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Erlotinib for Frontline Treatment Of Cancer Therapy: Clinical Erlotinib for Frontline Treatment of Advanced Non ^ Small Cell Lung Cancer: a Phase II Study Giuseppe Giaccone,1Marielle Gallegos Ruiz,1Thierry Le Chevalier,3 Nick Thatcher,4 Egbert Smit,2 Jose Antonio Rodriguez,1Pasi Janne,5 Dalila Oulid-Aissa,6 andJean-Charles Soria3 Abstract Purpose: Erlotinib has proven activity in pretreated patients with advanced non ^ small cell lung cancer (NSCLC). We evaluated erlotinib in the frontline treatment of advanced NSCLC and assessed biological predictors of outcome. Experimental Design: In this phase II study, chemotherapy-naive patients with stage IIIB/IV NSCLC received oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity occurred.Tumor response was assessed every 6 weeks, and samples were analyzed for potential molecular markers of treatment response and survival.The primary end point was the proportion of patients without disease progression after 6 weeks of treatment. Results: Fifty-three patients were eligible. The overall rate of nonprogression at 6 weeks was 52.8% (28 of 53 patients).Tumor response rate was 22.7%, with 1complete response, 11partial responses, and 16 cases of stable disease. Responses were seen across most patient clinical characteristics. The median duration of tumor response was 333 days; median overall survival was 391days; and median time to disease progression was 84 days. Erlotinib was well tolerated, the main treatment-related adverse events being mild-to-moderate rash and diarrhea. Histologic material for biological studies was available in 29 cases. Four of five responders and one patient with stable disease had a classic epidermal growth factor receptor tyrosine kinase mutation. Two progressing patients exhibited epidermal growth factor receptor point mutations (one with T790M mutation), and K-ras mutations were detected in 10 nonresponders. Conclusions: Erlotinib shows significant antitumor activity in the first-line treatment of advanced NSCLC and may be a viable alternative to chemotherapy. Patient selection cannot easily be based on clinical or biological variables. There are f1.2 million new cases of lung cancer diagnosed in only 30% to 40% of patients and a modest survival increase every year worldwide, and 1.1 million patients die of the (2, 3); in general, single agents are inferior to combinations. disease (1). Non–small cell lung cancer (NSCLC) represents Median survival and 1-year survival after first-line chemother- 80% of lung cancers. Surgery is the most important curative apy are 8 to 10 months and 30% to 40%, respectively (4). These modality in the treatment of early-stage NSCLC; however, regimens are associated with considerable toxicity, particularly only f20% to 30% of patients are diagnosed at an operable myelosuppression. More effective and less toxic treatments are stage. urgently needed for advanced NSCLC. Platinum-based doublet chemotherapy, the standard treat- Among the new drugs that have been introduced in the ment for advanced NSCLC, achieves mostly partial responses treatment of advanced NSCLC after failure of first- line chemotherapy are docetaxel, pemetrexed, and, recently, epidermal growth factor receptor (EGFR) tyrosine kinase (TK) Authors’ Affiliations: Departments of 1Medical Oncology and 2Pulmonary inhibitors. All of these agents produce a low response rate Diseases, Vrije Universiteit Medical Center, Amsterdam, the Netherlands; 3Institut (below 10%) and have different toxicity profiles. In a large 4 Gustave Roussy, Paris, France; Christie Hospital, Manchester NHSTrust, randomized study, erlotinib improved survival versus best Manchester, United Kingdom; 5Dana-Farber Cancer Center, Boston, Massachusetts; and 6Hoffmann-La Roche Ltd., Basel, Switzerland supportive care in second-line and third-line treatment (5). Received 2/6/06; revised 3/25/06; accepted 5/4/06. Erlotinib is a targeted agent that inhibits EGFR by competing Grant support: Hofmann-La Roche Ltd., Basel, Switzerland (G. Giaccone); with ATP at the intracellular TK domain of the receptor. AstraZeneca (G. Giaccone); and Genentech (P. Janne). Erlotinib is given orally continuously and is devoid of bone The costs of publication of this article were defrayed in part by the payment of page marrow and major organ toxicities (6). Common side effects charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. are diarrhea and skin toxicity. Note: N.Thatcher did an expert testimony for Roche. Despite promising preclinical data, the combination of Requests for reprints: Giuseppe Giaccone, Department of Medical Oncology, small-molecule inhibitors of EGFR with first-line chemotherapy Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, failed to improve survival, compared with chemotherapy alone the Netherlands. Phone: 31-20-444-4321; Fax: 31-20-444-4079; E-mail: [email protected]. in four large randomized studies that investigated erlotinib or F 2006 American Association for Cancer Research. gefitinib in combination with either carboplatin-paclitaxel or doi:10.1158/1078-0432.CCR-06-0260 cisplatin-gemcitabine (6). www.aacrjournals.org 6049 Clin Cancer Res 2006;12(20) October 15, 2006 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2006 American Association for Cancer Research. Cancer Therapy: Clinical We did a phase II study of single-agent erlotinib as first- Treatment line therapy in patients with advanced NSCLC. We also did Erlotinib 150-mg tablets were given orally daily, in the morning biological studies on tumor samples of patients entered in with 200 mLof water, and at least 1 hour before or 2 hours after ingestion the study to identify patients who benefited most from of food or medication. Caution was taken to avoid medications that treatment. interact with CYP 450-3A4 enzyme, and concomitant warfarin was not permitted. Assessment of toxicity was according to National Cancer Patients and Methods Institute Common Toxicity Criteria version 2.0. Dose adjustments, in 50-mg decrements, were done if grade 3 or 4 toxicity was encountered. Patients Before starting treatment, patients were assessed by physical Patients with a histologic or cytologic diagnosis of advanced examination, electrocardiogram, disease measurement by appropriate NSCLC not amenable to radical surgery or radiotherapy were eligible radiological techniques, complete blood cell counts, serum chemistries, for the study. No prior chemotherapy or other systemic treatment was and urine pregnancy test in females of childbearing potential. Patients allowed. Other eligibility criteria were measurable disease according to were evaluated every 3 weeks, and hematology and blood chemistry the Response Evaluation Criteria in Solid Tumors, ages z 18 years, were done; tumor measurements were assessed every 6 weeks. An performance status of 0 to 2, life expectancy z 12 weeks, at least electrocardiogram was repeated after 18 weeks of treatment and as 4 weeks since any prior surgery or radiotherapy, granulocyte count clinically indicated afterwards. Response assessment was according to z1.5 Â 109/L, platelet count z100 Â 109/L, bilirubin and trans- the Response Evaluation Criteria in Solid Tumors (7). All patients aminases V1.5 Â upper limit of normal, and serum creatinine V1.5 Â received the Lung Cancer Symptoms Score patient scale questionnaire at upper limit of normal, or creatinine clearance z60 mL/min. Females baseline and again at 3 and 6 weeks and every 6 weeks thereafter. of childbearing potential had to have a negative pregnancy test. Mutation analysis and chromogenic in situ Patients were excluded if they had unstable systemic disease (active infection, uncontrolled hypertension, unstable angina, congestive hybridization heart failure, myocardial infarction within the previous year, and Mutation analysis of EGFR, PIK3CA, and K-ras. Paraffin-embedded A serious cardiac arrhythmia requiring medication), any other malig- tumor material was cut into 4- m-thick sections and placed onto glass nancies within 5 years except for adequately treated carcinoma in situ slides, stained with H&E, and the presence of tumor cells was verified by of the cervix, or basal or squamous cell skin cancer. Patients with a pathologist. Tumor cells were microdissected, and genomic DNA was brain metastases were only allowed in the study if there was no isolated using the QIAamp DNA Micro kit (Qiagen, Venlo, The evidence of progression in the brain and in the absence of Netherlands). Nested PCRs were carried out using primers (Table 1) corticosteroid treatment. Patients with significant eye disorders were to amplify exons 18 to 21 of EGFR, exons 9 and 20 of PIK3CA, and excluded (severe dry eye syndrome, Sjogren syndrome, severe exons 1 to 2 of K-ras. To facilitate sequencing, internal primers incor- exposure keratinitis, and any other eye disorder likely to increase porated an M13Tag. Sequencing of PCR products was done with the the risk of corneal epithelial lesions). Signed informed consent was ABI PRISM 310 Genetic analyzer (Applied Biosystems, Foster City, CA). required for all patients. The study was conducted according to the Mutations were confirmed by sequencing independent PCR products. latest version of the Declaration of Helsinki, and the protocol was Because of concerns about the sensitivity of direct sequencing, DNA approved by the independent Ethics Committee and the Review Board from nine independent samples from Dana-Farber Cancer Institute and from
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