Originally published as JCO Early Release 10.1200/JCO.2005.03.1997 on October 24 2005

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thienelt, C. D. Articles by Kelly, K. Search for Related Content PubMed PubMed Citation Articles by Thienelt, C. D. Articles by Kelly, K.

Multicenter Phase I/II Study of Cetuximab With Paclitaxel and Carboplatin in Untreated Patients With Stage IV Non–Small-Cell Lung Cancer

From the Division of Medical Oncology and Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Aurora, CO; Indiana University, Indianapolis, IN; Bendheim Cancer Center, Greenwich, CT; and ImClone Systems Incorporated, Branchburg, NJ.

Address reprint requests to Karen Kelly, MD, Health Sciences Center, University of Colorado at Denver, 12801 East 17th Ave, Aurora, CO 80010; e-mail: karen.kelly{at}uchsc.edu

	ABSTRACT

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

 
PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have demonstrated antitumor activity in patients with non–small-cell lung cancer (NSCLC). This study examined the safety profile of the monoclonal antibody EGFR inhibitor, cetuximab, when added to paclitaxel and carboplatin in untreated patients with stage IV NSCLC. Secondary objectives included efficacy and paclitaxel and carboplatin pharmacokinetics during cetuximab treatment.

PATIENTS AND METHODS: Patients with tumor evidence of EGFR by immunohistochemistry, performance status of 0 to 2, and measurable disease received paclitaxel 225 mg/m² with carboplatin area under the curve = 6 on day 1 every 3 weeks. Cetuximab was administered at 400 mg/m², 1 week before paclitaxel and carboplatin, then weekly at 250 mg/m². The regimen continued until disease progression or intolerable toxicity.

RESULTS: Thirty-one of 32 enrolled patients were treated. The most common cetuximab toxicity was rash in 84% of patients (grade 3 in 13%). Pharmacokinetic sampling did not reveal an interaction between carboplatin, paclitaxel, and cetuximab. An objective response was observed in eight patients (26%). With a median follow-up of 19 months, the median time to progression was 5 months, median survival was 11 months, and the 1- and 2-year survival rates were 40% and 16%, respectively.

CONCLUSION: The combination of cetuximab, paclitaxel, and carboplatin was safe and well tolerated in this population of stage IV patients. The response rate, time to progression, and median survival were slightly superior to historical controls treated with paclitaxel and carboplatin alone. A randomized phase II trial has completed accrual.

	INTRODUCTION

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

 
Current American Society of Clinical Oncology guidelines established two-drug combination chemotherapy regimens for four cycles as the standard of care for patients with advanced non–small-cell lung cancer (NSCLC).¹ A number of randomized trials comparing these doublet combinations with triplet combinations with other cytotoxic agents, with matrix metalloproteinase inhibitors, with antisense oligonucleotides, with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and with rexinoids failed to produce a survival benefit.^2-10

The most extensively studied molecular target in lung cancer is the EGFR, its related Erb-B family receptors, and their signal transduction network. EGFR is expressed in approximately 80% of NSCLCs and plays a role in the development and progression of lung cancers.¹¹ In a few studies, increased EGFR gene copy numbers were associated with a poor prognosis and decreased survival in lung cancer, but many studies failed to show a relationship between EGFR expression and survival.¹² Two classes of EGFR inhibitors have been developed, the small molecule tyrosine kinase inhibitor (EGFR-TKIs) and the anti-EGFR monoclonal antibodies. Both types of inhibitors lead to an increase in tumor cell death by blocking receptor activation and downstream signaling.¹³ Monoclonal antibodies may also work by eliciting antitumor immune responses as well. In clinical trials, the oral TKIs gefitinib and erlotinib produced objective responses in 10% to 20% of previously treated patients.^14-16 Recently, erlotinib was shown to provide a superior survival compared with placebo in the second- and third-line setting, with a median survival of 6.7 months in the erlotinib arm and 4.7 months in the placebo arm (hazard ratio = 0.73; P < .001).¹⁷ Both oral TKIs are approved by the US Food and Drug Administration for the salvage treatment of advanced NSCLC. In contrast, no benefit in terms of increased response rate, time to progression or overall survival was demonstrated with the addition of erlotinib or gefitinib to cytotoxic chemotherapy in untreated patients with advanced NSCLC.^5-8

Cetuximab (Erbitux; ImClone Systems, Branchburg, NJ) is an immunoglobulin G₁ monoclonal antibody that binds with high affinity to the extracellular region of human EGFR. Cetuximab prevents endogenous ligands from binding to EGFR and disrupts the cell signaling pathway, leading to tumor proliferation.¹⁸ In preclinical experiments and clinical trials, cetuximab demonstrated antitumor activity in a variety of solid tumors.¹⁹

Cetuximab has shown improved efficacy in combination with chemotherapy and radiation in laboratory models and in human studies. In a randomized phase II trial of 329 patients with irinotecan-refractory colorectal cancer, cetuximab plus irinotecan produced an objective response rate of 22.9% versus 10.8% for cetuximab alone (P = .007), which translated into a prolonged time to progression of 4.1 months for the doublet versus 1.5 months for single-agent cetuximab (P < .001).²⁰ These data led to the US Food and Drug Administration approval of cetuximab alone or with irinotecan as salvage therapy for previously treated patients with colorectal cancer. A similar experience was observed in head and neck cancer where cetuximab was combined with radiotherapy. A randomized phase III trial of high-dose radiation with or without cetuximab in 424 patients with locally advanced head and neck cancer demonstrated a median survival of 54 months with a 2-year survival rate of 62% for the cetuximab arm versus a median survival of 28 months and a 2-year survival rate of 55% for the radiation alone arm (P = .02).²¹ This combination of cetuximab plus radiation therapy is awaiting US Food and Drug Administration approval. In both of these large trials, cetuximab was well tolerated, with skin rash being the most frequent cetuximab-related toxicity.

In lung cancer, preclinical studies evaluating the effect of cetuximab on NSCLC cell lines and human xenografts showed cetuximab inhibited tumor growth in EGFR-positive lung cancer cell lines alone and in combination with paclitaxel or cisplatin.²² Similar patterns of growth inhibition were seen in NSCLC xenografts treated with cetuximab or cetuximab plus cisplatin.²² Recently, the final results of a phase II trial of cetuximab in recurrent NSCLC were presented.²³ Partial responses were seen in two (3.3%) of 60 patients. Fifteen patients had stable disease. The median time to progression was 2.3 months, and the median survival was 8.1 months. Cetuximab was well tolerated, with skin rash being the most commonly reported toxicity. These data are similar to what was observed with single-agent cetuximab in patients with irinotecan-refractory colon cancer cited above.

We hypothesized that the addition of cetuximab to platinum-based chemotherapy could enhance antitumor activity in the first-line treatment of advanced NSCLC, a highly EGFR-expressing epithelial tumor. Thus this multi-institutional phase I/II trial was conducted to determine the feasibility of combining cetuximab with a standard lung cancer regimen of paclitaxel and carboplatin, in chemotherapy-naive patients with stage IV NSCLC. Secondary objectives were to evaluate the effect of cetuximab on the pharmacokinetics of paclitaxel and carboplatin and to collect preliminary efficacy data for response rate and duration of response.

	PATIENTS AND METHODS

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

 
Eligibility Criteria
All patients had histologically or pathologically confirmed NSCLC (cytologic specimens obtained by brushing, washing, or needle aspiration of a defined lesion were acceptable), stage IV disease (patients with controlled brain metastases were eligible), age greater than 18 years, immunohistochemical evidence of EGFR expression ( 1+), unidimensionally measurable disease, an Eastern Cooperative Oncology Group performance status (PS) of 0 to 2, adequate organ function, and ability to provide informed consent. Exclusion criteria included prior treatment with chemotherapy or cetuximab, less than 4 weeks since wide-field radiation therapy (local radiation for management of tumor-related symptoms was permitted), history of uncontrolled angina, arrhythmias, or congestive heart failure, presence of uncontrolled seizure disorder, active neurologic disease (not tumor related), or grade 2 neuropathy, hypersensitivity to polyoxyethylated castor oil (Cremophor EL; BASF, Ludwigshafen, Germany), pregnancy, breastfeeding, or treatment with any investigational agent within 30 days of study entry. All patients provided written informed consent and approval was obtained from the ethics committee at each trial center. The study followed the institutional guidelines of clinical research at each study center.

Trial Design
This was a multicenter, open-label, two-stage, phase Ib/II study for patients with EGFR-positive, chemotherapy-naive, stage IV NSCLC. Between December 2000 and August 2002, 47 patients were screened for EGFR immunohistochemical expression, and 45 patients (96%) were EGFR-positive, with 33 patients meeting all the entry criteria. Thirty-two patients were enrolled. One enrolled patient was initially thought to have lung cancer but on further pathologic review had metastatic germ cell cancer. This patient was not treated and was excluded from further analyses. All patients received a loading dose of cetuximab of 400 mg/m² (intravenous infusion over 2 hours) 1 week before chemotherapy. Subsequent doses of cetuximab were given weekly at 250 mg/m² infused over 1 hour. Intravenous paclitaxel at 225 mg/m² was administered 1 hour after cetuximab infusion over 3 hours, followed immediately by a 30-minute intravenous infusion of carboplatin (area under the curve [AUC] of 6 mg/min/mL) on day 1 every 3 weeks. All patients received diphenhydramine before cetuximab in an effort to prevent an allergic reaction. In addition, all patients received dexamethasone and cimetidine to avoid a hypersensitivity reaction to paclitaxel. The antiemetic regimen was determined by the treating physician.

All therapy was continued until disease progression or intolerable toxicity. Patients who did not tolerate chemotherapy because of toxicity could continue on weekly cetuximab monotherapy until disease progression or unacceptable toxicity. Nine patients underwent pharmacokinetic sampling to determine the effect of cetuximab on the pharmacokinetics of paclitaxel and carboplatin therapy. Pharmacokinetic sampling for paclitaxel and carboplatin was performed during the first week of treatment cycle 1 and 2.

Patients who developed a cetuximab-related grade 1 or 2 skin rash continued weekly cetuximab. In this protocol, a grade 3 skin rash was defined as any of the following: (1) symptomatic generalized erythroderma or macular, papular, or vesicular eruption or desquamation covering 50% of the body-surface area, (2) rash/desquamation with confluence, (3) rash/desquamation with pain requiring narcotics, or (4) rash/desquamation with erosion of the skin. Any one of these four definitions constituted a grade 3 acne-like rash. A grade 4 rash was defined according to the National Cancer Institute Common Toxicity Criteria version 2.0 as generalized exfoliative dermatitis or ulcerative dermatitis. In patients experiencing their first episode of grade 3 acne-like rash, cetuximab therapy was delayed for up to two consecutive infusions with no change in dose level. Concomitant treatment with topical and/or oral antibiotics was left to the discretion of the investigator. If the toxicity resolved to grade 2 or less by the following treatment period, treatment was resumed. With the second and third occurrences of grade 3 acne-like rash, cetuximab therapy was again delayed for up to 2 weeks with concomitant dose reductions to 200 mg/m² and 150 mg/m², respectively. Treatment with cetuximab was discontinued if there were more than two consecutive infusions held or if a fourth grade 3 acne-like rash occurred. Patients were sent for a dermatologic consultation whenever a grade 3 acne-like rash occurred, and photographs of the rash were taken at the time of occurrence and when the toxicity had resolved.

Patients that experienced a grade 3 hypersensitivity reaction or a cetuximab related grade 4 major organ toxicity were discontinued from the study. A grade 4 hypersensitivity reaction required the presence of symptomatic hypotension or oxygen saturation of 70% or less.

Cetuximab therapy was not withheld for paclitaxel/carboplatin related toxicities. In the event that the next infusion of paclitaxel/carboplatin was delayed, patients still received additional infusions of cetuximab, as part of the previous cycle of therapy. Patients were terminated from the study when cetuximab therapy was discontinued. In any case of cetuximab treatment delays, there was no reloading infusion and all subsequent treatments were administered at the assigned dose level.

Patients who developed febrile neutropenia or grade 3 nonhematologic toxicity required a dose reduction of both paclitaxel and carboplatin. The therapeutic use of cytokines was left to the clinical judgment of the treating physician. Dose modifications of carboplatin were required for grade 4 thrombocytopenia, whereas dose adjustments of paclitaxel were necessary for greater than grade 2 sensory neurotoxicity. Patients who experienced grade 4 nonhematologic toxicity (excluding alopecia and cetuximab-related acne-like rash), more than two chemotherapy dose reductions, or a delay in chemotherapy administration greater than 2 weeks were discontinued from chemotherapy but could continue to receive cetuximab. Dose re-escalations of paclitaxel and carboplatin were not allowed. In cases where treatment with one of the chemotherapy agents was discontinued, treatment with the other agent was also stopped.

Pharmacokinetics
Paclitaxel measurement in serum samples was performed by the University of Colorado Cancer Center Pharmacology Core using liquid chromatography tandem mass spectroscopy. Serum paclitaxel concentrations were calculated based on a comparison to a standard curve. Platinum analysis was performed by SGS Corporation (Denver, CO) using a previously validated atomic absorption spectrophotometric method. Pharmacokinetic modeling was performed using WINNonlin software version 4.1 (Pharsight Corporation, Mountain View, CA). Paclitaxel pharmacokinetic parameters were calculated using a three-compartmental model. Platinum parameters were calculated using noncompartmental analysis.

Statistical Analysis
Patients were accrued using the Simon's optimal two-stage design.²⁴ The response rate for the new regimen was estimated as 35%; a response rate of 15% was considered inadequate. When the chance of accepting a poor regimen is 0.10 (ie, response rate 15%) and the probability of rejecting a good regimen is also 0.10 (ie, response rate 35%), the study required enrollment of 33 patients. This design required enrollment of 19 patients in the first stage. If two or fewer patients responded to the treatment (complete response [CR] plus partial response [PR]), the regimen would have been declared ineffective. If three or more patients responded, 14 more patients would be entered onto the study. The regimen was deemed potentially effective if there were seven or more responses (CR+PR), for an estimated response rate of seven (21%) of 33, with an SE of less than 9%.

Descriptive statistics (mean, SD, median, and range) were used to display all laboratory parameters. Overall survival and time to progression were assessed from the start of therapy to the date of death (any cause) and the date of objective disease progression (death was considered a progression event in patients who died before disease progression), respectively. Patients without documented death or objective progression at the time of the final analysis were censored at the date last known to be alive or their last objective tumor assessment, respectively. Tumor response was evaluated according to Response Evaluation Criteria in Solid Tumors, the revised version of the International Union Against Cancer/WHO criteria.²⁵

Assessment and Follow-Up
A history and physical examination including PS, height, and weight were conducted on all patients at baseline. The physical examination was repeated at the start of every chemotherapy cycle. Tumor response was assessed at the completion of every two cycles of therapy. All patients who have received at least one dose of cetuximab were considered assessable for response.

During the trial, and for 4 weeks after the last dose of cetuximab, patients were monitored for adverse events, graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hematology and biochemistry assessment were performed at baseline and on day 1 of each cycle (every 21 days). Nadir blood counts were not required.

	RESULTS

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

 
Patients Characteristics
Baseline characteristics of the 31 treated patients are shown in Table 1. The median age was 57 years, with a range of 36 to 75 years. Approximately half the patients were females (48%), and the majority of patients were white (90%). Thirty-two percent of patients had an Eastern Cooperative Oncology Group PS of 0, 45% had a PS of 1, and 23% had a PS of 2. Adenocarcinoma was the primary histology in 25 patients (81%), and three patients (10%) had brain metastases. Analysis of EGFR receptor status showed that 22 patients (71%) stained 3+ positive for the EGFR receptor, six patients (19%) stained 2+ positive, and three patients (10%) stained 1+ positive.

View larger version (10K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curves of (A) progression-free survival (PFS) and (B) overall survival.

Nine patients with EGFR expression of 1+ and 2+ had a median survival of 7 months (95% CI, 2 to 17 months) versus 11 months (95% CI, 6 to 21 months) for 22 patients with EGFR expression of 3+. The one- and two-year survival rates were 25.9% and 0%, respectively, in patients with EGFR expression of 1+ and 2+, versus 44.6% and 21.3%, respectively, in patients with EGFR expression of 3+.

Twenty-two patients (71%) underwent second-line therapy after experiencing treatment failure with cetuximab plus carboplatin/paclitaxel. Four patients were treated with gefitinib, 15 patients were treated with various other chemotherapy regimens, and three patients were treated with radiation therapy alone.

Duration of Therapy, Dose Adherence, and Dose-Intensity
The median duration of treatment with cetuximab was 21 weeks, with a median number of doses of 19 (range, 2 to 78) and a median dose-intensity of 253 mg/m²/wk. For the cytotoxic chemotherapy, the median number of doses of carboplatin was four, with a range of one to 13, whereas the median number of doses of paclitaxel was four, with a range of one to 26. The relative dose-intensity was 101% for cetuximab, 98% for carboplatin, and 96% for paclitaxel. Eighteen patients (58%) had chemotherapy doses withheld or had dose modifications. This was primarily for neutropenia, myalgias, nausea, and thrombocytopenia. The same number of patients had dose modifications of cetuximab.

Paclitaxel and Carboplatin Pharmacokinetics
Pharmacokinetic (PK) measurements were performed in nine patients. Paclitaxel was modeled using a three-compartment model with a dose of 225 mg/m² and a 1-hour infusion. All paclitaxel PK profiles fit this three-compartment model. The calculated terminal half-life, clearance, AUC_inf, and maximum serum concentration parameters were all within ranges seen in previous paclitaxel pharmacokinetic studies with similar dosing regimens.^26-29

Ultrafiltrate platinum PKs were modeled using noncompartmental analysis. The half-life and clearance of platinum in ultrafiltrate was similar to previous studies.^30-32 Although the measured carboplatin AUC was slightly less than predicted by the Calvert dosing formula,³³ this phenomenon has been seen in previous studies investigating pharmacokinetic interactions of paclitaxel and carboplatin.^34,35 The overprediction may be explained by the methods used to measure serum creatinine and glomerular filtration rate.³⁶ In addition, the lack of a PK sample draw between 3 and 24 hours in our study may not have been ideal. All patients had undetectable levels of platinum in ultrafiltrate at 24 hours. The inability to use intermediate time points may have caused an underprediction of half-life, which would cause the model-dependent calculated AUC_inf to be underpredicted.

	DISCUSSION

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

 
This feasibility trial demonstrated that cetuximab given with standard doses of paclitaxel and carboplatin as first-line treatment for stage IV lung cancer was safe and well tolerated. The addition of cetuximab did not produce any apparent overlapping toxicity with cytotoxic chemotherapy. An acne-like rash was the most common toxicity related to cetuximab administration. The PK analysis showed no influence of cetuximab on paclitaxel and carboplatin PKs.

The mature results of this trial suggest the efficacy of this triple combination was promising, with a 26% objective response rate, a median time to progression of 5 months, and a median survival of 11 months. The median survival time is superior to the University of Colorado phase I/II study of paclitaxel and carboplatin that reported a median time to progression of 4.5 months and a median survival of 7.8 months.³⁷ In three large United States cooperative group trials, response rates for the paclitaxel plus carboplatin arms were 25%, 15%, and 30%, time to progression was 4, 3.3, and 4.6 months, and median survival was 8, 8.2, and 8.8 months, respectively.^38-40 All of these trials included patients with stage IIIB disease and excluded brain metastases in contrast to our trial.

Our efficacy results parallel those observed in the phase II study of cetuximab plus gemcitabine and carboplatin.⁴¹ This multi-institutional trial had a similar trial design and was conducted simultaneously. In the 35 stage IV patients enrolled onto this trial, efficacy was similar, with an objective response rate of 29%, time to progression of 5.5 months, and a median survival of 10.3 months. The regimen was well tolerated, and no unexpected toxicities were observed.

A European randomized phase II trial comparing the efficacy of cetuximab, cisplatin, and vinorelbine with that of cisplatin plus vinorelbine in patients with advanced stage IIIB and IV NSCLC has been performed. This trial of 86 patients (43 patients per arm) reported an objective response rate of 35% (95% CI, 21% to 51%) for the cetuximab plus chemotherapy arm and 28% (95% CI, 15% to 44%) for the chemotherapy alone arm.⁴² The cetuximab group experienced a median survival time of 8.3 months and a 1-year survival rate of 32% as compared with the cisplatin and vinorelbine group, which demonstrated a median survival time of 7 months and a 1-year survival rate of 26%. No patients were alive in the chemotherapy alone arm at 18 months versus 14% in the cetuximab arm. The authors concluded that efficacy was enhanced with the addition of cetuximab to chemotherapy. This has led to a randomized phase III trial to definitively determine the role of cetuximab with cisplatin and vinorelbine chemotherapy.

The suggestion of enhanced efficacy of cetuximab with chemotherapy highlights a clinically relevant difference between the EGFR antibody inhibitors and small molecule inhibitors in the treatment of lung cancer. Four large, randomized trials adding gefitinib or erlotinib to chemotherapy all failed to demonstrate an increase in any efficacy parameter including objective response rate, time to progression, or survival over standard doublet chemotherapy.^5-8 One possible explanation for this discrepancy is that patients receiving cetuximab were selected based on EGFR immunohistochemical expression, whereas biologic selection was not required with the oral TKIs. However, retrospective analyses of EGFR expression in the oral TKI studies did not show a correlation between expression levels and outcome, suggesting that EGFR selection would be unlikely to account for the differences in outcome between the two classes of inhibitors.^43-45 Although our study showed a longer survival time of 4 months for patients with 3+ EGFR expression, the numbers are small and other undefined factors may have influenced the prolonged survival time. A more plausible explanation relates to the innate differences between the agents in terms of mechanism of action, specificity, and selectivity of EGFR blockade.⁴⁶ Although both share a common goal of inhibiting EGFR phosphorylation and downstream signaling, their initial attack differs, with cetuximab blocking the extracellular receptor ligand-binding domain and oral TKIs blocking the intracellular tyrosine kinase domain of EGFR. Cetuximab, unlike oral TKIs, subsequently causes receptor internalization and degradation. The lack of the EGFR at the cell surface, which is necessary for additional ligand binding, could be contributing to its antitumor effects.⁴⁷ In addition, a unique property of immunoglobulin G1 antibodies such as cetuximab is their ability to potentiate the immune system through stimulation of antibody-dependent cell-mediated cytotoxicity. In animal experiments, cetuximab has demonstrated tumor growth inhibition of EGFR-expressing tumors through this antibody-dependent cell-mediated cytotoxicity mechanism.⁴⁸ Differences in specificity and selectivity of these targeted therapies could also influence outcome. Cetuximab is a specific and selective inhibitor of the EGFR ligand-binding domain, whereas TKIs are selective but not specific for EGFR and can target a variety of receptor tyrosine kinases. Finally, pharmacologic difference between antibodies and small molecules must be considered. Cetuximab is given intravenously, whereas TKIs are administered orally. The interpatient variability with oral absorption and the dependency of small molecules on the cytochrome p450 enzyme system for elimination makes accurate evaluation of dosing issues difficult to assess with the oral TKIs. Whether or not the different characteristics of cetuximab will translate into a survival benefit for patients with lung cancer awaits the result of ongoing trials.

Skin rash is the most common sequelae from all EGFR inhibitors. In a retrospective analysis of four studies of cetuximab with or without chemotherapy in various solid tumors, a correlation between the presence of an acne-like rash and survival (P < .05) was suggested.⁴⁹ Survival also tended to be more prolonged, with worsening severity of the rash. Similar results were observed in this small study in that the presence of any rash was associated with a higher likelihood of response and prolonged survival but there was no correlation with severity of the rash.

In conclusion, the combination of paclitaxel, carboplatin, and cetuximab warrants continued investigation. The Southwest Oncology Group recently completed accrual to a randomized phase II selection trial of concurrent cetuximab with paclitaxel and carboplatin or sequential therapy with paclitaxel plus carboplatin followed by cetuximab. A median survival of 10 months or greater in either arm is needed to pursue a randomized phase III trial.

	Authors' Disclosures of Potential Conflicts of Interest

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

 
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 Paul A. Bunn Jr Imclone/Bristol- Myers Squibb (A); AstraZeneca (A); OSI/Genetech (A) Imclone/Bristol- Myers Squib (A); AstraZeneca (A); OSI/Genetech (A) Nasser Hanna Bristol-Myers Squibb (C) Michael N. Needle Imclone Systems (B) Karen Kelly Imclone Systems (A); Bristol-Myers Squibb (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	NOTES

 
Supported by a grant from ImClone Systems Incorporated.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL.

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

	REFERENCES

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

 
1. Pfister DG, Johnson DH, Azzoli CG, et al: American Society of Clinical Oncology treatment of unresectable non–small-cell lung cancer guideline: Update 2003. J Clin Oncol 22:330-353, 2004[Free Full Text]

2. Williamson SK, Crowley JJ, Lara PN, et al: S0003: Paclitaxel/carboplatin (PC v PC + tirapazamine (PCT) in advanced non-small cell lung cancer (NSCLC)—A phase III Southwest Oncology Group (SWOG) Trial. Proc Am Soc Clin Oncol 22:622, 2003 (abstr 2502)

3. Rigas JR, Denham CA, Rinaldi DA et al: Randomized placebo-controlled trials of the matrix metalloproteinase inhibitor (MMP), BAY12-9566 as adjuvant therapy for patients with small cell and non-small cell lung cancer. Proc Am Soc Clin Oncol 22:628, 2003 (abstr 2525)

4. Lynch TJ, Raju R, Lind M, et al: Randomized phase III trial of chemotherapy and antisense oligonucleotide LY900003 (ISIS 3521) in patients with advanced NSCLC: Initial Report. Proc Am Soc Clin Oncol 22:623, 2003 (abstr 2504)

5. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 22:777-784, 2004[Abstract/Free Full Text]

6. Herbst RS, Giaccone G, Schiller J, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small cell lung cancer: A phase III trial—INTACT 2. J Clin Oncol 22:785-794, 2004[Abstract/Free Full Text]

7. Gatzemeier U, Pluzanska A, Szczesna A, et al: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). J Clin Oncol 22:617s, 2004 (suppl; abstr 7010)

8. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib HCI (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC). J Clin Oncol 22:617s,2004 (suppl; abstr 7011)

9. Blumenschein GR, Khuri F, Gatzemeier U, et al: A randomized phase III trial comparing bexarotene/carboplatin/paclitaxel versus carboplatin/paclitaxel in chemotherapy-naïve patients with advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 23:621s, 2005 (suppl; abstr 7001)

10. Jassem J, Zatloukal P, Ramlau R, et al: A randomized phase III trial comparing bexarotene/cisplatin/vinorelbine versus cisplatin/vinorelbine in chemotherapy-naïve patients with advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 23:627s, 2005 (suppl; abstr 7024)

11. Scagliotti GV, Selvaggi G, Novello S, et al: The biology of epidermal growth factor receptor in lung cancer. Clin Cancer Res 10:4227S-4232S, 2004 (suppl 12)[Abstract/Free Full Text]

12. Meert AP, Martin B, Delmotte P, et al: The role of EGF-R expression on patient survival in lung cancer: A systematic review with meta-analysis. Eur Respir J 20:975-980, 2002[Abstract/Free Full Text]

13. Herbst RS, Bunn PA Jr: Targeting the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 9:5813-5824, 2003[Abstract/Free Full Text]

14. Fukuoka M, Yano S, Giaccone G, et al: A multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 21:2237-2246, 2003[Abstract/Free Full Text]

15. Kris MG, Natale RB, Herbst RS, et al: A phase II trial of ZD1839 (Iressa) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol 21:292a, 2002 (abstr 1166)

16. Perez-Soler R, Chachoua A, Hammond LA, et al: Determinants of tumor response and survival with erlotinib in patients with non-small cell lung cancer. J Clin Oncol 22:3238-3247, 2004[Abstract/Free Full Text]

17. Shepherd FA, Pereira J, Ciuleanu TE: A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy: A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. J Clin Oncol 22:622s, 2004 (suppl; abstr 7022)

18. Goldstein NI, Prewett M, Zuklys K: 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]

19. Mendelsohn J: Epidermal growth factor inhibition by a monoclonal antibody as anticancer therapy. Clin Cancer Res 3:2703-2707, 1997[Abstract/Free Full Text]

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

21. Bonner JA, Giralt J, Harari M: Cetuximab prolongs survival in patients with loco regionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. J Clin Oncol 22:489s, 2004 (suppl; abstr 5507)

22. Raben D, Helfrich B, Chan DC, 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]

23. Lilenbaum R, Bonomi P, Ansari R, et al: A phase II trial of cetuximab as therapy for recurrent non-small cell lung cancer (NSCLC): Final results. J Clin Oncol 23:629s, 2005 (suppl; abstr 7036)

24. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989[Medline]

25. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

26. Longnecker SM, Donehower RC, Cates AE, et al: High-performance liquid chromatographic assay for taxol in human plasma and urine and pharmacokinetics in a phase I trial. Cancer Treat Rep 71:53-59, 1987[Medline]

27. Wiernik PH, Schwartz EL, Strauman JJ, et al: Phase I clinical and pharmacokinetic study of taxol. Cancer Res 47:2486-2493, 1987[Abstract/Free Full Text]

28. Schiller JH, Storer B, Tutsch K, et al: Phase I trial of 3-hour infusion of paclitaxel with or without granulocyte colony-stimulating factor in patients with advanced cancer. J Clin Oncol 12:241-248, 1994[Abstract]

29. Brown T, Havlin K, Weiss G, et al: A phase I trial of taxol given by a 6-hour intravenous infusion. J Clin Oncol 9:1261-1267, 1991[Abstract]

30. Curt GA, Grygiel JJ, Corden BJ, et al: A phase I and pharmacokinetic study of diamminecyclobutane-dicarboxylatoplatinum (NSC 241240). Cancer Res 43:4470-4473, 1983[Abstract/Free Full Text]

31. Oguri S, Sakakibara T, Mase H, et al: Clinical pharmacokinetics of carboplatin. J Clin Pharmacol 28:208-215, 1988[Abstract]

32. van Warmerdam LJ, Huizing MT, Giaccone G, et al: Clinical pharmacology of carboplatin administered in combination with paclitaxel. Semin Oncol 24:97-104, 1997 (suppl 2)

33. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989[Abstract]

34. Giaccone G, Huizing M, Postmus PE, et al: Dose-finding and sequencing study of paclitaxel and carboplatin in non-small cell lung cancer. Semin Oncol 22:78-82, 1995 (suppl 9)

35. Kearns CM, Belani CP, Erkmen K, et al: Pharmacokinetics of paclitaxel and carboplatin in combination. Semin Oncol 22:1-4, 1995 (suppl 12)

36. Calvert AH: A review of the pharmacokinetics and pharmacodynamics of combination carboplatin/paclitaxel. Semin Oncol 24:85-90, 1997 (suppl 2)

37. Kelly K, Pan Z, Murphy J, et al: A phase I trial of paclitaxel plus carboplatin in untreated patients with advanced non-small cell lung cancer. Clin Cancer Res 3:1117-1123, 1997[Abstract]

38. Kelly K, Crowley J, Bunn PA Jr, et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small cell lung cancer: A Southwest Oncology Group trial. J Clin Oncol 19:3210-3218, 2001[Abstract/Free Full Text]

39. Schiller JH, Harrington D, Belani CO, 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]

40. Lilenbaum RC, Herndon JE II, List MA, et al: Single-agent versus combination chemotherapy in advanced non-small cell lung cancer: The Cancer and Leukemia Group B (study 9730). J Clin Oncol 23:190-196, 2005[Abstract/Free Full Text]

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

42. 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 22:618s, 2004 (suppl; abstr 7012)

43. Bailey LR, Janas M, Schmidt K, et al: Evaluation of epidermal growth factor receptor (EGFR) as a predictive marker in patients with non-small-cell lung cancer (NSCLC) receiving first-line gefitinib combined with platinum-based chemotherapy. J Clin Oncol 22:418s, 2004 (suppl; abstr 7013)

44. Gatzemeier U, Heller A, Foernzler D, et al: Exploratory analyses EGFR, kRAS mutations and other molecular markers in tumors of NSCLC patients treated with chemotherapy +/– erlotinib (TALENT). J Clin Oncol 23:627s, 2005 (suppl; abstr 7028)

45. Lynch TJ, Bell D, Haber D, et al: Correlation of molecular markers including mutations with clinical outcomes in advanced non small cell lung cancer (NSCLC) patients treated with gefitinib, chemotherapy or chemotherapy and gefitinib in IDEAL and INTACT clinical trials. J Clin Oncol 23:622s, 2005 (suppl; abstr 7006)

46. Pal SK, Pegram M: Epidermal growth factor receptor and signal transduction: Potential targets for anti-0cancer therapy. Anticancer Drugs 16:483-494, 2005[CrossRef][Medline]

47. Sunada H, Yu P, Peacock JS, et al: Modulation of tyrosine, serine, and threonine phosphorylation and intracellular processing of the epidermal growth factor receptor by antireceptor monoclonal antibody. J Cell Physiol 142:284-292, 1990[CrossRef][Medline]

48. Bier H, Hoffmann T, Haas I, et al: Anti-(epidermal growth factor) receptor monoclonal antibodies for the induction of antibody-dependent cell-mediated cytotoxicity against squamous cell carcinoma lines of the head and neck. Cancer Immunol Immunother 46:167-173, 1998[CrossRef][Medline]

49. Saltz L, Kies M, Abbruzzese, L et al: The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 22:204, 2003 (abstr 817)

Submitted June 28, 2005; accepted August 23, 2005.

This article has been cited by other articles:

				F. R. Hirsch, R. S. Herbst, C. Olsen, K. Chansky, J. Crowley, K. Kelly, W. A. Franklin, P. A. Bunn Jr, M. Varella-Garcia, and D. R. Gandara Increased EGFR Gene Copy Number Detected by Fluorescent In Situ Hybridization Predicts Outcome in Non-Small-Cell Lung Cancer Patients Treated With Cetuximab and Chemotherapy J. Clin. Oncol., July 10, 2008; 26(20): 3351 - 3357. [Abstract] [Full Text] [PDF]

				P. S. Hodkinson, A. MacKinnon, and T. Sethi Targeting Growth Factors in Lung Cancer Chest, May 1, 2008; 133(5): 1209 - 1216. [Abstract] [Full Text] [PDF]

				R. Rosell, G. Robinet, A. Szczesna, R. Ramlau, M. Constenla, B. C. Mennecier, W. Pfeifer, K. J. O'Byrne, T. Welte, R. Kolb, et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer Ann. Onc., February 1, 2008; 19(2): 362 - 369. [Abstract] [Full Text] [PDF]

				C. A. Butts, D. Bodkin, E. L. Middleman, C. W. Englund, D. Ellison, Y. Alam, H. Kreisman, P. Graze, J. Maher, H. J. Ross, et al. Randomized Phase II Study of Gemcitabine Plus Cisplatin or Carboplatin, With or Without Cetuximab, As First-Line Therapy for Patients With Advanced or Metastatic Non-Small-Cell Lung Cancer J. Clin. Oncol., December 20, 2007; 25(36): 5777 - 5784. [Abstract] [Full Text] [PDF]

				K. Seitz and H. Zhou Pharmacokinetic Drug-Drug Interaction Potentials for Therapeutic Monoclonal Antibodies: Reality Check J. Clin. Pharmacol., September 1, 2007; 47(9): 1104 - 1118. [Abstract] [Full Text] [PDF]

				D. Morgensztern and R. Govindan Is There a Role for Cetuximab in Non Small Cell Lung Cancer? Clin. Cancer Res., August 1, 2007; 13(15): 4602s - 4605s. [Abstract] [Full Text] [PDF]

				P. Steiner, C. Joynes, R. Bassi, S. Wang, J. R. Tonra, Y. R. Hadari, and D. J. Hicklin Tumor Growth Inhibition with Cetuximab and Chemotherapy in Non-Small Cell Lung Cancer Xenografts Expressing Wild-type and Mutated Epidermal Growth Factor Receptor Clin. Cancer Res., March 1, 2007; 13(5): 1540 - 1551. [Abstract] [Full Text] [PDF]

				J. Kurai, H. Chikumi, K. Hashimoto, K. Yamaguchi, A. Yamasaki, T. Sako, H. Touge, H. Makino, M. Takata, M. Miyata, et al. Antibody-Dependent Cellular Cytotoxicity Mediated by Cetuximab against Lung Cancer Cell Lines Clin. Cancer Res., March 1, 2007; 13(5): 1552 - 1561. [Abstract] [Full Text] [PDF]

				N. Hanna, R. Lilenbaum, R. Ansari, T. Lynch, R. Govindan, P. A. Janne, and P. Bonomi Phase II Trial of Cetuximab in Patients With Previously Treated Non Small-Cell Lung Cancer J. Clin. Oncol., November 20, 2006; 24(33): 5253 - 5258. [Abstract] [Full Text] [PDF]

				T. E. Stinchcombe, D. Fried, D. E. Morris, and M. A. Socinski Combined Modality Therapy for Stage III Non-Small Cell Lung Cancer Oncologist, July 1, 2006; 11(7): 809 - 823. [Abstract] [Full Text] [PDF]

				D. S. Ettinger Clinical Implications of EGFR Expression in the Development and Progression of Solid Tumors: Focus on Non-Small Cell Lung Cancer. Oncologist, April 1, 2006; 11(4): 358 - 373. [Abstract] [Full Text] [PDF]

				D. A Frieze and J. S McCune Current Status of Cetuximab for the Treatment of Patients with Solid Tumors Ann. Pharmacother., February 1, 2006; 40(2): 241 - 250. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thienelt, C. D. Articles by Kelly, K.