Originally published as JCO Early Release 10.1200/JCO.2004.00.1438 on November 21 2005

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Phase I/IIa Study of Cetuximab With Gemcitabine Plus Carboplatin in Patients With Chemotherapy-Naïve Advanced Non–Small-Cell Lung Cancer

From the University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; M.D. Anderson Cancer Center, Houston, TX; M.D. Anderson Cancer Center Orlando, FL; Georgia Cancer Specialists, Marietta, GA; and ImClone Systems Inc, Branchburg, NJ.

Address reprint requests to Francisco Robert, MD, University of Alabama at Birmingham, Comprehensive Cancer Center, 1824 6th Ave S, NP-CC 2555D, Birmingham, AL 35294-3300; e-mail: pacorobertuab{at}cs.com

	ABSTRACT

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PURPOSE: This multicenter, open-label, phase I/IIa study was undertaken to establish the safety/toxicity profile of cetuximab in combination with gemcitabine and carboplatin in patients with chemotherapy-naïve, epidermal growth factor receptor–positive, stage IV non–small-cell lung cancer. Secondary objectives were to gather preliminary evidence of efficacy including tumor response rate, time to progression, and overall survival.

PATIENTS AND METHODS: Thirty-five patients received a total of 264 3-week cycles of treatment with cetuximab, carboplatin, and gemcitabine. An initial dose of cetuximab 400 mg/m² intravenously was administered the first week, followed by weekly doses of 250 mg/m². Carboplatin (area under the curve = 5, day 1) and gemcitabine 1,000 mg/m² on days 1 and 8 were administered every 3 weeks. Patients were evaluated for tumor response after every two cycles of therapy.

RESULTS: The most frequently reported adverse events related to cetuximab included an acne-like rash (88.6%), dry skin (34.3%), asthenia and skin disorders (31.4%), mucositis/stomatitis (25.7%), fever/chills (20%), and nausea/vomiting (17.1%). The majority of these toxicities were mild to moderate. One patient withdrew from the study because of a grade 3 allergic reaction. Myelosuppression was the most frequently observed toxicity related to chemotherapy. Responses among 35 assessable patients included 10 partial responses (28.6%). Twenty-one patients had stable disease. The median time to progression was 165 days, and the median overall survival was 310 days.

CONCLUSION: The combination of cetuximab, carboplatin, and gemcitabine was well tolerated with an acceptable toxicity profile. Most grade 3 adverse events were attributable to chemotherapy. The response rate and median survival are encouraging and warrant additional investigation.

	INTRODUCTION

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The epidermal growth factor receptor (EGFR) is a member of the Erb-B receptor tyrosine kinase (TK) family that includes ErbB-2, ErbB-3, and ErbB-4.^[1] It consists of an extracellular ligand-binding domain, a transmembrane region that anchors the receptor to the plasma membrane, and a cytoplasmic region containing a TK domain. The ligands of EGFR include epidermal growth factor (EGF) and transforming growth factor alpha (TGF-), which activate the receptor by binding to the extracellular domain and inducing the formation of receptor homodimers or heterodimers, followed by internalization of the receptor/ligand complex and autophosphorylation. It is now accepted that the EGFR signal transduction network plays an important role in multiple tumorigenic processes, including cell cycle progression, angiogenesis, and metastasis, as well as protection from apoptosis.^[2] Non–small-cell lung cancer (NSCLC) tumors have been demonstrated to synthesize TGF- and amphiregulin, forming an autocrine feedback loop with EGFR and, as a result, play an important role in tumorigenesis.^[3,4]

Several studies have shown that EGFR is commonly expressed or overexpressed in NSCLC cell lines and tumor specimens.^[3-6] The prognostic association of EGFR expression in lung cancer, however, is a controversial issue.^[5,7-9] Different conclusions regarding prognostic significance may reflect differences in detection methods, reagents, and population characteristics.^[10] Recently, Hirsch et al^[11] have found a positive correlation between gene copy numbers and level of protein expression of the EGFR by fluorescent in situ hybridization and immunohistochemistry. Patients with high gene copy numbers had a tendency to experience shorter survival times. Other mechanisms of increased EGFR signaling that might have prognostic implications include increased levels of extracellular ligand and heterodimerization of the EGFR.^[12,13] Tateishi et al^[12] found 67% of 138 pulmonary adenocarcinomas with strong expression of TGF-, and this finding was associated with poor prognosis.

Several classes of EGFR-targeted agents, including anti-EGFR monoclonal antibodies and the small molecule TK inhibitors, have demonstrated binding to the EGFR and/or blocking the function of the receptor and downstream signaling of tumor cell growth.^[14-19] Cetuximab (Erbitux [C225]; ImClone Systems Inc, Branchburg, NJ) is a chimeric antibody of the immunoglobulin G1 subclass that targets and blocks the human EGFR. The chimerization process resulted in an antibody with a relative affinity greater than that of the murine monoclonal antibody.^[20] Cetuximab blocks the binding of EGF and TGF- to EGFR and inhibits ligand-induced activation of this TK receptor. Cetuximab also stimulates EGFR internalization, effectively removing the receptor from the cell surface for interaction with the ligand.^[21] In this respect, removal of the EGFR from the cell surface may contribute to the inhibitory effects of this antibody.

There are key differences between the two types of EGFR inhibitors. First, monoclonal antibodies effectively block binding of EGF and TGF- to the EGFR, and concomitantly modulate its signaling properties.^[21] Second, a possible contributing immunologic effect exists, based on the engagement of immune mechanisms, in particular antibody-dependent cellular cytotoxicity.^[22,23] Third, antibodies downregulate the receptor by internalization, whereas the small molecules just inhibit temporarily or reversibly.^[21] In addition, antibodies have a long half-life, resulting in a continuous suppression and less variability in pharmacokinetics.^[24,25] Additional clinical investigations will determine the relative merits of these differences in terms of patient outcome.

Inhibitors of EGFR, such as cetuximab, were shown to inhibit the growth of some EGFR-overexpressing cell lines of various histologies including NSCLC both in vitro and in vivo.^{[14,20,21,26]} Other studies indicated that the combination of cetuximab with chemotherapeutic agents enhanced the growth inhibition in EGFR-expressing and cetuximab-sensitive cell lines both in vitro and in vivo.^[27-30]

On this basis, we deemed it reasonable to proceed with a feasibility phase I/IIa trial to evaluate the safety and toxicity profile of cetuximab in combination with gemcitabine and carboplatin in patients with advanced NSCLC.

	PATIENTS AND METHODS

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Study Design
This was a phase I/IIa study that enrolled patients with advanced NSCLC. The first patient enrolled May 24, 2001, and the last patient completed treatment February 11, 2003. In all, 35 patients were entered from four participating institutions in the United States. The primary objective was to establish the safety/toxicity profile of cetuximab in combination with gemcitabine and carboplatin in patients with chemotherapy-naïve, EGFR-positive, stage IV NSCLC. Secondary objectives were to gather preliminary evidence of efficacy including tumor response rate, time to progression, and overall survival.

Eligibility Criteria
To be eligible, patients were required to have the following characteristics: pathologically documented NSCLC; immunohistochemical evidence of EGFR expression ( 1+); stage IV disease; measurable tumor parameters; no prior chemotherapy; age 18 years; Karnofsky performance score of 80 to 100; adequate hematologic, hepatic, and renal function; and written informed consent.

To be consistent with previous ImClone-sponsored studies, the EGFR status was determined by immunohistochemistry and performed at the Impath Predictive Oncology Inc. The result was reported as positive if 10% of tumor cells demonstrated a 1+ membrane staining intensity (1+, faint or barely perceptible; 2+, weak to moderate staining of the complete cell membrane; and 3+, strong staining of the complete cell membrane).

Treatment
Treatment consisted of 3-week cycles of therapy. In the first cycle, a test dose of cetuximab (20 mg) was infused during 10 minutes followed by an observation period of 30 minutes. Patients were premedicated with 50 mg of intravenous diphenhydramine HCl before receiving the test dose. If no sign of anaphylaxis was observed, then the loading dose of cetuximab 400 mg/m² was administered during 120 minutes. Thereafter, cetuximab was infused weekly at maintenance doses of 250 mg/m² during 60 minutes. Vital signs were recorded before, during, at the completion of, and 1 hour after each cetuximab infusion. Cetuximab infusion was administered before the gemcitabine/carboplatin.

On days 1 and 8 of each cycle of therapy, gemcitabine (Eli Lilly, Indianapolis, IN) 1,000 mg/m² was administered during 30 minutes 1 hour after completion of the cetuximab infusion. Carboplatin (Bristol-Myers Squibb, Princeton, NJ) was infused during 30 minutes on day 1 of each cycle at a dose of area under the curve = 5 immediately after the gemcitabine infusion. In the absence of progressive disease, patients continued to receive cetuximab therapy.

In the event of a grade 1 or 2 allergic reaction, the cetuximab infusion rate was decreased for the current therapy and for subsequent infusions. Patients who experienced a grade 3 allergic reaction, persistent grade 1 or 2 allergic reaction despite reduction of the infusion rate, or a cetuximab-related grade 4 major organ toxicity were discontinued from the study. If a patient experienced a grade 3 acne-like rash, cetuximab therapy was delayed for up to two consecutive infusions with no change in the dose level. Concomitant treatment with topical and/or oral antibiotic was recommended for these grade 3 acne-like rashes. Cetuximab therapy was resumed once the acne-like rash resolved to a grade 2 or less. With the second and third occurrences of a grade 3 acne-like rash, cetuximab therapy was again delayed for up to 2 consecutive weeks with concomitant dose reductions to 200 and 150 mg/m², respectively.

Dose escalation of gemcitabine and carboplatin was not allowed in this study. Gemcitabine and carboplatin dosing were postponed until the absolute neutrophil count recovered to 1,500/µL and the platelet count recovered to 100,000/µL. Treatment with chemotherapy was discontinued in the event that therapy was delayed more than 2 weeks because of neutropenia or thrombocytopenia, or if toxicities persisted despite maximum dose reduction. The therapeutic use of growth factors (ie, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or erythropoietin) was allowed in this study.

Efficacy
Patients were evaluated for response according to the Response Evaluation Criteria in Solid Tumors.^[31] All patients who received at least one dose of cetuximab were considered assessable for response. Tumor assessments were performed within 4 weeks of study entry, and after every two cycles of therapy. After the initial evaluation, the confirmatory scans were performed no less than 4 weeks after criteria for response were met. An objective response was documented for two consecutive measurements for confirmation. Patients achieving a complete response should complete at least two cycles of therapy after documentation of response. Patients achieving a partial response or stable disease may continue receiving therapy for up to six cycles. In the absence of progressive disease, patients continue to receive cetuximab therapy.

Safety
All patients who received at least one dose of cetuximab were evaluated for safety analysis. Adverse events (AEs) were assessed using the established National Cancer Institute Common Toxicity Criteria, Version 2. Toxicities were classified by type, grade, onset, duration, and probable relationship to the study treatment.

A grade 3 acne-like rash was defined as any one of the following: symptomatic generalized erythroderma or macular, papular, or vesicular eruption or desquamation covering 50% of the body-surface area; rash/desquamation with confluence; rash/desquamation with pain requiring narcotics; and rash/desquamation with erosion of the skin.

Pharmacokinetics
Blood samples (serum) for cetuximab levels and anticetuximab antibody levels were drawn before the first cetuximab infusion, and before and 1 hour after the last cetuximab infusion of each cycle of therapy. The assay for cetuximab blood levels was a BIAcore (Pharmacia, Uppsala, Sweden) instrument-based method for the detection and quantitation of the chimerized antibody.^[32] The concentration of cetuximab in the serum samples was expressed as micrograms per milliliter.

Anticetuximab Response
The antibody (HACA) response against cetuximab was determined using a double-antigen radiometric assay.^[33] The results were expressed as nanograms per milliliter of bound cetuximab. A positive response was considered to be greater than 10 ng/mL cetuximab bound and greater than 2x baseline HACA levels.

Data Analysis and Statistical Considerations
In this trial, the primary end point was the toxicity rate. The dose-limiting toxicities were defined as a grade 3 acne-like rash that resulted in discontinuation of cetuximab therapy, and a grade more than 3 nonhematologic toxicity (except for nausea/vomiting and alopecia). The recommended dose would have been exceeded if more than 20% of the patients experienced any of these dose-limiting toxicities. With the sample size of 30 patients, the toxicity rate of this combination regimen was estimated to be within 18.6% with a 95% CI.

The response rate was estimated with a 95% CI, but because of the sample size of 30 to 35 patients, the CI is greater than 10%. Time to progression was defined as the time from initiation of therapy to the date of disease progression. The distribution of time to progression and survival time was estimated using the Kaplan-Meier method.^[34] The cumulative dose, the dose-intensity, and relative dose-intensity of cetuximab and gemcitabine were calculated by methods described previously.^[35]

	RESULTS

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Patients
A total of 35 patients were enrolled onto the study. The clinical characteristics of the study participants are shown in [Table 1]. Overall, the study population included 19 males (54.3%) and 16 (45.7%) females with a median age of 61 years (range, 19 to 84 years). The majority of patients were white (85.7%) and the median baseline Karnofsky performance score was 90. All patients were assessable for safety and efficacy. There were two early deaths during the first cycle of treatment. One patient died as a result of pericardial effusion (most likely related to progressive disease) after receiving chemotherapy and two doses of cetuximab. Another patient died as a result of complications of a small bowel obstruction during the first week of treatment.

Safety and Tolerability
The incidence of selected toxicities related to cetuximab is summarized in [Table 2], and the majority were mild to moderate. There was no incidence of dose-limiting toxicity resulting from the combination of cetuximab, gemcitabine, and carboplatin. The most frequently reported AEs related to cetuximab included an acne-like rash (88.6%), dry skin (34.3%), other skin disorders and asthenia (31.4% each), mucositis/stomatitis (25.7%), fever/chills (20%), and nausea/vomiting (17.1%). Grade 3 acne-like rash occurred in seven patients (20%); a dose reduction of cetuximab was required in one patient. One patient experienced a grade 3 allergic reaction during the initial infusion of cetuximab (total cumulative dose received, 134 mg) resulting in withdrawal from the study.

The most frequently reported nonhematologic toxicities related to chemotherapy included asthenia, constipation, anorexia, alopecia, diarrhea, nausea/vomiting, and mucositis/stomatitis. The majority of these AEs were mild to moderate. Twenty-seven patients who had sequential cardiac monitoring completed with multiple gated acquisition scans did not demonstrate any decline in their ejection fraction.

Twenty-seven patients discontinued the study because of disease progression (including one early death). An additional three patients discontinued because of AEs (after 1, 8, and 20 doses of cetuximab, respectively): a grade 3 allergic reaction to cetuximab; recurrent inguinal hernia; and a grade 3 hemoptysis/hypoxia, probably related to a thromboembolic event. Of the 23 patients (66%) who had serious AEs, nine patients had serious AEs that were considered related to cetuximab. Pulmonary embolus (n = 7, 20%) and deep thrombophlebitis and pleural effusion (n = 3 each, 8.6% each) were the most frequently reported serious AEs.

Of the 35 patients enrolled onto the trial, 30 patients (86%) required a treatment interruption of chemotherapy (gemcitabine and/or carboplatin), and 20 patients (57%) required a dose reduction of chemotherapy. The main reasons for dose interruptions were neutropenia, AEs requiring hospitalization, and thrombocytopenia. Dose reductions primarily were because of thrombocytopenia.

Response and Survival
The best overall tumor responses are listed in [Table 3]. Response to treatment reported in 35 patients evaluated for efficacy included 10 partial responses to yield an objective response rate of 28.6% (95% CI, 14.6% to 46.3%). Seven of the responses occurred within the first two cycles of treatment and the remaining three responses occurred within the first four cycles of treatment. An additional 21 patients had stable disease, producing a disease control rate of 88.6% (95% CI, 73.3% to 96.8%). The majority of the objective responses (n = 10) were observed in patients with adenocarcinoma. The objective response was 32.1% (95% CI, 15.9 to 52.4%) for patients with adenocarcinoma versus 14.3% (95% CI, 0.4 to 57.9%) for other histologies; P > .5 because of the small sample size. Five of the 35 patients were nonsmokers; three of them achieved a partial response and the other two had stable disease. However, there was no association between EGFR staining, skin rash, or sex and objective response. The median time to progression was 165 days (95% CI, 144 to 188 days).

View larger version (14K): [in this window] [in a new window]   Fig 1. Progression-free survival (PFS).

View larger version (14K): [in this window] [in a new window]   Fig 2. Overall survival.

Pharmacokinetics
Serum cetuximab concentrations reached maximal levels, for both peak and trough, by the fifth week of therapy. Serum concentrations remained constant through at least 23 weeks of treatment, indicating that cetuximab accumulation was not occurring. Median peak concentrations reached approximately 300 µg/mL and median trough concentrations were approximately 100 µg/mL cetuximab. These levels of cetuximab were consistent with the known pharmacokinetic behavior of cetuximab. The results are displayed in [Figure 3]. The median peak of cetuximab in patients who had a partial response was 390 µg/mL (range, 177 to 576 µg/mL), and 357 µg/mL (range, 35 to 544 µg/mL) for those with stable disease or progression (P = not significant). There were also no statistically significant differences between those patients with or without acneiform rash, or those with mild or moderate rash versus severe rash. There was no significant immune response (HACA) among the 28 patients tested in this study.

View larger version (20K): [in this window] [in a new window]   Fig 3. Median serum cetuximab peak (shaded) and trough (open) concentrations obtained 1 hour after infusion and before the infusion of the indicated week. Results are presented as a box (25% and 75% quartiles) and whisker (10% and 90% quartiles) plot where the median is indicated by the horizontal line.

	DISCUSSION

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The most frequently occurring AEs considered to be related to cetuximab were acne-like rash and dryness of the skin, which were generally mild. Otherwise, most of the AEs in this trial are consistent with known toxicities of the chemotherapy agents (eg, myelosuppression) and/or complications from the underlying malignancy. In this patient population with advanced NSCLC, it is difficult to attribute thromboembolic events to study treatment; instead, they can be attributed to the underlying disease, given that cancer patients have a substantial risk of recurrent thrombosis despite the use of anticoagulant therapy.^[48,49]

A relevant issue in the clinical development of cetuximab in NSCLC is whether the data with gefitinib (Iressa NSCLC Trials Assessing Combinaion Treatment) or erlotinib (Tarceva responses in conjunction with paclitaxel and carboplatin) will be predictive of similar lack of efficacy for concomitant administration of anti-EGFR monoclonal antibody with chemotherapy.^[50-53] In fact, several preliminary clinical observations with cetuximab in combination with chemotherapy may support the combined approach in NSCLC.^[54,55] Rosell et al^[54] compared the combination of cisplatin and vinorelbine ± cetuximab in a small randomized phase II study in chemotherapy-naïve patients with advanced NSCLC. The response rate (31.7% v 20%) and the time to progression (4.7 v 4.2 months) favored the cetuximab-based regimen. Kim et al^[55] reported a response rate of 28% with the combination of cetuximab and docetaxel in chemotherapy-refractory/resistant patients with advanced NSCLC. Additional support for a cetuximab-based chemotherapy approach stems from the increased efficacy of combination therapy (cetuximab + irinotecan) in patients with metastatic colorectal cancer whose disease had progressed after they received an irinotecan-based regimen.^[56]

The challenge for the clinical development of anti-EGFR agents alone or in combination with chemotherapy or radiation therapy will be the appropriate selection of potentially responding patients. The mechanism(s) of drug sensitivity to the EGFR inhibitors have not been clearly understood, but recent studies have shown predictive and prognostic implications of EGFR mutations in NSCLC patients treated with gefitinib and erlotinib.^[57-59] Other factors affecting sensitivity to EGFR inhibitors may include autocrine production of EGF and TGF-, or mutations in or expression levels of downstream signaling proteins such as ras, PTEN, Akt, or STAT-3.^[60-62]

In summary, we have shown that cetuximab in combination with gemcitabine and carboplatin in the treatment of advanced NSCLC is feasible and safe. The antibody therapy did not seem to exacerbate the toxicity of this chemotherapy regimen. The response and survival rates seem reasonable, if not encouraging, for patients with stage IV disease. Ultimately, the critical assessment of the role of cetuximab in the treatment of advanced NSCLC will require several essential steps: evaluation of a predictive marker(s) of sensitivity to the antibody; phase II testing to determine its single-agent activity; and a phase III randomized trial (cytotoxic ± cetuximab) in a larger patient population. Preliminary data from an ongoing phase II study of cetuximab as single-agent therapy in patients with recurrent NSCLC who have experienced treatment failure after at least one prior chemotherapy regimen demonstrated a response rate of 6.9%.^[63]

	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 Francisco Robert Bristol Myers Squibb (A) ImClone Systems (A) George Blumenschein Bristol Myers Squibb (A); ImClone Systems (A) Roy S. Herbst ImClone (A) Imclone (B); Bristol Myers Squibb (A) Jennifer Tseng Bristol Myers Squibb (A) Mansoor N. Saleh ImClone (A) Michael Needle ImClone (N/R) ImClone (B) ImClone (N/R)

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 Inc.

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

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

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