. 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.12.002
In October 2010, his disease progressed because of the presence of hydroperitoneum, which was improved by peritoneocentesis. Considering the more than 6 months of stable disease status and the excellent tolerability, icotinib was reintroduced with an escalating dose that was higher than in the original treatment after palliative chemotherapy with gemcitabine (1000 mg/m2 ) and oxaliplatin (85 mg/m2 ) which was terminated prematurely because of intolerability. The dosage scheme of 500 mg 3 times daily was carried out for 2 months with stable disease as the best response. Next, 625 mg 3 times daily was attempted for 1 month, resulting in disease progression. The main side effect was grade III anorexia and grade II nausea. The treatment was discontinued because of his poor performance status, and he expired in March 2011. The unexpected effectiveness of salvage therapy made serial mutation testing very important. Molecular analysis of the tumor tissue for this patient was unavailable. Interestingly, hydrothorax discharged 1 week after the initiation of salvage therapy with adenocarcinoma cells that were conﬁrmed by a pathologist did not show any molecular changes (Fig. 1c). However, a mutation of G719A in exon 18 of the EGFR gene was shown during icotinib treatment (Fig. 1d). The false-negative possibility was excluded by the results of the ampliﬁcation refractory mutation system (ARMS) method (Fig. 1e and f). The disparity regarding the mutation status from the cytology samples may be due to the insufﬁcient amount of the DNA samples that were sent for testing. Clinically, the 4-month stable disease response to erlotinib may not support the existence of EGFR TKIsensitive mutations at the beginning of the diagnosis. It seems that the “newly occurring” mutation may be the main reason for the dramatic and durable response to the salvage therapy. However, it is common that the EGFR TKI resistance mutation occurs during the development of one’s disease, but that the sensitive mutations are rare. If the sensitive mutation exists, the different responses to the two types of TKIs with the same mechanisms in
Letter to the Editor / Lung Cancer 83 (2014) 305–307
Fig. 1. Computed tomography and EGFR gene mutation testing results. Computed tomography before (a) and after (b) high-dose icotinib treatment. (a) Mass at the middle lobe of the right lung, diffuse lesions of the bilateral lung and moderate intra-cavity effusion; (b) improvement of bilateral lung disease and hydropericardium after 1 month of icotinib treatment. Sequencing chromatograms of EGFR exon 18 using DNA extracted from hydrothorax with adenocarcinoma cells conﬁrmed by a pathologist 1 week after the initiation of the treatment (c) and during icotinib treatment (d). (c) Negative EGFR mutation (a normal G at nucleotide 2156 marked with a yellow bar); (d): A G → C change at nucleotide 2156 (asterisked black peak), resulting in a missense point mutation in exon 18 and substitution of a glycine (G) to an alanine (A) at amino acid position 719 (G719A). Ampliﬁcation plots from the Scorpion ARMS assay for DNA samples extracted 1week after the initiation of the treatment. (e) Ampliﬁcation plots of EGFR positive controls; (f) negative EGFR mutation (single ascending curve indicates EGFR wild type).
this paper may be due to the dose escalation. One reason why erlotinib has activity in patients who failed geﬁtinib therapy is that the plasma or central nervous system (CNS) concentration of erlotinib is higher than that of geﬁtinib [1,8]. Pulsatile highdose weekly erlotinib may achieve therapeutic concentrations and control disease again for patients who failed the standard dose of erlotinib . High-dose imatinib has been an option for CML patients to achieve a superior cytogenetic and molecular response and a quick response that leads to improved survival . Highdose TKI may have different effectiveness toward tumor cells with a molecular target. A higher dose of icotinib deserves further study not only for patients who failed the standard dose of TKI but for newly diagnosed NSCLC patients with sensitive mutations. 1. Conﬂict of interest statement
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Yin Guan ∗ Department of Medical Oncology, The Chinese PLA General Hospital, Beijing 100853, China
None declared. Acknowledgements The authors thank Professor Tongjun Lin (Dalhousie University, Halifax, Canada) for reading the manuscript and Dr. Yinxiang Wang (Beta Pharma, Hangzhou, China) for providing the icotinib. References  Costa DB, Nguyen KSH, Cho BC, Sequist LV, Jackman DM, Riely GJ, et al. Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to geﬁtinib. Clin Cancer Res 2008;14:7060–7.  Kantarjian HM, Talpaz M, O’Brien S, Giles F, Garcia-Manero G, Faderl S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003;101:473–5.  Zhao Q, Shentu J, Xu N, Zhou J, Yang G, Yao Y, et al. Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors. Lung Cancer 2011;73:195–202.  Tan F, Shen X, Wang D, Xie G, Zhang X, Ding L, et al. Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efﬁcacy in preclinical studies. Lung Cancer 2012;76:177–82.  Zhao Q, Zhou J, Shentu J, Xu N, Tan F. A phase I/IIa study of icotinib hydrochloride, a novel oral EGFR-TKI, to evaluate its safety, tolerance, and preliminary efﬁcacy in advanced NSCLC patients in China. J Clin Oncol 2010;28:15s [suppl; abstr 7574].
Hong Zhao a,b Department of Medical Oncology, The Chinese PLA General Hospital, Beijing 100853, China b Department of Medical Oncology, The Chinese PLA General Hospital (Hainan Branch), Sanya 572013, China a
Jing Meng Xiang Yan ShunChang Jiao ∗∗ Department of Medical Oncology, The Chinese PLA General Hospital, Beijing 100853, China ∗ Corresponding
author at: Department of Medical Oncology, The Chinese PLA General Hospital, #28 Fuxing Road, Haidian District, Beijing 100853, China. Tel.: +86 10 66937878; fax: +86 10 66939128.
Letter to the Editor / Lung Cancer 83 (2014) 305–307 ∗∗ Corresponding
author at: Department of Medical Oncology, The Chinese PLA General Hospital, #28 Fuxing Road, Haidian District, Beijing 100853, China. Tel.: +86 10 66939761; fax: +86 10 68236546.
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(S. Jiao) 2 June 2013