|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 26, No 7 (March 1), 2008: pp. 1182-1184 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.9039
Differential Responses to Erlotinib in Epidermal Growth Factor Receptor (EGFR)-Mutated Lung Cancers With Acquired Resistance to Gefitinib Carrying the L747S or T790M Secondary MutationsDivision of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA To the Editor: Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib, and erlotinib, is emerging as the main obstacle in managing lung cancer patients with activating EGFR mutations. The secondary resistant T790M mutation1 has been identified in around 50% of progressing patients,2 and ongoing clinical trials of second-generation, irreversible EGFR inhibitors are attempting to overcome the resistance generated by this mutation. The acquired amplification of the MET oncogene was recently reported as occurring in around 20% of TKI-resistant patients and sometimes concomitantly with T790M.3 Few other secondary mutations have been described.2,4 The optimal management of EGFR-mutated tumors that progress on gefitinib or erlotinib has not been established, but likely will depend on the mechanism of acquired resistance. Cho and colleagues published in the Journal their phase II trial experience of erlotinib for gefitinib-progressive patients.5 We propose a molecular explanation for the positive or negative response to a gefitinib to erlotinib switch in gefitinib-resistant EGFR-mutated non–small-cell lung cancers by reporting the in vitro and clinical effects of these EGFR inhibitors in two secondary mutations, L747S and T790M. Our group recently reported a patient with the L858R-EGFR–activating mutation that acquired the secondary L747S mutation after a 40-month response to gefitinib.4 L858R-L747S, in vitro, generated a pattern of partial resistance to both gefitinib and erlotinib (Fig 1A). Increasing doses of these reversible EGFR inhibitors led to enhanced proliferation arrest. However, the L858R mutation alone is more sensitive to the antiproliferative and apoptotic effects of gefitinib and erlotinib at all dose ranges tested.4 This is similar to the pattern of partial resistance described for the L858R-D761Y gefitinib-resistant mutation.2 Based on our in vitro data (Fig 1A), we predicted that an increase in the clinical doses of gefitinib or switching to erlotinib, which is given at its maximum tolerated dose,5 would lead to beneficial clinical effects in L858R-EGFR–mutant patients that acquired L747S after exposure to gefitinib. Our in vitro data also predicted that L858R-T790M (Fig 1A) or exon 19 deletion-T790M1 containing tumors would be resistant to either gefitinib or erlotinib at the currently used clinical doses. The mean steady-state serum concentration of gefitinib following a 225-mg daily dose varies from 0.03 to 0.32 µg/mL, with an average of 0.16 µg/mL6 or 0.358 µmol/L. The mean concentration increases to 0.24 µg/mL at the 300-mg daily dose and to 1.1 µg/mL at 1,000-mg a day of gefitinib.6 At the maximum tolerated and currently used dose of erlotinib (150 mg per day), the steady-state through values ranged from 0.33 to 2.64 µg/mL with a median of 1.26 ± 0.62 µg/mL7 or 2.9 µmol/L.
After progression on daily 250 mg of gefitinib, the patient with the acquired L858R-L747S-EGFR was exposed to an experimental EGFR inhibitor without a measurable response. Due to progressive pulmonary, pleural (Fig 1B), and osseous lesions, erlotinib was started at 150 mg a day. Within 1 week of use, the patient developed a moderate rash involving the face and, to a lesser extent, scalp, accompanied by severe pruritus of the lesions and other skin areas. These toxicities far exceeded her maximum toxicity to gefitinib (Fig 1C). The increase in skin-related side effects likely represents a higher biologic dose of EGFR inhibition conferred by erlotinib 150 mg a day when compared to gefitinib 250 mg a day. The patient's osseous pain and pulmonary symptoms markedly improved, and imaging studies demonstrated a partial response to erlotinib (Fig 1B), which was maintained for 6 months. Another gefitinib-resistant EGFR-mutated patient1 from our service (carrying the delL747-S752 exon 19 deletion) was also given erlotinib 150 mg a day after progression on gefitinib 250 mg a day; however, progressive symptomatic and radiographic disease was noted within the first weeks of therapy. This patient harbored the T790M mutation1 and, based on our in vitro models,1 T790M negates the activating mutation hypersensitivity to EGFR inhibitors (Fig 1A) and generates high-grade resistance to achievable clinical doses of gefitinib and erlotinib.6,7 Our clinical and biologic observations may explain the response to a gefitinib to erlotinib switch in the patient with the acquired L858R-L747S-EGFR mutation and the lack of response to such an approach in other series of EGFR-mutated, gefitinib-responsive patients that eventually progressed,5 since the T790M mutation might have been the culprit of those cases. These cases also underscore the need for utilizing tumor-derived molecular markers to understand and overcome acquired mechanisms of resistance to TKI therapy in EGFR mutated tumors. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS Funding was provided through a National Institution of Health grant (K99CA126026 to S.K.) and Specialized Program of Research Excellence in Lung Cancer (CA090578 to D.G.T); a Young Investigator Award by the American Society of Clinical Oncology, an American Association for Cancer Research–AstraZeneca-Cancer Research and Prevention Foundation Fellowship in Translational Lung Cancer Research, and a Clinical Investigator Training Program–Beth Israel Deaconess Medical Center, Harvard Medical School/MIT (to D.B.C). REFERENCES
1. Kobayashi S, Boggon TJ, Dayaram TJ, et al: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786-792, 2005 2. Balak MN, Gong Y, Riely GJ, et al: Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12:6494-6501, 2006 3. Engelman JA, Zejnullahu K, Mitsudomi T, et al: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039-1043, 2007 4. Costa DB, Halmos B, Kumar AS, et al: BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med 4:e315, 2007[CrossRef] 5. Cho BC, Im CK, Park MS, et al: Phase II study of erlotinib in advanced non–small-cell lung cancer after failure of gefitinib. J Clin Oncol 25:2528-2533, 2007 6. Baselga J, Rischin D, Ranson M, et al: Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20:4292-4302, 2002 7. Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001 Related Reply
Related Article
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
