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Originally published as JCO Early Release 10.1200/JCO.2005.07.119 on July 11 2005 © 2005 American Society of Clinical Oncology. Phase II Multicenter Study of the Antiepidermal Growth Factor Receptor Monoclonal Antibody Cetuximab in Combination With Platinum-Based Chemotherapy in Patients With Platinum-Refractory Metastatic and/or Recurrent Squamous Cell Carcinoma of the Head and NeckFrom the Vall d'Hebron University Hospital; Hospital Clinic, Barcelona; Hospital Universitario 12 de Octubre, Madrid, Spain; Institut Gustave-Roussy, Villejuif; Centre Jean Perrin, Clermont-Ferrand, France; Merck KGaA, Darmstadt; and Medizinische Hochschule, Hannover, Germany Address reprint requests to José Baselga, Vall d'Hebron University Hospital, Oncology Service, P Vall d'Hebron 119-129, Barcelona 08035, Spain; e-mail: jbaselga{at}vhebron.net
PURPOSE: To evaluate the efficacy and safety of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) followed by platinum chemotherapy at the same dose and schedule at which progressive disease was documented before entry onto the study. RESULTS: The response rate, based on an independently read assessment, in the intent-to-treat population was 10%, with a disease control rate (complete response, partial response [PR], and stable disease) of 53%. The median time to progression and overall survival were 85 and 183 days, respectively; both were longest in patients achieving a PR (median, 203.5 and 294 days, respectively). Treatment was well tolerated. The most common cetuximab-related adverse events were skin reactions, particularly an acne-like rash. CONCLUSION: The combination of cetuximab and platinum chemotherapy is an active and well-tolerated approach to the treatment of this poor-prognosis patient population with platinum-refractory recurrent or metastatic SCCHN for whom there are no recommended standard therapeutic options.
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer in the world, with approximately 600,000 new cases per year.1 Recurrent and/or metastatic SCCHN patients have a poor prognosis, which has not changed significantly for 30 years.2,3 More than 50% of newly diagnosed patients with SCCHN are not cured and will relapse locally or at a distant site; 10% of newly diagnosed patients with SCCHN present with distant metastases. Several therapeutic options are available for recurrent and/or metastatic SCCHN patients, including reirradiation and salvage surgery and chemotherapy, with best supportive care for patients unable or unwilling to undergo treatment. Palliative chemotherapy has demonstrated survival advantages over best supportive care,4 and the most commonly used agents are cisplatin and carboplatin, generally in combination regimens with infusional fluorouracil (FU) or a taxane. Only approximately one third of patients will respond to first-line platinum-based therapy, and the median overall survival time can be expected to be approximately 6 to 9 months.4 Patients with advanced SCCHN have limited alternative therapeutic options once they progress on platinum-based chemotherapy, and response rates are generally poor (approximately 3%).5 Thus, there is clearly an unmet therapeutic need for new active agents for the treatment of patients with recurrent and/or metastatic SCCHN, particularly patients who have progressed on first-line therapy. Epidermal growth factor receptor (EGFR) has emerged as a promising target for cancer therapy. EGFR is a tyrosine kinase receptor of the ErbB family that is highly expressed and/or abnormally activated in many epithelial tumors, including SCCHN, colorectal cancer, and non–small-cell lung cancer.6-8 Studies in SCCHN and nasopharyngeal cancer (NPC) showed that the vast majority of patients demonstrated increased levels of EGFR expression.7,9,10 EGFR expression in tumors is usually associated with more aggressive disease, increased resistance to chemotherapy and radiotherapy, increased metastasis, poor prognosis, and decreased survival.11,12 In SCCHN, multivariate analyses have shown EGFR levels to be an independent predictor of poor outcome.9,13 Cetuximab is an immunoglobulin G1 monoclonal antibody that binds to the extracellular domain of the EGFR with high affinity and competitively inhibits endogenous ligand binding.14 It also induces antibody-mediated receptor dimerization resulting in receptor downregulation and degradation.6,15-17 A series of phase I and II studies of cetuximab administered alone or in combination either with chemotherapy or radiation have now been completed.6 After an initial clinical observation that the addition of cetuximab to irinotecan and to cisplatin induced responses in patients with irinotecan-refractory advanced colorectal carcinoma and with cisplatin refractory SCCHN, respectively,18 a series of phase II studies were initiated in colorectal cancer and SCCHN. Cetuximab has documented clinical efficacy in the treatment of colorectal cancer19,20 and has been approved for use in combination with irinotecan in Europe and the United States and as monotherapy in the United States for use in the treatment of EGFR-expressing metastatic colorectal cancer that has progressed on irinotecan-containing therapy. The rationale for targeted therapy with cetuximab in SCCHN is compelling; as mentioned, SCCHNs express high levels of EGFR, and cetuximab has shown both in vitro21 and in vivo activity against SCCHN-derived cells and tumors.22 Importantly, cetuximab has been shown to enhance the antitumor activity of cisplatin23 and radiation therapy22,24 and is known to have no effect on the pharmacokinetic profile of cisplatin.25 In the clinical setting, a phase IB study in patients with SCCHN demonstrated that the combination of cetuximab and cisplatin was active, even in a subset of patients who had been previously treated with cisplatin and had documented cisplatin resistance.26 The aim of the present study was to determine, in a phase II setting, the response rate to the combination of cetuximab and platinum chemotherapy in patients with recurrent and/or metastatic SCCHN who had progressed on prior treatment with between two and four cycles of the same platinum regimen. This is a poor-prognosis patient population for whom there is currently no standard treatment approach.
Patient Eligibility Patients were eligible for entry onto the study if they fulfilled the following criteria: age  18 years (19 years in Austria); Karnofsky performance status (KPS) 60%; histologically confirmed diagnosis of stage III and IV SCCHN stage (according to American Joint Committee on Cancer staging system); not candidates for local therapy; measurable disease; documented progressive disease (PD) after a minimum of two and a maximum of four cycles of cisplatin-based ( 60 mg/m2/cycle) or carboplatin-based ( 250 mg/m2/cycle) chemotherapy, with baseline disease being documented in the 30 days before the start of the platinum-based regimen the patient was taking on study entry; tumor tissue available for immunohistochemical staining to demonstrate EGFR expression; and adequate hematologic, renal, and hepatic function. Exclusion criteria included: history of drug abuse; pregnancy or lactation; NPC; prior or concomitant surgery or irradiation in the past 30 days (platinum-containing definitive radiochemotherapy was allowed if terminated at least 6 months before the platinum-based regimen on which progression was documented); known hypersensitivity to any of the treatment agents; and concomitant malignant disease, except adequately treated basal cell cancer of the skin or cervical carcinoma-in-situ. This was a multicenter study. The study protocol and any amendments were approved by independent ethics committees in each country, and the study was conducted in accordance with the Declaration of Helsinki (October 1996). All patients provided written informed consent before entry onto the study.
Treatment Carboplatin or cisplatin were administered after the 1-hour observation period after the end of the cetuximab infusion at the same dose, schedule, and route of administration as in the cycle during which PD was documented before study entry. Treatment was administered in 3- or 4-week cycles, according to the schedule the patient progressed on before study entry. Patients were intended to receive a minimum of two cycles of therapy. At this point, patients achieving stable disease (SD) or better continued treatment until PD or the occurrence of unacceptable side effects (see Dose Reductions and Delays). Patients with PD at any time point in the study discontinued treatment. Concomitant treatment with topical and/or oral antibiotics in the case of skin reactions was allowed. In addition, supportive care to manage the side effects of chemotherapy was permitted (eg, corticosteroids and antiemetics).
Dose Reductions and Delays
In the case of unacceptable platinum-associated toxicity (
End Points
Baseline evaluation of lesions was determined according to modified WHO criteria on the basis of computed tomography (CT) or magnetic resonance imaging (MRI) scans. A maximum of 10 index lesions (lesions, which were measurable in two dimensions, reflecting the extent of the disease and able to be followed up on serial imaging) were selected at baseline for evaluation. Nonindex lesions, which did not meet the measurable requirement for index lesions, were also assessed. Tumors were assessed by the same modality (CT or MRI) used for baseline evaluation. Tumor responses, based on assessments for index lesions and nonindex lesions, were defined as follows: CR, disappearance of all index lesions; PR, a Secondary end points were time to response, duration of response, time to progression (TTP; defined as the number of days from the first dose of cetuximab to the earliest day of progression, as determined by the IRC), overall survival (OS; calculated as the number of days from the first dose of cetuximab until death, regardless of the cause), symptomatic changes, changes in KPS, and quality of life.
Pretreatment Assessments and Response and Toxicity Evaluations EGFR expression was evaluated qualitatively using a standardized immunohistochemistry assay (DakoCytomation, Glostrup, Denmark) designed to assess cell membrane staining. Control slides provided with the kit comprised formalin-fixed, paraffin-embedded human cell lines with staining intensity scores of 2+ and 0. Assays were performed centrally by an independent pathologist on biopsy tissue fixed in 4% formalin. The percentage of stained cells and the staining intensity (0, no expression; 1+, faint; 2+, weak; 3+, strong) were evaluated by the same independent pathologist. Tumor response was assessed on day 15 or 22 of every other 3- or 4-week cycle, respectively, starting in cycle 2. Quality of life and KPS were evaluated every cycle on day 15 or 22. Adverse events were recorded according to National Cancer Institute Common Toxicity Criteria (version 2). For this study, a special adverse events category was defined comprising pooled Coding Symbols for Thesaurus of Adverse Reaction Terms preferred terms for areas of clinical relevance. Adverse events were recorded at each weekly visit before treatment administration. Investigations for human antichimeric antibodies were made on blood samples stored on day 15 or 22 of 3- and 4-week cycles, respectively. Follow-up assessments were made 4 weeks after the last dose of study medication.
Statistical Analyses
Between February 2000 and May 2001, 98 patients with SCCHN were enrolled onto the study from 32 centers in seven European countries (Austria, Belgium, France, Germany, Spain, Switzerland, and Poland). Two patients did not meet the entrance criteria (one patient had suspected drug abuse and one patient died during screening), leaving 96 patients in the ITT population. There were 64 patients in the IRC-PD population. The difference in the ITT and IRC-PD populations reflects the fact that some patients entering the study whose disease was designated as PD at entry by the investigator were considered by the IRC not to have PD. Additionally, in some cases, the poor quality or absence of scans precluded a definite confirmation of PD by the IRC. At the cutoff date for the analysis (May 31, 2003), five patients were still undergoing treatment. The ITT population comprised 85 males and 11 females (median age, 56 years; Table 1). The median KPS was 80%, the median duration of disease was 16.7 months, and the median TTP on the most recent platinum regimen was 15 days. The most common site of the primary tumor was the pharynx (48%), and 41% of patients had metastatic disease. EGFR expression at baseline was determined in 86 of 96 patients in the ITT population (56 of 64 patients in the IRC-PD population). The collection of data for the remaining patients was not available for a variety of reasons; these patients were considered to have minor protocol deviations and, as such, were not excluded from the ITT analysis. EGFR-expressing cells were found in 98% and 96% of ITT and IRC-PD patients tested, respectively. Overall, 63% of the 86 ITT patients with EGFR data had strong EGFR staining (3+), 19% had weak staining (2+), 16% had faint staining (1+), and two patients (2%) had no staining. Sixty-six patients (77%) showed EGFR staining in between 75% and 100% of the cells analyzed.
All patients had received cisplatin or carboplatin alone (n = 5, 5%) or in combination with other agents; the most common combinations were cisplatin/FU (n = 38, 40%) and carboplatin/FU (n = 10, 10%). Seven (7%) of patients had received cisplatin/docetaxel, three patients (3%) had received carboplatin/docetaxel, and five patients (5%) had received carboplatin/paclitaxel. Fifty-five patients received platinum therapy according to a 3-week cycle, and 41 received platinum therapy according to a 4-week platinum cycle. Just over half the patients (53%) had received two cycles of therapy; the remaining patients had received either three or four cycles. The median time between the end of the prior platinum-based chemotherapy cycle and the first dose of cetuximab was 15 days (range, 0 to 50 days).
Exposure to Cetuximab and Cisplatin Therapy
Response and Disease Control Rates
Response is also presented separately for patients receiving 3- and 4-week platinum cycles. The response rate and disease control rate were higher for patients receiving the 3-week platinum cycle (13% and 64%, respectively) compared with patients receiving the 4-week cycle (7% and 39%, respectively). Subgroup analysis revealed that there was a trend for older age, a higher baseline KPS, and the absence of metastases to favor a higher response and/or disease control rate (Table 3), although these data were not subject to formal statistical analysis, and therefore, there were no significant differences observed.
TTP and OS The median TTP and median OS were 85 and 183 days, respectively, in the ITT population and 72 and 150 days, respectively, in the IRC-PD population (Figs 1 and 2). In general, characteristics favoring a prolonged TTP and OS were a higher baseline KPS and no metastases (Table 3). In both populations, there was a trend for TTP and OS to be longest in those patients achieving a PR (median, 203.5 and 294 days, respectively, for the ITT population and 185 and 272 days, respectively, for the IRC-PD population). In addition, the median TTP and median OS were longer in patients receiving the 3-week platinum cycle compared with patients receiving the 4-week cycle. The median TTP for the 3- and 4-week cycles were 88 days (95% CI, 72 to 154 days) and 65 days (95% CI, 55 to 115 days), respectively. The median OS times for the 3- and 4-week cycles were 191 days (95% CI, 158 to 247 days) and 179 days (95% CI, 132 to 212 days), respectively. However, because none of these data were subject to statistical analysis, significant differences were not reported.
Quality of Life and KPS Trends Because of the small number of questionnaires completed, it was not possible to assess the impact of treatment on quality of life. However, KPS modifications seemed to correlate with response rate, TTP, and OS. These data are not presented here.
Efficacy End Points and Early Skin Reactions
Adverse Events All 96 patients who were treated experienced at least one adverse event. Apart from anemia and asthenia, the frequency of grade 3 and 4 events was less than 15%. The frequencies of adverse events (according to the special adverse event category) are listed in Table 5. The most frequent adverse events were skin reactions and acne-like rash. All but three patients with skin reactions and acne-like rash were classified as having grade 1 or 2 reactions. Most cases of acne-like rash occurred within the first 21 days of treatment. The median time to resolution of skin reactions and acne-like rash after treatment discontinuation was 29 days (range, 7 to 401 days) and 29 days (range, 7 to 84 days), respectively. The patient for whom resolution occurred 401 days after treatment discontinuation had a nonmalignant lesion on the nose, which was considered probably related to cetuximab. Three patients had hypersensitivity reactions, two of whom had received prophylactic corticosteroids and one of whom had not. There were no grade 3 or 4 hypersensitivity reactions. Serious adverse events were reported in 55% of patients and were considered to be related to cetuximab in 15 patients (16%).
Sixteen patients (17%) discontinued platinum-based chemotherapy mainly because of side effects; all of these patients continued receiving cetuximab monotherapy. Cetuximab-related adverse events led to the discontinuation of cetuximab in eight patients (8%), seven of whom were receiving cetuximab and platinum combination therapy (one patient each had life-threatening anemia, cardiovascular problems [atrial fibrillation], allergic reaction, anaphylactoid reaction, stomatitis, mucositis, and inflammation of a toe/nail disorder) and one of whom was receiving cetuximab monotherapy (asthenia). Cetuximab-related adverse events led to the discontinuation of cetuximab and platinum chemotherapy in three patients (3%). There were no cetuximab-related deaths in the study.
This study demonstrates that the combination of cetuximab and platinum chemotherapy has good activity in this population of platinum-refractory SCCHN patients. The primary end point of response rate, as assessed by IRC, was 10%, and responses lasted for a median of more than 5 months. Among responders, the median TTP was nearly 7 months, and OS was nearly 10 months, which are both highly encouraging findings for a second-line therapy in these poor prognosis patients. The results are particularly promising in view of the fact that nearly half of the patients had received prior treatment with more than two cycles of platinum-based therapy. It should be noted that there was quite a marked difference in the number of patients in the ITT population and the IRC-PD population. This is mainly a reflection of the stringent criteria used by the IRC in assessing PD. Despite this, it is notable that the response rates between the two populations were almost identical (10% ITT and 11% IRC-PD). These results suggest that it is probable that many of the patients classified by the IRC as nonassessable did actually have PD. The trend towards a higher response rate and median TTP observed with the 3-week compared with the 4-week cycle of platinum is of unclear significance because the sample size is too small to draw a conclusion. The results from our study are similar to those reported from another phase II study reported by Kies et al.27 In their study, patients with recurrent SCCHN who had progressed on two cycles of platinum-based chemotherapy received cetuximab combined with platinum at the same dose and schedule previously administered.27 There was an overall response rate of 12%, with a median TTP among responders of more than 5 months.27 The combination of cetuximab and carboplatin has also shown activity in NPC patients who experienced treatment failure on platinum analog-based chemotherapy.28 Recently, we have observed that single-agent cetuximab can produce major objective responses in patients with platinum-refractory recurrent or metastatic SCCHN with acceptable toxicity.29 Phase II studies with gefitinib and erlotinib have also demonstrated the activity of EGFR blockade in refractory recurrent or metastatic SCCHN.30,31 Cetuximab was well tolerated in this study, with the most common associated adverse events being skin reactions, particularly an acne-like rash. Skin reactions are not unique to cetuximab and are now an accepted and characteristic side effect of treatment with EGFR-directed monoclonal antibodies and tyrosine kinase inhibitors.31-34 In our study, most skin reactions were of grade 1 or 2 severity. The acne-like rash decreases in severity over time during treatment and resolves completely after treatment cessation.35 In the present study, the median time to resolution of the rash was 29 days. As expected, patient outcome after treatment was influenced by a number of factors, including good performance status and the absence of metastases. We also noted a relationship between the outcome to treatment and the development of the skin reactions. Patients developing skin reactions seemed to have a prolonged TTP and OS compared with patients not developing such reactions. A relationship between rash and response with cetuximab has previously been reported for metastatic colorectal cancer, pancreatic cancer, and recurrent or metastatic SCCHN in the phase II study reported by Kies et al27 and a randomized study in the first-line setting.36,37 In addition, Saltz et al37 reported that the more intense the rash, the longer the survival seems to be. However, the small number of patients developing grade 3 to 4 rash in our study precluded any conclusion regarding the impact of rash severity on outcome. A link between rash and response has also been observed with the EGFR tyrosine kinase inhibitors erlotinib30,34 and gefitinib.31 The relationship between rash and patient outcome after cetuximab continues to be investigated. An important aspect of targeting EGFR in SCCHN is whether there is a correlation between EGFR levels and response to cetuximab. In our study, although EGFR positivity was not an inclusion criterion, we were able to study EGFR expression in the majority of patients (86 of 96 patients) using the same determination criteria as in the cetuximab pivotal cancer colon study.19 However, there is no standardized method to determine EGFR expression in tumors. More importantly, the level of EGFR expression required in the tumor to obtain clinical benefit with cetuximab is not known at the present time.6 In our study, the majority of patients showed 2+ or 3+ EGFR staining intensity (70 patients), and a total of 60 patients showed EGFR expression in between 75% and 100% of the cells tested. However, our study was not large enough to study the relationship between EGFR expression and response to cetuximab. One of the most interesting aspects of cetuximab is that it seems to circumvent tumor resistance to chemotherapy, such that the tumor again responds to therapy on which it had previously progressed. This was noted in nonclinical studies with cetuximab plus irinotecan in irinotecan-refractory colorectal xenografts38 and was confirmed in the clinical setting.19 In our study, the clinical activity could have also been caused by reversal of platinum resistance. In a subsequent study with single-agent cetuximab in patients with platinum-refractory SCCHN, clinical activity has also been observed.29 Therefore, the question of whether cetuximab, in addition to its own antitumor activity, has the capacity to reverse platinum resistance in SCCHN would require a two-arm randomized study of cetuximab alone versus cetuximab plus platinum in this study population. The data available to date show that cetuximab is likely to play an important role in the treatment of SCCHN. The results from our studies and from that of Kies et al27 demonstrate the activity of cetuximab alone and in combination with platinum in the setting of cisplatin- or carboplatin-refractory recurrent or metastatic SCCHN.29 A phase III study by Burtness et al36 demonstrated that the combination of cisplatin and cetuximab was active in the first-line treatment of recurrent or metastatic SCCHN.36 The efficacy analysis showed a statistically significant higher response rate for cisplatin plus cetuximab compared with cisplatin plus placebo (26% v 10%, respectively; P = .048). In the cisplatin plus cetuximab and the cisplatin plus placebo arms, there was no significant difference in median progression-free survival (4.2 and 3.4 months, respectively) and overall survival (9.3 and 8.0 months, respectively). It is possible that the lack of a difference in survival between the treatment arms may be, at least in part, a result of underpowering of the trial. In addition, the activity of cetuximab in combination with radiation for locoregionally advanced SCCHN was suggested by an early phase I study39 and recently confirmed by a phase III study.40 The effective integration of cetuximab in the clinical setting will depend greatly on the selection of patients who will most likely respond to treatment. Some markers, for example skin reactions and downstream signaling transduction markers like mitogen-activated protein kinase, may be useful once cetuximab therapy is initiated. However, the identification of pretreatment predictive markers is a priority. A major advance has recently been made in this area with the identification of mutations in the adenosine triphosphate–binding cleft of the EGFR that predicts for increased receptor signaling and sensitivity to gefitinib in patients with non–small-cell lung cancer.41,42 It will be important to observe whether a similar relationship exists for cetuximab. In summary, this study shows that the combination of cisplatin or carboplatin and cetuximab in recurrent and/or metastatic SCCHN patients refractory to platinum-based chemotherapy has good clinical efficacy and an acceptable safety profile in this population of poor-prognosis patients for whom there are no recommended standard therapeutic options.
The following investigators were involved in this study: Austria: J. Meindl (Linz), K. Boheim (St Pölten), G. Kornek (Vienna); Belgium: S. van Belle (Gent), A. van Oosterom (Leuven), J. Vermorken (Edegem); Germany: A. Eckardt (Hannover), W. Eberhardt (Essen), T. Beinert (Berlin), R. Knecht (Frankfurt), B. Will (Kassel), B. Wollenberg (Munich), P. Volling (Oldenburg); Poland: J. Jassem (Gdansk), P. Koralweski (Krakow); France: J. Bourhis (Villejuif), M. Debled (Rouen), F. Rolland (Nantes), X. Pivot (Nice), P. Pommier (Lyon), J. Tortochaux (Clermont-Ferrand), L. Cals (Toulon), D. Cupisol (Montpellier); Spain: J.M. Trigo (Barcelona), R. Hitt and H. Cortés-Funes (Madrid), V. Guillem Porta (Vallencia), E. Diaz-Rubio (Madrid), A. Lopez Pousa and P. Gascon (Barcelona); and Switzerland: F. Heitzmann (Aarau), M. Pless (Basel).
Although all authors have completed the disclosure declaration, the following authors or their immediate family members have 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Supported by Merck KGaA, Darmstadt, Germany. Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
4 weeks before the start of the study), and quality of life (using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Head and Neck 35). The median duration of disease was defined as the difference between the date of the first cetuximab infusion and the date of diagnosis (defined as the earliest date of histologic confirmation, surgery, or other cancer therapy). 
