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© 2001 American Society for Clinical Oncology Phase I Study of Anti–Epidermal Growth Factor Receptor Antibody Cetuximab in Combination With Radiation Therapy in Patients With Advanced Head and Neck CancerByFrom the Division of Hematology/Oncology, Department of Radiation Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, and Birmingham Veterans Administration, Birmingham, AL; University of Utah Medical Center, Salt Lake City, UT; and ImClone Systems, Inc, Somerville, NJ. Address reprint requests to Francisco Robert, MD, University of Alabama at Birmingham, Comprehensive Cancer Center, Wallace Tumor Institute, Rm 230, 1824 Sixth Ave South, Birmingham, AL 35294-3300; email: pacorobertuab{at}cs.com
PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of a chimeric anti–epidermal growth factor receptor monoclonal antibody, cetuximab, in combination with radiation therapy (RT) in patients with advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: We treated 16 patients in five successive treatment schedules. A standard dose escalation procedure was used; three patients entered onto the study at each dose level of cetuximab received conventional RT (70 Gy, 2 Gy/d), and the final three patients received hyperfractionated RT (76.8 Gy, 1.2 Gy bid). Cetuximab was delivered as a loading dose of 100 to 500 mg/m2, followed by weekly infusions of 100 to 250 mg/m2 for 7 to 8 weeks. Circulating levels of cetuximab during therapy were determined using a biomolecular interaction analysis core instrument. Human antichimeric antibody response was evaluated with a double-antigen radiometric assay. The recommended phase II/III dose was defined as the optimal cetuximab dose level based on the pharmacologic parameters and adverse events. RESULTS: The most commonly reported adverse events were fever, asthenia, transaminase elevation, nausea, and skin toxicities (grade 1 to 2 in most patients). Skin toxicity outside of the RT field was not strictly dose-dependent; however, grade 2 or higher events were observed in patients treated with higher dose regimens. There was one grade 4 allergic reaction. Most acute adverse effects were associated with RT (xerostomia, mucositis, and local skin toxicity). No antibodies against cetuximab were detected. All patients achieved an objective response (13 complete and two partial remissions). CONCLUSION: Cetuximab can be safely administered with RT. The recommended dose for phase II/III studies is a loading dose of 400 to 500 mg/m2 and a maintenance weekly dose of 250 mg/m2.
RADIATION THERAPY (RT) is the mainstay of treatment for locally advanced, unresectable squamous cell carcinoma of the head and neck (SCCHN). However, with conventional fractionation of 1.8 to 2.0 Gy per fraction for a total dose of 60 to 75 Gy, the rate of relapse-free survival is approximately 25%, and the majority of patients die from locoregional disease.1,2 Tumor cell repopulation during treatment, tumor hypoxia, and intrinsic radioresistance represent biologic barriers implicated as causes of treatment failure after primary RT.3-5 Numerous attempts to improve local control and long-term survival in advanced SCCHN have been undertaken, such as altered fractionated regimens, combined RT and chemotherapy, radiation sensitizers, and hyperbaric oxygen.6-11 Although some of these therapeutic approaches have shown encouraging results, not all of them have shown an unequivocal survival benefit, and the treatments often are associated with significant toxicity. Thus, there is a need for newer therapies that produce long-term local control and less toxicity. One novel approach to treatment has been the development of new agents that target specific growth factors and growth factor receptors. One particular growth factor receptor and signal transduction system that has been shown to play an important role in the pathogenesis of SCCHN is the epidermal growth factor receptor (EGFR) and its ligand.12-14 The EGFR system represents a promising therapeutic target because it is commonly overexpressed in these tumors.15-17 Tumor levels of EGFR and its ligand, transforming growth factor alpha, have been shown to be significant predictors of tumor staging and clinical outcome.17,18 In addition, several studies have reported that repopulation of epithelial tumor cells after exposure to radiation is related to the activation and expression of EGFR.19,20 These findings suggest that EGFR blockade may be important in reducing tumor cell repopulation by modulation of cellular proliferation and enhancement of tumor radioresponse. Inhibition of the EGFR-induced signal transduction pathways, either by higher than physiologic concentrations of epidermal growth factor or by monoclonal antibodies (mAbs) directed at the EGFR, has been shown to inhibit the growth of EGFR-expressing human cancer cells.21-23 One such antibody is cetuximab (C225; ImClone Systems, Inc, Somerville, NJ), a mouse-human chimeric anti-EGFR mAb that binds with high affinity to the receptor, blocks ligand-induced activation of receptor tyrosine kinase, and induces dimerization and downregulation of the EGFR, which prevents further receptor binding and activation by the ligands.24-28 In addition, cetuximab has been shown to inhibit the proliferation of a variety of cultured human tumor cell lines that overexpress EGFR and to enhance the antitumor activity of several chemotherapeutic agents in xenograft models.27,28-30 Furthermore, we and others have shown that cetuximab enhanced the radioresponse of EGFR-expressing A431 tumor cells in vitro and in tumor xenografts.31,32 Given the correlation of EGFR expression with poor prognosis and the fact that preclinical studies identified cetuximab as a radiosensitizer, a phase I study was undertaken to assess the interaction of cetuximab and RT in patients with locally advanced, unresectable SCCHN. The purposes of this study were to establish a safety profile of cetuximab administered over a range of dose levels during RT and to determine the dose-dependent pharmacokinetics and human immune response to the antibody.
This single-center, phase I, open-label study evaluated different dose levels of cetuximab with concomitant RT in patients with locally advanced SCCHN. Five treatment groups (Table 1) with at least three assessable patients were considered for this study to determine the recommended phase II/III dose. Patients received eight to nine weekly infusions of cetuximab. The initial infusion was a loading dose of either 100, 200, 400, or 500 mg/m2 administered over 60 to 120 minutes. Subsequent infusions of cetuximab consisted of 100-, 200-, or 250-mg/m2 maintenance doses administered over 60 minutes. Single daily fractions or twice-daily hyperfractionated RT was started on day 8 (week 2) of the treatment course and continued for approximately 7 weeks. The protocol was approved by the institutional review board, and all patients gave written informed consent before they were entered onto the study.
Patient Eligibility Patients enrolled onto this study were at least 18 years old and had a histologically confirmed diagnosis of SCCHN. The inclusion criteria were as follows: all sites of the head and neck except the nasopharynx, stage III or IV33 disease or recurrent disease that was not resectable for curative intent, no evidence of metastatic disease, and no history of prior RT or chemotherapy. In addition, patients had a Karnofsky performance status of at least 60% and preserved hematologic parameters (absolute neutrophil count  1,500/µL, platelet count 100,000/µL, and hemoglobin level 9 gm/dL), liver function (alkaline phosphatase < 2.6 times the normal limit, AST level < 2.6 times the normal limit, and total bilirubin < 1.5 times the normal limit), and normal renal function (creatinine < 1.5 times the normal limit). Exclusion criteria were pregnancy or lactation, prior murine mAb or cetuximab therapy, significant comorbid conditions, or investigational therapy for diseases within 1 month of study entry. Representative tumor tissue (paraffin tumor blocks) for EGFR assessment was obtained before the start of the study, but a positive result was not required as a prestudy parameter because of the high reported expression levels in SCCHN.17,18 The presence of the EGFR was determined in a two-step immunostaining process, which involved, first, the binding of a murine anti-EGFR antibody (M225) to the receptor and, second, the detection and visualization of bound antibody by application of an enzyme chromogenic reagent. Tumors were considered to overexpress EGFR if positive cytoplasmic rimming was observed in 10% or more of the cells. All patients were evaluated initially by a multidisciplinary team that consisted of radiation oncologists, otolaryngologists, and medical oncologists. The stage of the tumor was determined on the basis of a physical examination, chest x-ray, and computed tomography or magnetic resonance imaging of the head and neck. A routine blood chemical analysis, complete blood count, and urinalysis were performed within 2 weeks before enrollment. Dental evaluation was performed in each patient, and at least 10 days were allowed for healing gingivae after extraction.
Definitions The maximum-tolerated dose was defined as the highest dose level at which zero of three or one of five patients experienced a DLT. The recommended phase II/III dose was defined as the optimal cetuximab dose level based on pharmacologic parameters and adverse events.
Investigational Agent
Treatment Plan Patients received eight to nine weekly cetuximab infusions with an initial loading dose on day 1 that ranged from 100 to 500 mg/m2 administered intravenously over 60 or 120 minutes (Table 1). Subsequent infusions of cetuximab consisted of 100-, 200-, and 250-mg/m2 maintenance doses administered over 60 minutes. Patients received a test dose of cetuximab (20 mg) over 10 minutes before the initial loading dose. They received the remainder of their infusion after completion of the observation period (30 minutes). Patients were premedicated with diphenhydramine (50 mg intravenously) and an H2 blocker before the test dose. All treatments were given in the outpatient setting. Vital-sign measurements were obtained before administration of cetuximab, midway through the infusion, and every 15 minutes during the 1-hour observation period after administration of the antibody therapy. The weekly doses of cetuximab were scheduled for Mondays and were administered before RT. An additional weekly infusion of cetuximab (ninth dose) was given to patients who required RT breaks. If a patient experienced a grade 1 or 2 allergic reaction, premeditation with 50 mg of diphenhydramine and an H2 receptor antagonist was administered before each treatment with cetuximab. The duration of the remaining and subsequent infusions was increased, but it did not exceed 4 hours. Concurrent treatment with oral diphenhydramine and a topical antibiotic was considered for skin toxicity grades 1 through 3. In addition, cetuximab dose reduction and/or dose delays were required for grade 3 skin toxicity. In the event of a grade 4 skin toxicity or grade 4 allergic reaction, the patient was removed from the study.
RT began on day 8 (week 2). Patients in four initial treatment groups received once-daily RT that consisted of 2.0 Gy per fraction, five fractions per week, for a total dose of 70 Gy in 7 weeks. After administration of 50 Gy, boost fields to the primary tumor and gross nodal disease with margin were given with photons or electrons in the 4- to 20-MeV range. The entire neck and supraclavicular regions were irradiated to a dose of at least 44 Gy. Patients in the last treatment group received RT bid that consisted of 1.2 Gy per fraction, 10 fractions per week, for a total of 76.8 Gy in 7 weeks. After administration of 45.6 Gy, boost fields to the primary tumor and gross nodal disease with margin were given with photons or electrons in the 4- to 20-MeV range. The entire neck and supraclavicular regions were irradiated to a dose of at least 45.6 Gy. Treatment breaks because of confluent mucositis (grade Surgical treatment was used only after the completion of therapy. Neck dissection was permitted for any patient with residual cervical adenopathy or as a planned treatment for any nodal disease with an initial diameter of 3 cm or more.
Pharmacokinetics and Whole-Body Retention Data Serum concentrations of cetuximab were determined using a Biosensor (Pharmacia, Uppsala, Sweden) biomolecular interaction analysis core instrument, which measures changes in surface plasmon resonance. In this method, a serum sample that contains the antibody is flowed over a dextran-coated fold film to which EGFR has been conjugated. The binding of cetuximab to the immobilized EGFR produces a change in the angle of light reflected from the gold film, and from this relationship, a standard curve can be created to express the concentration of cetuximab in the serum sample. In addition, whole-body probe counts were performed after radiolabeled antibody infusion in patients in treatment groups 1 through 4 only. For each dose, approximately 1 mg of cetuximab was radiolabeled with 10 mCi of iodine-131 (131I) and was administered intravenously over 2 to 3 minutes after the infusion of the first (loading dose) and last maintenance dose of unlabeled cetuximab. Radiolabeling was performed under aseptic conditions using standard iodogen methodology. Quality control of the radiolabeled product was monitored by immunoreactivity, high-performance liquid chromatography analysis, limulus amebocyte lysate assay, and sterility testing. To block uptake of 131I by the thyroid, patients received a saturated solution of potassium iodide, beginning 48 hours before the administration of 131I-cetuximab and continuing for 14 days. Serial total-body sodium iodide probe counts were measured to determine whole-body retention data from each patient during the first and final 131I-cetuximab infusions. The residence time (area under the curve of a percentage of the injected dose) was calculated using a trapezoidal integration method. The biologic half-life (T1/2) for 131I-cetuximab also was derived from a monoexponential regression fit of whole-body count data.
Human Antichimeric Antibody Response
Criteria for Toxicity and Response The initial tumor response assessment was performed 4 to 6 weeks after treatment was completed. Tumor response was determined by physical examination and imaging studies (computed tomography or magnetic resonance imaging). Extended follow-up was performed at approximately 3-month intervals. A complete response was defined as resolution of all evidence of measurable and assessable disease. A partial response was defined as a 50% or greater reduction in the sum of the products of the longest perpendicular diameters of measurable lesions, with no new lesion development. Progressive disease was defined as a greater than 25% increase of the sum of the products of the maximum diameters of the measurable lesions or the appearance of a new lesion. In addition to analyzing tumor response, we analyzed several clinical events, including the time to progression, actuarial locoregional progression-free survival, and overall survival. These data were analyzed using the Kaplan-Meier method.36 The Student’s t test was used for the comparison of the resident time and biologic T1/2 between the first and last radiolabeled antibody infusions.
Patient Characteristics A total of 16 patients were enrolled onto this study between April 1997 and August 1998. Table 2 outlines the characteristics of the patients. The median age was 55 years (range, 34 to 72 years). Fifteen patients were treatment-naïve, and one patient with recurrent disease had been treated previously with surgery. The majority of patients (81%) had stage IV disease. Nodal metastases were present in 81% of the patients, and six patients had N2 disease. Of a total of 15 patients tested for tumor EGFR expression, only two were negative.
Of the 16 patients, 15 received the planned cetuximab infusions and RT, with minimal interruption or delay. One patient in the second treatment group developed a reversible grade 4 anaphylactic reaction approximately 5 minutes into the first infusion, which required his removal from the study.
Toxicity
Four patients experienced allergic reactions during the first infusion (Table 3). Two of these patients had a grade 3 or higher reaction; one patient with reversible anaphylactic reaction (grade 4) was removed from the study. Patients with allergic reactions lower than grade 4 received subsequent infusions with premedication (diphenhydramine and H2-receptor antagonists), and the time of infusions was increased. No further allergic manifestations were observed in these patients after these treatment alterations. Most of the acute grade 2 and higher adverse events observed during treatment were associated with standard aggressive irradiation, ie, xerostomia, mucositis, odynophagia, and local skin toxicity in the radiotherapy fields (Table 4). The incidence of confluent mucositis and local skin toxicity was virtually the same in all of the treatment groups. Long-term effects of treatment included mild to moderate xerostomia in the great majority of the patients and one case of soft tissue necrosis with exposure of bone.
Pharmacokinetics and Whole-Body Retention Data The cetuximab concentration-versus-time data during treatment for the five treatment groups are shown in Fig 1. Visual inspection of the individual concentration versus time curves indicates that circulating cetuximab peak and trough levels increased progressively in patients treated with loading doses of 100 to 500 mg/m2 and maintenance weekly doses of 100 to 250 mg/m2. The mean serum peak levels in the first four treatment groups were 358, 656, 1,291, and 1,478 nmol/L. Mean serum trough levels in the same treatment groups were 39, 202, 504, and 772 nmol/L. It is obvious that the interpatient variability with these fixed regimens is high, especially at higher doses of cetuximab.
The mean Km (the concentration of the antibody at which its elimination is half of its maximum) for this group of patients was 482 nmol/L. The inadequacy of the first two dosing regimens is readily apparent. The concentrations of cetuximab generated with these two dosing regimens persistently fell below the population Km, which indicates that within this dose range, saturation of drug clearance was not achieved. A complete analysis of the pharmacokinetic data will be presented in a separate report. The sodium iodide probe count data from the first and last infusion of cetuximab for the first four treatments groups is shown in Fig 2. The mean value for the residence time in the first infusion was 85.3 hours, as compared with 83.7 hours for the last infusion (P = .69; t test). The mean biologic T1/2 was 94.5 hours with the first infusion and 89.6 hours with the last infusion. Individual patient data indicate a trend in the residence time and biologic T1/2 with increased doses of cetuximab.
HACA Response The sera of 14 patients who completed therapy were analyzed for the presence of HACAs. None of these patients developed an immune response to cetuximab.
Clinical Responses
The median follow-up of surviving patients was 36 months (range, 23 to 42 months). Six patients had relapsed, with a median time to progression of 8 months (range, 4.5 to 31 months). All recurrences were at the locoregional sites. Five of these patients died from progressive disease, and the cause of death of one patient is unknown. The actuarial 1- and 2-year disease-free survival rates were 73% and 65%, respectively. The median survival of these patients has not been reached.
The combination of cetuximab and RT was well tolerated in this group of patients with advanced SCCHN. The most common reported cetuximab-related adverse events were fever, asthenia, transaminase elevation, nausea, and skin toxicities. These adverse events were grades 1 and 2 in the majority of the patients and were not related to the dose level of the antibody therapy. Only one patient experienced grade 3 skin toxicity (a follicular/maculopapular rash) outside of the RT fields. Otherwise, the majority of the grade 2 and 3 skin toxicities were within the RT fields and not necessarily related to cetuximab therapy. In addition to the skin toxicity, one patient experienced a grade 4 anaphylactic reaction shortly after the initiation of the first cetuximab infusion, which was completely reversible. The remainder of the grade 2 and 3 antibody-related local/systemic toxicities were of little consequence and required no cetuximab dose modification or RT delays. In recent studies of hyperfractionated RT alone or combined RT and chemotherapy, the most common grade 3 adverse event was acute mucositis in 67% to 77% of patients.11,37,38 In the first report of RTOG 9003, the incidence of grade 3 or worse acute mucositis was 25% for standard fractionation and 43% for altered fractionation RT.9 In that study, the incidence of grade 3 or higher skin toxicity was 7% for standard fractionation and 9% for altered fractionation RT. In our study, the incidence of grade 3 mucositis was 73%, and the incidence of grade 3 in-field skin toxicity was 33%. An important relevant issue is whether cetuximab increases the local toxicity of RT. Our data suggest some enhanced toxicity, which implies a biologic interaction between the antibody and RT. However, a definite conclusion cannot be reached at this time because of the small number of patients in this study. A critical issue in clinical studies with an anti-EGFR mAb is definition of the optimal biologic dose and schedule. The hypothesis that has driven the clinical development of cetuximab is that complete saturation of EGFR binding might require saturation of the mechanism(s) responsible for the antibody’s elimination from the body. Indeed, it is likely that a major route for cetuximab clearance involves the binding of the antibody to EGFR on hepatocytes, with subsequent internalization of the cetuximab-EGFR complex. On the basis of this hypothesis, the optimal biologic dose is the lowest dose of cetuximab required to continuously maintain zero-order antibody elimination. Analysis of the pharmacokinetic data of previous phase I studies has shown that cetuximab displayed nonlinear pharmacokinetics, with antibody doses in the range of 200 to 400 mg/m2 associated with complete saturation of systemic clearance.39 On the basis of these findings, the recommended maintenance dose for phase II studies will be close to the 200-mg/m2 dose level. Our preliminary analysis suggests that the cetuximab dosing regimens in the first two groups of patients (loading and maintenance doses of 100 mg/m2 and 200 mg/m2, respectively) do not provide optimal steady-state serum concentrations to keep circulating antibody levels close to or above the estimated Km value. The dosing regimen in treatment group 4 (500 mg/m2/250 mg/m2) provided better antibody concentration, although we have information for only two patients. However, even at higher doses (treatment groups 4 and 5), the dosing regimens failed to achieve consistent trough levels above the estimated Km value during treatment. Although all of our dose schedules failed to achieve 100% saturation of drug elimination, most of the patients at different dose levels experienced skin toxicity that undoubtedly reflected the antibody’s interaction with EGFR. This skin toxicity could be an important clinical marker of in vivo EGFR targeting by the antibody. Indirect evidence of this interaction is the observation that only grade 2 and higher skin eruptions (outside the RT fields) were seen in patients treated with higher dosing regimens. The whole-body retention data (131I-cetuximab) is in agreement with a previous phase I trial39 of the nonlinear pharmacokinetic behaviors of cetuximab. Individual patient data demonstrated a steady increase in residence time and biologic T1/2, which indicates that some aspect of the pharmacokinetics is saturable. The reproducibility of the whole-body residence time at two different time intervals indicates that no patients in this study developed an immune response from this chimeric mAb. This is an important observation that showed the relative safety and applicability of multiple antibody administrations. In most patients with advanced SCCHN, conventional RT does not result in long-term locoregional control of the tumor and overall survival is poor. In recent years, several strategies have been tested to improve this situation. These approaches include a variety of fractionation schedules (hyperfractionation, accelerated fractionation, and their variants), as well as the combination RT with concurrent chemotherapy.7-11,38 In RTOG study 9003,9 patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better locoregional control than those treated with conventional fractionation. There was also a trend toward improved disease-free survival for those groups of patients, although the difference in overall survival was not significant. In addition to this RTOG trial, hyperfractionation also has been shown to improve the outcome of RT for SCCHN in four other randomized trials.8,37,40,41 Furthermore, several regimens of concurrently administered RT and chemotherapy have shown an apparent improvement over RT alone.11,42 Recent meta-analyses also have concluded that concurrent administration is superior to sequential treatment.43,44 The major limitation of these therapeutic strategies is increased acute reaction, primarily acute mucositis. Despite the improvements in local control and relapse-free survival with the use of altered fractionation RT or combined RT and chemotherapy, approximately more than 50% of the patients ultimately died of their disease, mostly from sequelae of locoregional failure. New treatment modifiers are needed to further improve locoregional control and survival of patients with locally advanced SCCHN. Cetuximab seems to be a novel biologic modifier, in view of the role of EGFR in the pathogenesis of head and neck cancer,12-18 and the preclinical data showing an in vivo enhancement of tumor radioresponse by this antibody.31,32 The outcome of this trial in terms of safety and efficacy is encouraging. In summary, this is the first clinical trial to show the feasibility of combining conventional or hyperfractionated RT with an anti-EGFR mAb in patients with advanced SCCHN. In this trial, we found that cetuximab can be administered safely for prolonged periods of time in combination with RT. Although a dose schedule that completely saturates the body clearance mechanisms was not clearly defined, doses greater than 200 mg/m2 seem to be clinically feasible. There were no DLTs at the higher dose levels of cetuximab. The maximum-tolerated dose and recommended phase II/III dose, based on the protocol design of our study, is a loading dose of 400 to 500 mg/m2 and a maintenance weekly dose of 250 mg/m2. No significant immune response to this chimeric mAb have been found, which confirms that cetuximab is well suited for further clinical trials. Given the reported findings, a multi-institutional phase III trial to compare cetuximab combined with RT (conventional or hyperfractionated) versus RT alone is currently being conducted.
Supported by grant no. 5U01CA743392 from the National Institutes of Health, Bethesda, MD.
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ABSTRACT
INTRODUCTION
