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Journal of Clinical Oncology, Vol 23, No 30 (October 20), 2005: pp. 7738-7740 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.4471
Modern Treatment of Lung CancerCASE 2. Response to Erlotinib After Failure of Gefitinib in a Patient With Advanced Non–Small-Cell Lung CarcinomaDepartment of Medicine, University of Colorado Health Sciences Center, Aurora, CO An 80-year-old white man presented with a 1-month history of cough and right-sided, nonpleuritic, anterior chest wall pain. Chest x-ray and computed tomography (CT) scans in May 2004 demonstrated bilateral upper lobe masses, larger on the right (8.5 cm) than the left side, with invasion of a right rib anteriorly. Performance status (PS) was 1. Medical history was pertinent for 40 to 60 pack-years of smoking until 30 years prior. His father, mother, and sister all were said to have died of lung cancer. CT-guided fine-needle aspiration (FNA) in May 2004 showed cells compatible with NSCLC, cell type not specified. In June, treatment was started with carboplatin/paclitaxel and zoledronic acid. He received four cycles, and had a brief, partial response (PR) manifested by less cough, reduced anterior chest pain, and an improved chest x-ray appearance. However, by August, disease had progressed in the same thoracic sites, and in September, he was found to have a single, 8-mm brain metastasis. He received radiation to the rib and whole brain and was started on gefitinib, 250 mg/d. He had neither rash nor diarrhea and had no response in the chest. He was then given two courses of Alimta in November to December, again without response. At that time, PS was 3 and he was, therefore, transferred from home to nursing home in December. An anterior-posterior (AP) chest x-ray in early January showed a large, right upper lobe (RUL) mass, with 1 to 2 additional masses inferiorly, as well as smaller left upper lobe (LUL) masses (Fig 1, see three arrows, LUL masses not visible). Early in January 2005, erlotinib, 150 mg/d, was started. Within 1 week, he developed rash and diarrhea, had disappearance of his chest pain, but now had a PS of 4. Erlotinib was held for 1 week until toxicity improved, and was restarted at 150 mg, every other day. By mid-March 2005, the only toxicity was mild rash on the dorsum of his hands. PS was 2. AP chest x-ray showed a significant decrease in the size of the RUL mass and virtual disappearance of the inferior lesions on the right. Further decrease was noted at the end of April 2005, after almost 4 months of erlotinib. (Fig 2, see 2 arrows), and further decrease was noted one month later. However, 2 months later, there was slight growth of the RUL mass, and the LUL mass had reappeared, though he remained at PS2. Erlotinib was increased to 150 mg/d. His rash briefly worsened but then receded without treatment. Two months later, an AP chest x-ray showed that the two masses had stabilized.
Gefitinib was granted accelerated approval by the US Food and Drug Administration in May 20031 for use only in patients with NSCLC progressing after standard treatment with platinum-based drugs and docetaxel. This decision was based on results of phase I/II studies2,3 with AstraZeneca (Wilmington, DE) required to conduct additional clinical trials to confirm that gefitinib did, in fact, provide clinical benefit to patients with NSCLC. Subsequently, a similar, but not identical tyrosine kinase inhibitor (TKI), erlotinib, was compared with placebo in a phase III study for patients failing at least one chemotherapy regimen. In this study, median survival of the erlotinib group was 6.7 v 4.7 months for placebo (hazard ratio [HR] = 0.73; P < .001); 1-year survival, 31.2% v 21.5%; progression-free survival, 9.9 v 7.9 weeks (HR = 0.59; P < .001); response rate, 8.9% v 0.9% (P < .001); and median response duration 34.3 v 15.9 weeks. All patient subsets benefited, with the greatest benefit being seen in patients whose tumors expressed EGFR protein (HR = 0.65) and in never-smokers (HR = 0.42).4 Based on these findings, on November 18, 2004, the US Food and Drug Administration granted full approval to erlotinib for use in patients who had failed one chemotherapy regimen.5 In March 2005, results of a phase III study (ISEL), comparing gefitinib with placebo, demonstrating no survival advantage for gefitinib, were presented to US Food and Drug Administration.6,7 Although these are two separate phase III trials, current practice is to treat no new patients with gefitinib, though those having clinical benefit should continue with it. However, all new patients should be treated with erlotinib. This appears to be the first patient reported to respond to erlotinib after failing gefitinib. This is not surprising given the results of the two phase III previously treated studies mentioned above,4,7 and suggests a significant clinical difference between the two TKIs. One can only speculate why, however. One hypothesis is that the enhanced efficacy of erlotinib is dose related.8,9 Administering an EGFR TKI at the maximum tolerated dose, as with erlotinib, may be necessary for adequate blockade of EGFR signaling in patients with wild-type receptor.10 However, in phase II studies, 250 mg of gefitinib is as effective as 500 mg, though the latter is not the maximum tolerated dose.2,3 Preliminary examination of subset analyses in the two phase III studies4,7 reveals two observations. First, while erlotinib benefits all NSCLC subsets, those of gefitinib are seen primarily in certain subsets, including women, never to minimal smokers, those of East Asian descent, those whose tumors have certain EGFR tyrosine kinase mutations, those with increased EGFR gene copy number ("fluorescent in situ hybridization positive"),11,12 and are adenocarcinomas (ADC) or ADC with bronchioloalveolar features. This also does not answer the questions of whether/why patients benefiting from gefitinib may derive greater benefit from erlotinib, or respond to the latter after failing the former. Second, erlotinib seems to demonstrate a survival benefit in several subsets in which gefitinib does not appear to be active, such as non-ADC–type NSCLC.13 Unfortunately, nothing is known about this patient’s lung cancer other than that cytology is compatible with NSCLC. Genetic and/or environmental factors may be involved, since three first-degree relatives are said to have died of lung cancer. Finally, the stabilization of the two lesions on increasing the dose of erlotinib is of interest since it may be due to using the maximum tolerated dose. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest.
REFERENCES
1. Cohen MH, Williams GA, Sridhara R, et al: United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res 10:1212-1218, 2004
2. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small cell lung cancer. J Clin Oncol 21:2237-2246, 2003
3. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer. JAMA 290:2149-2158, 2003
4. Shepherd FA, Pereira JR, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005
5. Johnson JR, Cohen M, Sridhara R, et al: Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res 11:6414-6421, 2005 6. Oncology Drug Advisory Committee Meeting, March 4, 2005 7. Thatcher N, Chang A, Parikh P, et al: Results of a phase III placebo-controlled study (ISEL) of gefitinib (IRESSA) plus best supportive care (BSC) in patients with advanced non-small-cell lung cancer (NSCLC) who had received 1 or 2 prior chemotherapy regimens. Proc Am Assoc Cancer Res 2005; Late Breaking Session:LB-6
8. 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
9. Ranson M, Hammond LA, Ferry D, et al: ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 20:2240-2250, 2002
10. Giaccone G: Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol 23:3235-3242, 2005 11. Hirsch FR, Varella-Garcia M, McCoy J, et al: Increased EGFR gene copy number detected by FISH associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes. J Clin Oncol 23: 10.1200/JCO.2005.01.2823
12. Janne PA, Engelman JA, Johnson BE: Epidermal growth factor receptor mutations in non-small cell lung cancer: Implications for treatment and tumor biology. J Clin Oncol 23:3227-3234, 2005
13. Comis RL: The current situation: Erlotinib (Tarceva®) and gefitinib (Iressa®) in non-small cell lung cancer. Oncologist 10:467-470, 2005 This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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