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Phase II Trial of Cetuximab in Patients With Previously Treated Non–Small-Cell Lung Cancer

Nasser Hanna, Rogerio Lilenbaum, Rafat Ansari, Thomas Lynch, Ramaswamy Govindan, Pasi A. Jänne, Philip Bonomi

From the Indiana University, Indianapolis; Michiana Oncology/Hematology, South Bend, IN; Mt Sinai Cancer Center, Miami Beach, FL; Massachusetts General Hospital; Dana-Farber Cancer Institute, Boston, MA; Washington University, St Louis, MO; and Rush Medical College, Chicago, IL

Address reprint requests to Nasser Hanna, MD, 535 Barnhill Dr, RT 473, Indianapolis, IN 46202; e-mail: nhanna{at}iupui.edu

	ABSTRACT

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Purpose: To determine the efficacy of cetuximab in patients with recurrent or progressive non–small-cell lung cancer (NSCLC) after receiving at least one prior chemotherapy regimen.

Patients and Methods: This was an open-label, phase II study of patients with epidermal growth factor receptor (EGFR) –positive and EGFR-negative advanced NSCLC with Eastern Cooperative Oncology Group performance status 0 to 1. Patients received cetuximab 400 mg/m² intravenously (IV) during 120 minutes on week 1 followed by weekly doses of cetuximab 250 mg/m² IV during 60 minutes. A cycle was considered as 4 weeks of treatment and therapy was continued until disease progression or intolerable toxicities. The primary end point was to assess response rate. Secondary end points included an estimation of time to progression and survival.

Results: Patient and disease characteristics (n = 66) included EGFR-positive status (n = 60); EGFR-negative status (n = 6); number of prior regimens (one, n = 28; two, n = 27; three, n = 11); male (n = 41); female (n = 25); adenocarcinoma (n = 36); and smoking status (never, n = 13; former, n = 45; current, n = 8). Grade 3/4 toxicities included acne-like rash (6.1%), anaphylactic reactions (1.5%), and diarrhea (1.5%). The response rate for all patients (n = 66) was 4.5% (95% CI, 0.9% to 12.7%) and the stable disease rate was 30.3% (95% CI, 19.6% to 42.9%). The response rate for patients with EGFR-positive tumors (n = 60) was 5% (95% CI, 1.0% to 13.9%). The median time to progression for all patients was 2.3 months (95% CI, 2.1 to 2.6 months) and median survival time was 8.9 months (95% CI, 6.2 to 12.6 months).

Conclusion: Although the response rate with single-agent cetuximab in this heavily pretreated patient population with advanced NSCLC was only 4.5%, the disease control rates and overall survival seem comparable to that of pemetrexed, docetaxel, and erlotinib in similar groups of patients.

	INTRODUCTION

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The majority of patients with non–small-cell lung cancer (NSCLC) will be diagnosed at an advanced stage (IIIB/IV) and subsequently succumb to the disease, usually within 2 years.¹ Many regimens given in the first-line setting result in a median survival time of 8 to 10 months, with 1- and 2-year survival rates of 35% to 45%, and 10% to 20%, respectively.² Approximately half of all patients achieve a partial response or stable disease (SD), which typically lasts for 3 to 6 months. Unfortunately, progression of cancer is inevitable and therapeutic options in the second-line setting and beyond are limited. Based on benefits seen in phase III trials, two chemotherapy agents, docetaxel and pemetrexed, have been approved by the US Food and Drug Administration to treat patients in the second-line setting.^3,4 In addition, erlotinib, an inhibitor of the tyrosine kinase of the epidermal growth factor receptor (EGFR), recently has gained regulatory approval for treatment in the second- or third-line setting.⁵

The EGFR is expressed in many normal human tissues, and activation of this proto-oncogene results in overexpression in many tumor types, including NSCLC.⁶ The extracellular domain of the EGFR binds transforming growth factor alpha and the epidermal growth factor itself. On ligand binding, the intracellular domain is activated, triggering cellular mechanisms that regulate cell growth.⁷ Cetuximab, a chimerized antibody of the immunoglobulin G1 subclass, has a five-fold greater affinity for the EGFR than the natural ligands, and inhibits ligand-induced activation of the EGFR.⁸ Cetuximab stimulates EGFR internalization, effectively removing the receptor from the cell surface for interaction with the ligands.⁹ In addition, due to its immunoglobulin G1 construct, in vitro cetuximab has been shown to mediate antibody-dependent cellular cytotoxicity against certain tumor types. Both in vitro and in vivo studies demonstrate that cetuximab inhibits lung cancer cell lines and tumor xenografts in nude mice.⁷ On the basis of these preclinical data, and the efficacy demonstrated by EGFR tyrosine kinase inhibitors at the time this study was initiated, we conducted this multi-institutional phase II study to evaluate the efficacy of cetuximab in patients with advanced NSCLC previously treated with chemotherapy.

	PATIENTS AND METHODS

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Eligibility criteria included age 18 years; histologic or pathologic confirmation of NSCLC; prior treatment with at least one chemotherapy regimen for recurrent or metastatic disease, including at least one platinum-based combination; measurable disease by the Response Evaluation Criteria in Solid Tumors Group response criteria; an Eastern Cooperative Oncology Group performance status 0 or 1; and tumor tissue available for EGFR assessment. Patients were required to have adequate baseline hematologic (absolute neutrophil count 1,500/µL, platelets 100,000/µL, and hemoglobin 8 g/dL), renal (serum creatinine level 2.0 mg/dL or calculated creatinine clearance 50 mL/min), and hepatic (alkaline phosphatase, AST, and ALT levels 2.5x upper limit of normal, and total bilirubin 1.5x upper limit of normal) function. Patients with asymptomatic brain metastases who were adequately treated at least 3 weeks before enrollment and were not receiving corticosteroids were eligible. Patients were excluded if they had prior treatment with an anti-EGFR agent or prior therapy with a monoclonal antibody. Prior radiation therapy was to be completed at least 3 weeks before enrollment, and could not have been given to the only site of measurable disease unless there was documentation of disease progression postirradiation. Prior chemotherapy must have been completed at least 30 days before the first infusion of cetuximab. Patients with significant history of cardiac disease or those undergoing major thoracic or abdominal surgery within 30 days before the first infusion of cetuximab were ineligible. The protocol was approved by the institutional review boards with jurisdiction over the specific sites that registered patients onto the study. Each patient provided written informed consent before enrollment.

Patients underwent the following pretreatment evaluations: a 12-lead ECG and a computed tomography scan of the chest and upper abdomen was performed within 28 days before treatment, with a bone scan and/or computed tomography scan or magnetic resonance imaging of the brain also performed within 28 days before treatment at the treating physician's discretion. A medical history, physical examination, assessment of Eastern Cooperative Oncology Group performance status, a CBC with differential and platelet count, and a chemistry panel were completed within 14 days of treatment. Women of childbearing potential had to have a negative urine or serum pregnancy test within 72 hours before treatment. Tumor EGFR expression was assessed with a DakoCytomation EGFR pharmDx immunohistochemistry kit (Dako) and classified as either positive (based on any positive staining) or negative.

Treatment Plan
All patients received an initial dose of cetuximab 400 mg/m² administered intravenously during 120 minutes followed by weekly doses of cetuximab at 250 mg/m² (during 60 minutes). Treatment continued until disease progression or unacceptable toxicity. A treatment cycle was defined as 4 weeks of treatment. Patients received premedication before the first cetuximab dose consisting of 50 mg intravenous diphenhydramine hydrochloride (or a similar agent). Premedication before subsequent doses was recommended and could be reduced at the investigator's discretion. Response assessments (based on Response Evaluation Criteria in Solid Tumors Group criteria) were performed every 8 weeks. Responses were confirmed with repeat assessments no less than 4 weeks after the initial claim of response.

A maximum of two cetuximab dose level reductions was permitted per patient: first to 200 mg/m², then to 150 mg/m². In the event of grade 3 diarrhea or nausea/vomiting, the dose of cetuximab was maintained. For a second event, cetuximab was reduced one dose level, and for a third event, cetuximab was reduced two dose levels. For grade 3 headaches, the infusion rate was reduced by 50%. For all other grade 3 nonhematologic toxicities, the dose was decreased by one dose level. In the event of a grade 1 hypersensitivity reaction, the cetuximab infusion rate was decreased by 50% and the patient was monitored closely for any worsening. If a grade 2 hypersensitivity reaction occurred, treatment was stopped and the patient was treated as appropriate. The infusion could be resumed at 50% of the previous rate once the event resolved or decreased to grade 1 in severity. If a second hypersensitivity reaction was experienced, treatment was stopped and the patient was removed from the study. For a grade 3 or 4 hypersensitivity reaction, the patient was treated as appropriate and taken off study with no additional cetuximab treatment. If a patient experienced a grade 3 acne-like rash (rash/desquamation), cetuximab therapy was held for up to four consecutive infusions. If the toxicity resolved to grade 2 by the following treatment period, treatment could have been resumed. Cetuximab was reduced by one dose level for a second occurrence of grade 3 acne-like rash, and two dose levels for a third occurrence.

Statistical Analysis
This was a phase II, open-label, nonrandomized study. A modified Gehan two-stage design was used to determine sample size, with separate decision rules for EGFR-negative and EGFR-positive patients. An accrual of 50 response-assessable patients per subgroup was calculated for a total of 100 patients on the study. For each subgroup, 29 response-assessable patients were to be accrued to the first stage. If no responses were observed in that subgroup, no additional patients would be accrued, and it would be concluded that the true response rates is unlikely to be 10% for that subgroup. Otherwise, if at least one response were seen in the subgroup, accrual to that subgroup would continue to the second stage (total 50 patients). For each subgroup, this design would result in at least a 95% chance of continuing accrual after the first stage given that the true response rate is at least 10%. With a total accrual of 50 patients, the maximum width of the exact two-sided 95% Clopper-Pearson CI in each subgroup is 27% when the response rate is in the expected range of 5% to 30%. However, due to anticipated differences in enrollment rates, it was determined before initiating the study that the study would be closed to enrollment after approximately 50 EGFR-positive patients and that the analysis of EGFR-negative patients would be exploratory.

The primary objective of this study was to determine the tumor response rate for single-agent cetuximab in the EGFR-positive subgroup. Secondary objectives were to determine the tumor response rate for the overall study population and for the EGFR-negative subgroup, and to determine the time to disease progression, survival, and safety within each subgroup and for the overall population. Demographic and baseline laboratory results were summarized using descriptive statistics for all treated patients. An exact two-sided 95% Clopper-Pearson CI was computed for each response rate. For the secondary efficacy measures of survival and time to progression, Kaplan-Meier estimates were calculated, and medians with two-sided 95% CIs are reported. Worst toxicity grades (using National Cancer Institute Common Toxicity Criteria, Version 2) per patient were tabulated for selected adverse events and laboratory measurements.

	RESULTS

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Between May 2003 and March 2004, 66 patients were enrolled from eight sites. Patient demographics and disease characteristics are summarized in Table 1. Two thirds of patients were male, the median age was 63 years (range, 39 to 79 years), all but six patients had EGFR-positive tumors, and 58% of patients had received two or more prior regimens. Enrollment to the EGFR-negative cohort was closed after only six patients because of the low incidence of EGFR-negative tumors and slow accrual. Twenty percent of patients enrolled onto this study were never smokers. Only 35% of patients had not been receiving therapy 3 months before enrollment, and 38% of patients had received prior docetaxel, whereas none had received prior pemetrexed or erlotinib.

Safety
Toxicity data for all patients (n = 66) are summarized in Table 5. Hematologic toxicity was minimal. Nonhematologic toxicity generally was grade 1 or 2 and consisted primarily of GI disorders, with 21.2% of patients experiencing any grade constipation, 22.7% experiencing any grade diarrhea, and 31.8% experiencing any grade nausea. Any grade acne-like rash occurred in 89.4% of all patients; however, only four patients (6.1%) had rash more than grade 2. The time until first occurrence of rash was in week 1 or 2 in 86.4% of those experiencing rash. One patient experienced a grade 3 anaphylactic reaction. Many patients experienced fatigue (56.1%), infections (31.8%), and dyspnea (40.9%), although most of these events were grade 1 or 2 and believed to be unrelated to cetuximab. Six patients required a dose reduction due to toxicities (including skin toxicity and one patient with delayed hematologic recovery), and no patient required more than one dose reduction.

	DISCUSSION

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The US Food and Drug Administration has granted approval to four agents in the second- or third-line setting, including docetaxel, pemetrexed, erlotinib, and gefitinib.^3-5,12 The response rate of each agent is reported to be less than 10% in phase III trials. With these agents, the median time to disease progression is approximately 2 to 3 months and the median survival time is 5 to 8 months.

It has been reported that somatic mutations within the EGFR tyrosine kinase domain predict for responsiveness to EGFR tyrosine kinase inhibitors.^13,14 It is noteworthy that inhibition of the extracellular domain of the EGFR has differing effects on lung cancer cells compared with inhibition of the intracellular tyrosine kinase. Mukohara et al¹⁵ evaluated NSCLC cell lines carrying wild-type EGFR (A549, H441, and H1666) or mutant EGFR (H3255, DFCILU-011, PC-9, and HCC827) treated with cetuximab or gefitinib. Growth of NSCLC lines with wild-type EGFR were inhibited by both cetuximab and gefitinib, whereas the mutant type was more effectively inhibited by gefitinib. Notably, two of the three patients in our study with EGFR mutations achieved SD as best response to cetuximab. Two of these three patients known to have mutations in our study received subsequent treatment with gefitinib and both are reported to have achieved a subsequent response. This suggests that the mechanism that results in tumor response differs between these agents.

The role of cetuximab in combination with chemotherapy, EGFR tyrosine kinase inhibitors, or radiation therapy in patients with NSCLC is undergoing investigation. In preclinical studies, cetuximab alone inhibits the in vitro growth of some, but not all EGFR-expressing NSCLC cell lines.¹⁶ Increased antitumor effects have been observed in vitro when cetuximab was combined with chemotherapy.¹⁶ Enhanced efficacy has been observed in patients with colorectal cancer and head/neck cancer when treated with cetuximab plus chemotherapy compared with cetuximab alone.^17-19 Cunningham et al¹⁷ randomly assigned 329 patients with colorectal cancer, whose disease had progressed after an irinotecan-based regimen, to receive cetuximab with or without irinotecan. Response rates and time to disease progression were prolonged significantly for the combination arm. Similarly, Baselga et al¹⁸ evaluated 96 platinum-refractory patients with recurrent or metastatic head/neck cancer receiving cetuximab plus platinum chemotherapy and reported a disease control rate of 53%, including 10% of patients with a partial response. Herbst et al¹⁹ have reported similar results with a cetuximab/cisplatin regimen for patients with platinum-refractory head/neck cancer. These collective data suggest that chemotherapy-refractory cells may become resensitized to chemotherapy when combined with cetuximab.

Three studies have combined cetuximab with chemotherapy in the first-line setting in patients with metastatic NSCLC, whereas one study has combined cetuximab with docetaxel in the second-line setting.^20-23 From these studies we can conclude that it is feasible to combine cetuximab with various chemotherapy agents in full dosages and that there are no untoward adverse effects. Whether these combinations will improve survival compared with chemotherapy alone is the subject of ongoing phase III trials.

Raben et al¹⁶ also report that treatment with cetuximab plus radiation in EGFR-expressing cell lines results in a marked improvement in tumor growth inhibition compared with either modality alone. Furthermore, the combination of chemotherapy, radiation, and cetuximab may yield even greater benefits in vivo when compared with cetuximab plus radiation or chemoradiotherapy alone.¹⁶ This preclinical observation has been demonstrated clinically in a study reported by Bonner et al.²⁴ In this trial, patients with locoregionally advanced squamous cell carcinoma of the head and neck were randomly assigned to radiation alone or cetuximab plus radiation. The locoregional control rates were substantially higher in the cetuximab arm, which translated into a significant survival advantage. Testing of this hypothesis in locally advanced NSCLC is being undertaken by the Cancer and Leukemia Group B and the Radiation Therapy Oncology Group. Patients enrolled onto these trials will receive chemoradiotherapy with or without cetuximab during radiation.

Finally, what is the role of combined EGFR inhibition by receptor antibodies and tyrosine kinase inhibitors? Huang et al²⁵ examined the combination of cetuximab with either gefitinib or erlotinib across a variety of cancer cell lines and noted enhanced cell inhibition and tumor regression in mice with the combination compared with any of the single agents alone. Similarly, Matar et al²⁶ reported synergistic effects on cell proliferation and superior inhibition of EGFR-dependent signaling and induction of apoptosis with the combination of cetuximab plus gefitinib. Phase I/II trials are ongoing and initial results testing this hypothesis in patients with advanced NSCLC should be available soon.

In conclusion, cetuximab is well tolerated in heavily pretreated patients with advanced NSCLC. The efficacy of cetuximab seems comparable but not superior to currently available chemotherapy drugs or EGFR tyrosine kinase inhibitors. However, the use of cetuximab for the treatment of lung cancer remains investigational. The assessment of cetuximab in combination with chemotherapy, radiation therapy, and EGFR tyrosine kinase inhibitors in patients with NSCLC is underway in clinical studies.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Nasser Hanna Bristol-Myers Squibb Co Rogerio Lilenbaum Genentech; CTI Sanofi-aventis Thomas Lynch ImClone Systems Inc; OSI Pharmaceuticals; Genentech Genentech; OSI Pharmaceuticals Pasi A. Jänne Genentech; Genzyme

	Author Contributions

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Conception and design: Nasser Hanna, Rogerio Lilenbaum, Thomas Lynch, Ramaswamy Govindan, Pasi A. Jänne, Philip Bonomi Provision of study materials or patients: Nasser Hanna, Rogerio Lilenbaum, Rafat Ansari, Thomas Lynch, Ramaswamy Govindan, Pasi A. Jänne, Philip Bonomi Manuscript writing: Nasser Hanna, Rogerio Lilenbaum, Thomas Lynch, Ramaswamy Govindan, Pasi A. Jänne, Philip Bonomi Final approval of manuscript: Nasser Hanna, Rogerio Lilenbaum, Rafat Ansari, Thomas Lynch, Ramaswamy Govindan, Pasi A. Jänne, Philip Bonomi

 

	NOTES

 
Supported by a grant from Bristol-Myers Squibb Co.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2004, New Orleans, LA; the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; and the International Association for the Study of Lung Cancer, July 3-6, 2005, Barcelona, Spain.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
1. Mountain C: Revisions in the international system for staging lung cancer. Chest 111 : 1710 -1717, 1997[Medline]

2. Schiller J, Harrington D, Belani C, et al: Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 346 : 92 -98, 2002[Abstract/Free Full Text]

3. Shepherd F, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18 : 2095 -2103, 2000[Abstract/Free Full Text]

4. Hanna N, Shepherd F, Fossella F, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol 22 : 1589 -1597, 2004[Abstract/Free Full Text]

5. Shepherd F, Rodrigues J, Ciuleanu T, et al: Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 353 : 123 -132, 2005[Abstract/Free Full Text]

6. Rowinsky E: The erbB family: Targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med 55 : 433 -457, 2004[CrossRef][Medline]

7. Yarden Y, Ullrich A: Growth factor receptor tyrosine kinases. Annu Rev Biochem 57 : 443 -478, 1988[CrossRef][Medline]

8. Goldstein N, Prewett M, Zuklys K, et al: Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1 : 1311 -1318, 1995[Abstract]

9. Waksal H: Role of an anti-epidermal growth factor receptor in teating cancer. Cancer Metastasis Rev 18 : 427 -436, 1999[CrossRef][Medline]

10. Massarelli E, Andre F, Liu D, et al: A retrospective analysis of the outcome of patients who have received two prior chemotherapy regimens including platinum and docetaxel for recurrent non-small cell lung cancer. Lung Cancer 39 : 55 -61, 2003[CrossRef][Medline]

11. Hanna N, Paul S, De Marinis F, et al: Multiple regression analysis of prognostic variables for survival from the phase III study of pemetrexed vs. docetaxel in non-small cell lung cancer (NSCLC). Lung Cancer 41 : S5 , 2003 (suppl 2; abstr O-5)

12. Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small cell lung cancer: Results from a randomized, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366 : 1527 -1537, 2005[CrossRef][Medline]

13. Paez J, Janne P, Lee J, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304 : 1497 -1500, 2004[Abstract/Free Full Text]

14. Lynch T, Bell D, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med 350 : 2129 -2139, 2004[Abstract/Free Full Text]

15. Mukohara T, Engelman J, Hanna N, et al: Differential effects of gefitinib and cetuximab on non-small cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst 97 : 1185 -1194, 2005[Abstract/Free Full Text]

16. Raben D, Helfrich B, Chan D, et al: The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin Cancer Res 11 : 795 -805, 2005[Abstract/Free Full Text]

17. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351 : 337 -345, 2004[Abstract/Free Full Text]

18. Baselga J, Trigo J, Bourhis J, et al: Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy inpatients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 23 : 5568 -5577, 2005[Abstract/Free Full Text]

19. Herbst R, Arquette M, Shin D, et al: Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 23 : 5578 -5587, 2005[Abstract/Free Full Text]

20. Rosell R, Daniel C, Ramlau R, et al: Randomized phase II study of cetuximab in combination with cisplatin (C) and vinorelbine (V) vs. CV alone in the first-line treatment of patients (pts) with epidermal growth factor receptor (EGFR)-expressing advanced non-small cell lung cancer (NSCLC). J Clin Oncol 22 : 620s , 2004 (suppl; abstr 7012).

21. Thienelt C, Bunn P, Hanna N, et al: Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small cell lung cancer. J Clin Oncol 23 : 8786 -8793, 2005[Abstract/Free Full Text]

22. Robert F, Blumenschein G, Dicke K: Phase Ib/IIa study of anti-epidermal growth factor receptor (EGFR) antibody, cetuximab, in combination with gemcitabine/cisplatin in patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 22 : 643 , 2003 (abstr 2587)

23. Kim E, Mauer A, Fossella F, et al: A phase II study of Erbitux (IMC-C225), an epidermal growth factor receptor (EGFR) blocking antibody, in combination with docetaxel in chemotherapy refractory/resistant patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21 : 293 , 2002 (abstr 1168)

24. Bonner J, Harari P, Giralt J, et al: Radiotherapy plus cetuximab for squamous cell carcinomaof the head and neck. N Engl J Med 354 : 567 -578, 2006[Abstract/Free Full Text]

25. Huang S, Armstrong E, Benavente S, et al: Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): Combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res 64 : 5355 -5362, 2004[Abstract/Free Full Text]

26. Matar P, Rojo F, Cassia R, et al: Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefitinib (ZD1839) and the monoclonal antibody cetuximab (IMC-C225): Superiority over single-agent receptor targeting. Clin Cancer Res 10 : 6487 -6501, 2004[Abstract/Free Full Text]

Submitted July 10, 2006; accepted September 13, 2006.

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