European Journal of Cancer (2014) 50, 1399– 1401
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
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 b
Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands 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 erlotinib administered in a weekly schedule (hereafter called ‘pulsatile erlotinib’) is thought to achieve higher concentrations in the cerebrospinal fluid and has several times been described as a salvage option for patients with leptomeningeal metastases [3–7]. Interestingly, a single ⇑ Corresponding author: Address: Department of Pulmonary Diseases, 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: [email protected] (J.L. Kuiper).
http://dx.doi.org/10.1016/j.ejca.2014.02.005 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved.
patient refractory to standard dose erlotinib who was treated with high-dose, weekly erlotinib (‘pulsatile erlotinib’) for leptomeningeal metastases, showed a response of thoracic lesions as well [8]. Also, in imatinib-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 therapeutic option for advanced, EGFR-mutated NSCLCpatients with acquired resistance to TKIs. We therefore evaluated pulsatile erlotinib in advanced EGFR-mutated NSCLC-patients with extracranial 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
1400
J.L. Kuiper et al. / European Journal of Cancer 50 (2014) 1399–1401
Fig. 1. Progression-free survival on pulsatile tyrosine kinase inhibitor (TKI)-treatment.
progression), progression-free survival (PFS), toxicity and safety were evaluated. Simon’s two-stage optimal design (p0 = 0.40, p1 = 0.60, a = 0.05, b = 0.20) was applied [11], to be able to discontinue the trial in an early phase in case of insufficient activity. When eleven patients were enrolled between October 2011 and February 2013 in the first phase of the study, ten patients were evaluated to have progressive disease (PD) or stable disease (SD) as best response. According to the predefined criteria, this was insufficient to continue to the second phase of the trial and the trial was discontinued after the first phase. Objective response rate was 9.1%, disease control rate was 36.4% and median PFS was 1.6 months (95% confidence interval (CI) 1.3–2.0 months) (Fig. 1). Two patients had a prolonged progression-free period; one patient was progressionfree for 5.9 months and one patient for 10.7 months. All patients were heavily pre-treated and received pulsatile erlotinib therapy as second to sixth line of treatment. There were no treatment interruptions and progressive disease was the only reason for discontinuation of treatment. Toxicity was acceptable in the majority of the patients; all adverse events were grade 1–2, except one grade 3 liver enzyme elevation. Nausea was the most commonly reported adverse event (63.4%). There were no treatment deaths in this trial. We initiated this trial to evaluate the effect of pulsatile erlotinib therapy in patients with extracranial progressing lesions on TKI-treatment in standard dose, after having observed a response in an individual patient refractory to standard dose erlotinib. However, response rate was unsatisfying and the trial was discontinued prematurely according to predefined assessment criteria. We therefore do not recommend this treatment to be further evaluated nor to be used in EGFR-mutated
NSCLC-patients with extracranial progressive disease on TKI-treatment in standard dose. As long as no alternative treatment options have been proven effective, chemotherapy or inclusion in a clinical trial will provide a better treatment option for these patients. Funding source None. Conflict of interest statement P.E. Postmus received honoraria from Boehringer Ingelheim. All other authors declare that they have no conflict of interest. References [1] Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR–TKI therapy in 155 patients with EGFRmutant lung cancers. Clin Cancer Res 2013;19(8):2240–7. [2] Milton DT, Azzoli CG, Heelan RT, Venkatraman E, Gomez JE, Kris MG, et al. A phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer. Cancer 2006;107(5):1034–41. [3] Clarke JL, Pao W, Wu N, Miller VA, Lassman AB. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol 2010;99(2): 283–6. [4] Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro-oncol 2011;13(12):1364–9. [5] Hata A, Kaji R, Fujita S, Katakami N. High-dose erlotinib for refractory brain metastases in a patient with relapsed non-small cell lung cancer. J Thorac Oncol 2011;6(3):653–4.
J.L. Kuiper et al. / European Journal of Cancer 50 (2014) 1399–1401 [6] Jackman DM, Holmes AJ, Lindeman N, Wen PY, Kesari S, Borras AM, et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol 2006;24(27):4517–20. [7] Togashi Y, Masago K, Fukudo M, Tsuchido Y, Okuda C, Kim YH, et al. Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation. Cancer Chemother Pharmacol 2011;68(4):1089–92. [8] Kuiper JL, Smit EF. High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases-One with a remarkable thoracic response as well. Lung Cancer 2013;80(1):102–5.
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[9] Blanke CD, Rankin C, Demetri GD, Ryan CW, von MM, Benjamin RS, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008;26(4):626–32. [10] 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(2):473–5. [11] Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10(1):1–10.
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
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 b
Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands 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 erlotinib administered in a weekly schedule (hereafter called ‘pulsatile erlotinib’) is thought to achieve higher concentrations in the cerebrospinal fluid and has several times been described as a salvage option for patients with leptomeningeal metastases [3–7]. Interestingly, a single ⇑ Corresponding author: Address: Department of Pulmonary Diseases, 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: [email protected] (J.L. Kuiper).
http://dx.doi.org/10.1016/j.ejca.2014.02.005 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved.
patient refractory to standard dose erlotinib who was treated with high-dose, weekly erlotinib (‘pulsatile erlotinib’) for leptomeningeal metastases, showed a response of thoracic lesions as well [8]. Also, in imatinib-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 therapeutic option for advanced, EGFR-mutated NSCLCpatients with acquired resistance to TKIs. We therefore evaluated pulsatile erlotinib in advanced EGFR-mutated NSCLC-patients with extracranial 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
1400
J.L. Kuiper et al. / European Journal of Cancer 50 (2014) 1399–1401
Fig. 1. Progression-free survival on pulsatile tyrosine kinase inhibitor (TKI)-treatment.
progression), progression-free survival (PFS), toxicity and safety were evaluated. Simon’s two-stage optimal design (p0 = 0.40, p1 = 0.60, a = 0.05, b = 0.20) was applied [11], to be able to discontinue the trial in an early phase in case of insufficient activity. When eleven patients were enrolled between October 2011 and February 2013 in the first phase of the study, ten patients were evaluated to have progressive disease (PD) or stable disease (SD) as best response. According to the predefined criteria, this was insufficient to continue to the second phase of the trial and the trial was discontinued after the first phase. Objective response rate was 9.1%, disease control rate was 36.4% and median PFS was 1.6 months (95% confidence interval (CI) 1.3–2.0 months) (Fig. 1). Two patients had a prolonged progression-free period; one patient was progressionfree for 5.9 months and one patient for 10.7 months. All patients were heavily pre-treated and received pulsatile erlotinib therapy as second to sixth line of treatment. There were no treatment interruptions and progressive disease was the only reason for discontinuation of treatment. Toxicity was acceptable in the majority of the patients; all adverse events were grade 1–2, except one grade 3 liver enzyme elevation. Nausea was the most commonly reported adverse event (63.4%). There were no treatment deaths in this trial. We initiated this trial to evaluate the effect of pulsatile erlotinib therapy in patients with extracranial progressing lesions on TKI-treatment in standard dose, after having observed a response in an individual patient refractory to standard dose erlotinib. However, response rate was unsatisfying and the trial was discontinued prematurely according to predefined assessment criteria. We therefore do not recommend this treatment to be further evaluated nor to be used in EGFR-mutated
NSCLC-patients with extracranial progressive disease on TKI-treatment in standard dose. As long as no alternative treatment options have been proven effective, chemotherapy or inclusion in a clinical trial will provide a better treatment option for these patients. Funding source None. Conflict of interest statement P.E. Postmus received honoraria from Boehringer Ingelheim. All other authors declare that they have no conflict of interest. References [1] Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR–TKI therapy in 155 patients with EGFRmutant lung cancers. Clin Cancer Res 2013;19(8):2240–7. [2] Milton DT, Azzoli CG, Heelan RT, Venkatraman E, Gomez JE, Kris MG, et al. A phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer. Cancer 2006;107(5):1034–41. [3] Clarke JL, Pao W, Wu N, Miller VA, Lassman AB. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol 2010;99(2): 283–6. [4] Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro-oncol 2011;13(12):1364–9. [5] Hata A, Kaji R, Fujita S, Katakami N. High-dose erlotinib for refractory brain metastases in a patient with relapsed non-small cell lung cancer. J Thorac Oncol 2011;6(3):653–4.
J.L. Kuiper et al. / European Journal of Cancer 50 (2014) 1399–1401 [6] Jackman DM, Holmes AJ, Lindeman N, Wen PY, Kesari S, Borras AM, et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol 2006;24(27):4517–20. [7] Togashi Y, Masago K, Fukudo M, Tsuchido Y, Okuda C, Kim YH, et al. Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation. Cancer Chemother Pharmacol 2011;68(4):1089–92. [8] Kuiper JL, Smit EF. High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases-One with a remarkable thoracic response as well. Lung Cancer 2013;80(1):102–5.
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[9] Blanke CD, Rankin C, Demetri GD, Ryan CW, von MM, Benjamin RS, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008;26(4):626–32. [10] 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(2):473–5. [11] Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10(1):1–10.
