Multicenter, Phase II Study of Cetuximab in Combination With Carboplatin in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma
http://www.100md.com
《临床肿瘤学》
the Cancer Therapeutics Research Group, Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
Taiwan Cooperative Oncology Group, Departments of Otolaryngology and Oncology, National Taiwan University Hospital
Taiwan Cooperative Oncology Group, Division of Cancer Research, National Health Research Institute, Taipei, Taiwan
Cancer Therapeutics Research Group, Department of Clinical Oncology, National University Hospital
Cancer Therapeutics Research Group, Johns Hopkins-National University Hospital International Medical Center, Singapore
Cancer Therapeutics Research Group, Sydney Cancer Center, Sydney, Australia
Merck KGaA, Darmstadt, Germany
ABSTRACT
PURPOSE: To evaluate efficacy and toxicity of cetuximab plus carboplatin in recurrent or metastatic nasopharyngeal carcinoma (NPC) resistant to platinum treatment.
PATIENTS AND METHODS: A multicenter, open-label, single-arm, phase II study in patients with epidermal growth factor receptor–expressing NPC who progressed on or within 12 months after termination of platinum-based chemotherapy for recurrent or metastatic disease. Cetuximab was administered at an initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2. Carboplatin area under the curve 5 was administered every 3 weeks up to a maximum of eight cycles.
RESULTS: Sixty patients were enrolled (46 males, 14 females; median age, 44.5 years; range, 23 to 64 years), and all patients were included in the intent-to-treat and safety analyses. Of the 59 patients assessable for efficacy, there were seven partial responses (11.7%), 29 patients (48.3%) with stable disease, and 23 patients (38.3%) with progressive disease, giving an overall response rate of 11.7% (95% CI, 4.8% to 22.6%). The median time to progression was 81 days in all patients and was longest in the group of patients with a confirmed response (173 days). The median overall survival time was 233 days in all patients. Six patients (10%) experienced serious treatment-related adverse events. Grade 3 or 4 toxicities occurred in 31 patients (51.7%); of these patients, only 19 (31.7%) were considered to have toxicity related to cetuximab.
CONCLUSION: Cetuximab in combination with carboplatin demonstrates clinical activity and an acceptable safety profile in heavily pretreated patients with recurrent or metastatic NPC who had previously experienced treatment failure with platinum-based therapy.
INTRODUCTION
In many parts of Asia, including Southern China and Southeast Asia, nasopharyngeal carcinoma (NPC) is the most common head and neck cancer, with an incidence of between 15 and 50 cases per 100,000 people. The primary treatment for American Joint Committee on Cancer stage T1-4N1-3M0 nonmetastatic NPC is a course of radical external-beam radiotherapy (RT) for early-stage disease and concurrent cisplatin-RT for locally advanced disease.1 More accurate treatment planning through tumor localization by computed tomography (CT) and better RT technique have contributed to improvement in local control of this disease, with a local failure-free rate of approximately 80%.2 However, patients with advanced disease (International Union Against Cancer stage III and IV) have significant rates of local relapse or distant metastasis after primary treatment. For patients who relapse with distant metastasis, the prognosis is poor, with reported median survival times ranging from only 5 to 11 months.3-7
Epidermal growth factor receptor (EGFR) represents a promising new therapeutic target in cancer. EGFR is highly expressed in most human epithelial carcinomas and has been correlated with a more aggressive phenotype, resistance to treatment, and a poor prognosis.8,9 EGFR expression in NPC has been previously reported.10-15 Our recent prospective study has demonstrated that EGFR was expressed in more than 85% of NPC.16 Furthermore, high EGFR expression has been shown to be an independent predictor of poor clinical outcome in NPC.16,17
The use of monoclonal antibodies to inhibit EGFR was the first approach to target the aberrant signaling of EGFR in malignant cells. Cetuximab (Erbitux; ImClone Systems Inc., New York, NY) was the first chimeric human-mouse monoclonal antibody to be explored in clinical studies.18 Several preclinical studies demonstrated the antitumor effect of cetuximab in a variety of cell types and mouse xenografts either as single agent or in combination with chemotherapeutic agents or RT.19-23 Although cetuximab has modest activity as monotherapy in some systems, it consistently demonstrated better activity when administered in conjunction with cytotoxic chemotherapy. A phase II study demonstrated that cetuximab achieved nearly complete saturation of EGFR in tumor tissue and a high percentage of tumor response in combination with cisplatin, when an initial dose of 400 mg/m2 and a weekly dose of 250 mg/m2 were administered to patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).24 This suggested the need for additional concurrent chemotherapy if receptor-targeting therapy with a monoclonal antibody was to be useful against cancer in the clinical setting.
Clinical studies of cetuximab in a variety of indications and settings have provided further support to the theory that the response of a tumor to standard chemotherapy is improved by combination of the usual regimen with cetuximab.25 Indeed, cetuximab’s first marketing approval in the European Union was based on the positive results of a pivotal phase II study looking at cetuximab in combination with irinotecan in metastatic colorectal cancer after failure with an irinotecan-based regimen.26 In addition, several studies in head and neck cancer patients suggested that the addition of cetuximab to platinum analogs may be able to overcome resistance against these drugs.27,28
Further indications for EGFR as a possible target to treat NPC were suggested by the anti-NPC activity observed in preclinical models with specific inhibitors of the EGFR family of tyrosine kinases.29 Given this scientific background and early clinical data, we conducted a phase II study formally to evaluate the activity and safety of cetuximab plus carboplatin in patients with recurrent and/or metastatic NPC who had experienced treatment failure with platinum-based chemotherapy. Because there is a high rate of initial response to first-line platinum-based regimens, most patients would have received six to eight cycles of treatment. Hence, on subsequent progression of disease, further treatment with cisplatin would be associated with a higher risk of occurrence of cumulative toxicities such as nephrotoxicity, ototoxicity, and neurotoxicity. Carboplatin is less toxic to nerves and kidneys than cisplatin and likely to be better tolerated by this patient population; therefore, the combination of cetuximab and carboplatin was selected for the study.
PATIENTS AND METHODS
Study Design and Entry Criteria
We conducted a multicenter, open-label, single-arm phase II study, which was planned to enroll up to 60 patients with recurrent or metastatic NPC. The study was performed in six centers in the Asia-Pacific region. Patients were eligible if they had disease progression on or within 12 months after the end of treatment with a platinum-based chemotherapy for recurrent or metastatic disease. Additionally, patients had to have a confirmed histologic diagnosis of NPC, recurrent or metastatic disease, EGFR expression in the target tumor, and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)30 either by CT scan or magnetic resonance imaging. Patients had to be aged 18 years or older and had to have a Karnofsky performance status of at least 60%. Patients were required to have hemoglobin 9 g/dL, WBC count 3,000/μL, platelet count 100,000/μL, ALT or AST 3 x the upper limit of normal, bilirubin 2 x the upper limit of normal, and serum creatinine 1.5 x the upper limit of normal.
Ethics
The study protocol was reviewed and approved by the institutional review board of each participating center, and all patients gave written informed consent before participation.
EGFR Expression
The EGFR assessment on tumor specimen was performed locally at each study site and also centrally at the Prince of Wales Hospital at the Chinese University of Hong Kong to avoid any discrepant assessment caused by, for instance, the quality of tumor specimens or heterogeneity of tumors. The assessment was performed using the EGFR pharmDX kit system (DakoCytomation, Copenhagen, Denmark). The results of immunohistochemical examination of EGFR expression in tumor tissue specimens was graded as a score of 0, 1+, 2+, or 3+. The extent of stained cells per section was defined and scored as 0 for no staining or less than 10% staining of the tumor cells, 1+ for faint staining in more than 10% of the tumor cells, 2+ for weak to moderate complete membrane staining in more than 10% of the tumor cells, and 3+ for strong complete membrane staining in more than 10% of the tumor cells. A tissue was declared to be an EGFR-expressing tissue when it could be classified as at least 1+. Patients whose tumors were classified as expressing EGFR by either the local or central test were permitted to be enrolled onto this study. The EGFR results of the central test were used in this report.
Therapy
Cetuximab was administered at an initial dose of 400 mg/m2 over 120 minutes and was subsequently administered as weekly doses of 250 mg/m2 over 60 minutes. All patients were pretreated with an antihistamine. Carboplatin with a targeted area under the curve of 5 (according to the Calvert formula) was administered after the cetuximab infusion on day 1 of a 21-day treatment cycle. The duration of treatment with cetuximab in combination with carboplatin was planned until progressive disease (PD) or unacceptable toxicity or a maximum of eight cycles. If patients had still not progressed at this stage, treatment with cetuximab as monotherapy could be administered until PD. In the case of carboplatin-associated toxicity, dosage reduction and delays were permitted. If carboplatin discontinuation was required because of unacceptable toxicity but the patient was still experiencing benefit from therapy with cetuximab, treatment with cetuximab as monotherapy was continued until PD was diagnosed.
Dose Modifications for Cetuximab
If a patient experienced grade 3 skin toxicity, cetuximab therapy could be interrupted for up to two consecutive infusions with no change in the dose level. If toxicity resolved to grade 2 or less after up to 2 weeks of interruption, treatment could be resumed. On the second and third occurrence of grade 3 skin toxicity, cetuximab therapy could be interrupted again for up to 2 consecutive weeks, with subsequent dose reductions to 200 and 150 mg/m2, respectively. Patients had treatment discontinued if more than two consecutive infusions were withheld or if a fourth occurrence of grade 3 skin toxicity occurred. The chemotherapy was continued independently of temporary interruption of cetuximab. Cetuximab was not withheld for carboplatin-related toxicities, unless the patient developed a concomitant illness that, in the opinion of the investigator, mandated interruption of therapy. Study treatment was terminated on discontinuation of cetuximab therapy.
Evaluation of Patients
Routine evaluation of patients was performed at pretreatment and then weekly for the duration of the study. These evaluations included a physical examination, vital signs, laboratory hematologic and biochemical results, and the recording of concomitant medication and adverse events (AEs). All AEs were documented and coded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Blood sampling for routine laboratory tests was performed twice per cycle. Human antichimeric antibody was assessed every second treatment cycle.
Patients were evaluated for response every other treatment cycle with an assessment of Karnofsky performance status. The response evaluation of the tumor to therapy was based on CT scan or magnetic resonance imaging, and patients were classified by the investigator according to the Response Evaluation Criteria in Solid Tumors criteria as having a complete response (CR), partial response (PR), stable disease (SD), or PD or as not assessable. To be assigned a status of PR or CR, a confirmation assessment was required no less than 4 weeks after the criteria for response were first met.
Statistical Analysis
The primary objective was to determine the response rate. Secondary objectives were to evaluate time to response, duration of response, time to progression (TTP), and overall survival and to collect safety data. The sample size was fixed at 60 patients without a formal sample size calculation. Because of the explorative nature of the study, no formal sample size estimation was performed. Assuming a response rate of 30%, observation of 14 or more responders out of 60 patients with a probability of approximately 90% was expected. Alternatively, assuming a response rate of 15%, the probability of observing 14 or more responders was only approximately 5%. Therefore, a sample size of 60 patients was regarded as appropriate for this study. The intent-to-treat and safety population included all patients who received any dose of cetuximab. The primary efficacy variable was the response rate based on each patient’s best response during the study. The response rate and its 95% CI (using the method of Pearson and Clopper) were calculated. TTP and survival time were estimated using the Kaplan-Meier method. Descriptive statistics were used for safety evaluations.
RESULTS
Patients Characteristics
All of the 60 enrolled patients were included in the intent-to-treat and safety population, which included 46 male patients (77%) and 14 female patients (23%). The median age of the patients was 44.5 years (range, 23 to 64 years), and the majority of patients (n = 56, 93%) was Chinese. The demographic and baseline characteristics of the 60 patients are listed in Table 1. At the baseline of the study, four patients (6.7%) had stage III disease, and 56 patients (93.3%) had stage IV disease, and among these patients, 51 (85%) had distant metastasis.
Prior Treatment
The study protocol did not restrict the number of previous palliative chemotherapy lines; the patients only had to be progressive after platinum-based chemotherapy. Cetuximab plus carboplatin was administered in this study as second-line therapy in 40 patients (70%) and as third- to seventh-line therapy in the remaining 18 patients (30%; Table 1). The median time from the start of recent platinum-based chemotherapy to PD was 203 days (range, 50 to 414 days). The median time from the date PD was diagnosed to the first dose of cetuximab was 29 days (range, 9 to 232 days), whereas the median time from the end of recent platinum-based chemotherapy to the first dose of cetuximab was 116 days (range, 2 to 407 days).
Besides prior platinum agents and FU, several other agents had been used, such as paclitaxel in 12 patients (20%), gemcitabine in nine patients (15%), vinorelbine in four patients (7%), and docetaxel in one patient (2%; Table 1). In total, most patients had received between two and five different agents, with some patients having had exposure to eight different compounds. In addition, 55 patients (92%) had other prior therapy administered either before or after the recent platinum-based therapy. In total, 46 patients (77%) had received other prior chemotherapies (of whom, 28 patients, or 47%, were treated with platinum-based chemotherapy), whereas 53 patients (88%) had received RT.
Treatment With Cetuximab and Carboplatin
The median number of infusions of cetuximab was 10 (range, one to 30 infusions). Twenty-one patients (35%) received six to 10 infusions, which was the biggest proportion. This was followed by 16 patients (27%) who received 11 to 20 infusions. The relative dose-intensity of cetuximab was 90% in 55 patients (91.75%) and 80% in 58 patients (97%; Table 2). A total of 25 patients had minor dose reductions that resulted from small variations in body surface area. No patients required dose modification of cetuximab as a result of skin toxicity as defined in the study protocol.
The numbers of carboplatin infusions in this population are listed in Table 2. Approximately half of the patients (n = 32, 53.3%) received at least three infusions, and 10 patients (16.7%) received the maximum of eight infusions. The dose-intensity of carboplatin was 80% of the planned dose in 45 patients (75%).
EGFR Expression
Of 66 patients screened for tumor EGFR expression, 61 (92.4%) were assessed as expressing EGFR. In 60 enrolled patients, compatible assessments concerning the grade of positivity from both laboratories were seen in 51 patients (85%), whereas a difference of one grade was measured in six patients (10%), and a difference of two grades was measured in one patient (1.6%). In addition, two patients (3.3%) were not evaluated as expressing EGFR by the central lab. In just over half of the patients (55%), the tumors were assessed as 3+. EGFR expression as determined by the central laboratory is listed in Table 3.
Efficacy
No patient achieved a CR, seven patients (11.7%) achieved a PR, 29 patients (48.3%) had SD, and 23 patients (38.3%) had PD. One patient had no postbaseline assessment and was, therefore, not assessable. The confirmed response rate was 11.7% (95% CI, 4.8% to 22.6%), and the disease control rate (CR + PR + SD) was 60% (95% CI, 46.5% to 72.5%). There was no obvious association between the level of EGFR expression and best response (Table 3). Responses were seen in six (13.0%) of 46 patients with undifferentiated carcinoma, and one (7.1%) of 14 patients with other histologic types of tumor.
In the seven patients with a confirmed response, the median time to response after the beginning of treatment with cetuximab was 42 days (range, 39 to 82 days). Of these seven patients, two were still in confirmed response (PR) at the cutoff date of the study. The median duration of response was 99 days. The median TTP was 81 days in all patients; it was longest in the group of patients with confirmed response (173 days), followed by the groups of patients with disease control (127 days) and SD (106 days). Patients with PD had a median TTP of 41.5 days. No association was found between TTP and skin toxicities (Fig 1).
Survival and Subgroup Analysis
The median survival time was 233 days in all patients. In the groups with disease control and SD, the median survival times were equal (241 days). The shortest survival time occurred in the group of patients with PD (114 days).
The following factors seem to be associated with a prolonged survival time: sex (male compared with female), a Karnofsky performance status 80% at baseline compared with one of less than 80%, setting of cetuximab plus carboplatin as second-line therapy compared with a setting of third-line therapy or higher, and an interval of more than 90 days between recent platinum-based chemotherapy and the start of cetuximab plus carboplatin compared with an interval of 90 days. No noticeable impact on survival time could be detected for the following factors evaluated: age, baseline tumor staging, metastasis stage at screening, and prior RT.
There was no obvious association between the level of EGFR expression and survival time (Table 4). However, the median survival time seemed to be longest in patients who developed grade 3 and 4 early skin reaction or acne-like rash, but this result is inconclusive because this group consisted of only two patients (Fig 2).
AEs
AE frequencies in this patient population are listed in Table 5. All of the 60 patients in this study experienced AEs. The most common AEs were (in order of decreasing frequency) rash, nausea, and vomiting (frequency 40% of the patients); fever, asthenia, dry skin, cough, and anorexia (frequency 30% and < 40% of the patients); nail disorder, dyspnea, anemia, constipation, insomnia, stomatitis, diarrhea, and thrombocytopenia (frequency 20% and < 30% of the patients); and epistaxis, pain, pruritus, acne, headache, infection, leukopenia, neuropathy, rhinitis, and increased sputum (frequency 15% and < 20% of the patients). The most common grade 3 and 4 AEs were (in order of decreasing frequency): anemia, dyspnea, and thrombocytopenia (frequency 10% of the patients); and rash, asthenia, hypochromic anemia, vomiting, and neuralgia (frequency > 5% of the patients). Fifty-eight patients (97%) experienced AEs that were considered by the investigator to be related to cetuximab. A total of 11 patients (18.3%) experienced AEs that led to discontinuation of study medication. However, cetuximab-related AEs that caused discontinuation of cetuximab were experienced by five patients (8%). Grade 3 or 4 toxicity occurred in 31 patients (51.7%), and in 19 of these patients (31.7%), these AEs were assessed as cetuximab-related events. No cetuximab-related hypersensitivity reaction was reported. The hypersensitivity reaction (grade 1) in one patient was associated with carboplatin by the investigator. Seven patients (11.7%) died while enrolled on the study or within 30 days after their last dose of cetuximab. None of the deaths were considered as being related to treatment with cetuximab.
Because of the underlying recurrent and/or metastatic malignant disease and because of previously received chemotherapy, most patients already had abnormal laboratory findings before inclusion onto the clinical study. During the course of this study, grade 3 and 4 on-treatment hematologic toxicities (laboratory value) were reported in 40 patients (66.7%), and hematologic grade 4 toxicities were only reported for hemoglobin (four patients, 6.7%) and neutrophils (one patient, 1.7%). Grade 3 and 4 on-treatment blood chemistry toxicities (laboratory value) were reported in 19 patients (31.7%) and exceeded 5% only for alkaline phosphatase (nine patients, 15.0%), sodium (seven patients, 11.7%), and gamma-glutamyltransferase (six patients, 10.0%). Only three clinically relevant urine analysis values were reported. One patient had increased protein and blood levels in urine at the end-of-study visit, which was a result of a urinary tract infection. Another patient had an increased protein level in urine at the end-of-study visit. None of the serum samples showed a positive human antichimeric antibody response.
DISCUSSION
A wide range of chemotherapeutic agents has been used in the treatment of locally recurrent or metastatic NPC. Although the activity of platinum-based chemotherapy in patients with recurrent or metastatic NPC is high, with response rates greater than 50%, the duration of response and survival time are limited, and palliative second-line chemotherapy is only reserved for good-performance patients.31 A small number of publications have reported the outcome of treatments administered to recurrent or metastatic NPC patients who progressed after palliative platinum-based chemotherapy. Airoldi et al32 reported a small series of 12 patients with recurrent NPC treated with carboplatin and paclitaxel as third-line therapy (after cisplatin and fluorouracil). Three patients (25%) obtained a PR, one patient (8.3%) had a minimal response, and three patients (25%) showed no change. The median survival time was 14 months for patients who had a PR or minimal response or no change and 5 months for nonresponders. Median overall survival time was 9.5 months. The treatment was reported to be well tolerated, with manageable toxicity.32 Similarly, Chua et al33 reported a small phase II study in which 17 patients with recurrent or metastatic NPC received oral capecitabine as second-line therapy after platinum-based chemotherapy administered either as adjuvant or as first-line therapy. The overall response rate was 23.5%, and the median survival time was 7.6 months. Treatment-related AEs were reported to be generally mild, except for hand-foot syndrome, which occurred in 58.8% of patients.33
Cetuximab is the first monoclonal antibody targeting the EGFR approved for biologic therapy to treat colorectal cancer. This study demonstrated that the combination therapy of cetuximab (250 mg/m2/wk) with carboplatin (area under the curve 5) has clinical efficacy, even in heavily pretreated NPC patients, of whom approximately 30% had received more than two and up to six prior chemotherapy regimens. This combination exhibited an 11.7% response rate, and nearly 50% of the patients had stabilization of their disease, resulting in a disease control rate of 60% in the study. Moreover, a median TTP of 3 months and a median survival time of 8 months were observed and are comparable to the results in the study reported by Chua et al,33 in which patients with metastatic or recurrent NPC received chemotherapy regimens as second-line treatment. In view of the intensely pretreated patients, the results from this study look promising. The inclusion and exclusion criteria of this study resulted in a clearly refractory patient population, which makes comparison with literature data somewhat difficult because most published studies consisted of metastatic or recurrent patient populations who received mainly first-line chemotherapy with probably better prognosis. Our study is also consistent with results reported from clinical studies of cetuximab in platinum-refractory SCCHN.28,34
Because the patients enrolled onto this study had advanced disease and were heavily pretreated, it was expected that many AEs would be observed in this setting of combination. The typical side effects associated with cetuximab are skin reactions, whereas the other side effects were either associated with the underlying disease or the well-described toxicities of carboplatin that were not aggravated by cetuximab. The combination of cetuximab with carboplatin demonstrated acceptable tolerability, and no dose modifications were necessary. Therefore, the favorable benefit to risk ratio of cetuximab plus carboplatin justifies the use of this combination as treatment for patients who experienced treatment failure with standard chemotherapy for NPC. Cetuximab in combination with standard cytotoxic therapies has now shown consistent anticancer activity across a wide range of EGFR-expressing tumors, including NPC, SCCHN, colorectal cancer, and non–small-cell lung cancer.
Previous studies have shown that cetuximab seems to be able to overcome resistance to previously administered chemotherapy.26 The present study supports this finding, with the combination of cetuximab with carboplatin showing activity in tumors that would otherwise be expected to have no or minimal response to carboplatin monotherapy. The mechanism by which cetuximab is able to overcome resistance is as yet unclear.
Subgroup analysis also showed that there does not seem to be a correlation between the level of EGFR expression in the target tumor and the activity of treatment. This is similar to the results of another study using cetuximab or cetuximab in combination with irinotecan to treat patients with metastatic colorectal cancer.26 Whether this is because the amount of activated EGFR in a tumor cell does not affect the rate of tumorigenesis or, instead, because of an inherent problem with the immunohistochemical visualization system used has yet to be determined. A clinical study of cetuximab in EGFR nondetectable patients will show whether the presence of EGFR in a tumor is a prerequisite for activity. Simultaneously, efforts are ongoing in an attempt to find molecular markers other than EGFR that could be used to select patients for cetuximab treatment with greater success in terms of the clinical response and survival; candidates include MAPK, Akt, p67, and phosphorylated EGFR activities. In the meantime, there may be a practical alternative because we did observe a link (albeit inconclusive) between treatment activity and the severity of cetuximab-induced skin reactions, as reported in the other study with cetuximab-based therapy.25 The potential use of skin reaction as a predictor of cetuximab treatment efficacy and patient selection is currently being investigated in a titrate to rash clinical study, which evaluates the tumor response to a dose escalation of cetuximab until skin reaction occurs in patients without tumor response to the current regimen.
Several studies are ongoing looking at the combination of cetuximab and chemotherapy as first-line treatment in SCCHN, with promising interim results.35,36 In addition, Bonner et al37 recently released data showing a significant survival benefit when cetuximab was added to RT in the same setting. On the basis of these and the present results, evaluation of the potential for cetuximab in earlier lines of treatment for NPC is justified.
Authors' Disclosures of Potential Conflicts of Interest
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. Employment: Matthias Mueser, Merck Pte Ltd Singapore; Nadia Amellal, Merck KGaA; Xiao Lin, Merck Pte Ltd Singapore. Consultant/Advisory Role: Michael J. Millward, Merck KGaA; Alex Y. Chang, AstraZeneca, Bristol-Myers Squibb. Honoraria: Michael J. Millward, Merck KGaA; Alex Y. Chang, Bristol-Myers Squibb. Research Funding: Michael J. Millward, Merck KGaA; Alex Y. Chang, AstraZeneca, Aventis, Bristol-Myers Squibb, Pfizer. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Supported by Merck KGaA.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2003, and at the 12th Annual European Cancer Conference Meeting, Copenhagen, Denmark, September 19-25, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Chan AT, Teo PM, Johnson PJ: Nasopharyngeal cancer. Cancer Treat Res 114 : 275 -293, 2003
Teo P, Yu P, Lee WY, et al: Significant prognosticators after primary radiotherapy in 903 nondisseminated nasopharyngeal carcinoma evaluated by computer tomography. Int J Radiat Oncol Biol Phys 36 : 291 -304, 1996
Teo PM, Kwan WH, Lee WY, et al: Prognosticators determining survival subsequent to distant metastasis from nasopharyngeal carcinoma. Cancer 77 : 2423 -2431, 1996
Vikram B, Mishra UB, Strong EW, et al: Patterns of failure in carcinoma of the nasopharynx: Failure at distant sites. Head Neck Surg 8 : 276 -279, 1986
Leung SF, Teo PM, Shiu WW, et al: Clinical features and management of distant metastases of nasopharyngeal carcinoma. J Otolaryngol 20 : 27 -29, 1991
Geara FB, Sanguineti G, Tucker SL, et al: Carcinoma of the nasopharynx treated by radiotherapy alone: Determinants of distant metastasis and survival. Radiother Oncol 43 : 53 -61, 1997
Hui EP, Leung SF, Au JS, et al: Lung metastasis alone in nasopharyngeal carcinoma: A relatively favorable prognostic group—A study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Cancer 101 : 300 -306, 2004
Ciardiello F, Tortora G: A novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor. Clin Cancer Res 7 : 2958 -2970, 2001
Mendelsohn J: Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 20 : 1S -13S, 2002 (suppl)
Zheng X, Hu L, Chen F, et al: Expression of Ki67 antigen, epidermal growth factor receptor and Epstein-Barr virus-encoded latent membrane protein (LMP1) in nasopharyngeal carcinoma. Eur J Cancer B Oral Oncol 30B : 290 -295, 1994
Roychowdhury DF, Tseng A Jr, Fu KK, et al: New prognostic factors in nasopharyngeal carcinoma: Tumor angiogenesis and C-erbB2 expression. Cancer 77 : 1419 -1426, 1996
Sheen TS, Huang YT, Chang YL, et al: Epstein-Barr virus-encoded latent membrane protein 1 co-expresses with epidermal growth factor receptor in nasopharyngeal carcinoma. Jpn J Cancer Res 90 : 1285 -1292, 1999
Fujii M, Yamashita T, Ishiguro R, et al: Significance of epidermal growth factor receptor and tumor associated tissue eosinophilia in the prognosis of patients with nasopharyngeal carcinoma. Auris Nasus Larynx 29 : 175 -181, 2002
Leong JL, Loh KS, Putti TC, et al: Epidermal growth factor receptor in undifferentiated carcinoma of the nasopharynx. Laryngoscope 114 : 153 -157, 2004
Putti TC, To KF, Hsu HC, et al: Expression of epidermal growth factor receptor in head and neck cancers correlates with clinical progression: A multicentre immunohistochemical study in the Asia-Pacific region. Histopathology 41 : 144 -151, 2002
Ma BB, Poon TC, To KF, et al: Prognostic significance of tumor angiogenesis, Ki 67, p53 oncoprotein, epidermal growth factor receptor and HER2 receptor protein expression in undifferentiated nasopharyngeal carcinoma: A prospective study. Head Neck 25 : 864 -872, 2003
Chua DT, Nicholls JM, Sham JS, et al: Prognostic value of epidermal growth factor receptor expression in patients with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys 59 : 11 -20, 2004
Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21 : 2787 -2799, 2003
Fan Z, Baselga J, Masui H, et al: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53 : 4637 -4642, 1993
Huang SM, Bock JM, Harari PM: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59 : 1935 -1940, 1999
Ciardiello F, Bianco R, Damiano V, et al: Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res 5 : 909 -916, 1999
Inoue K, Slaton JW, Perrotte P, et al: Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma. Clin Cancer Res 6 : 4874 -4884, 2000
Prewett MC, Hooper AT, Bassi R, et al: Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 8 : 994 -1003, 2002
Shin DM, Donato NJ, Perez-Soler R, et al: Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res 7 : 1204 -1213, 2001
Humblet Y: Cetuximab: An IgG(1) monoclonal antibody for the treatment of epidermal growth factor receptor-expressing tumours. Expert Opin Pharmacother 5 : 1621 -1633, 2004
Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351 : 337 -345, 2004
Baselga J, Trigo J, Bourhis J, et al: Cetuximab (C225) plus cisplatin/carboplatin is active in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on a same dose and schedule platinum-based regimen. Proc Am Soc Clin Oncol 21 : 226 , 2002 (abstr 900)
Trigo J, Hitt R, Koralewski P, et al: Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN): Results of a phase II study. Proc Am Soc Clin Oncol 23 : 488 , 2004 (abstr 5502)
Sun Y, Fry DW, Vincent P, et al: Growth inhibition of nasopharyngeal carcinoma cells by EGF receptor tyrosine kinase inhibitors. Anticancer Res 19 : 919 -924, 1999
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92 : 205 -216, 2000
Chan AT, Teo PM, Leung TW, et al: The role of chemotherapy in the management of nasopharyngeal carcinoma. Cancer 82 : 1003 -1012, 1998
Airoldi M, Pedani F, Marchionatti S, et al: Carboplatin plus Taxol is an effective third-line regimen in recurrent undifferentiated nasopharyngeal carcinoma. Tumori 88 : 273 -276, 2002
Chua DT, Sham JS, Au GK: A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol 39 : 361 -366, 2003
Kies MS, Arquette MA, Nabell L, et al: Final report of the efficacy and safety of the anti-epidermal growth factor antibody Erbitux (IMC-C225), in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) refractory to cisplatin containing chemotherapy. Proc Am Soc Clin Oncol 21 : 232 , 2002 (abstr 925)
Humblet Y, Vega-Villegas E, Mesia R, et al: Phase I study of cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil (5-FU) in patients (pts) with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 23 : 491 , 2004 (abstr 5513)
Burtness BA, Li Y, Flood W, et al: Phase III trial comparing cisplatin (C) + placebo (P) to C + anti-epidermal growth factor antibody (EGF-R) C225 in patients (pts) with metastatic/recurrent head and neck cancer (HNC). Proc Am Soc Clin Oncol 21 : 226 , 2002 (abstr 901)
Bonner JA, Giralt J, Harari PM, et al: Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. Proc Am Soc Clin Oncol 23 : 489 , 2004 (abstr 5507)(Anthony T.C. Chan, Mow-Mi)
Taiwan Cooperative Oncology Group, Departments of Otolaryngology and Oncology, National Taiwan University Hospital
Taiwan Cooperative Oncology Group, Division of Cancer Research, National Health Research Institute, Taipei, Taiwan
Cancer Therapeutics Research Group, Department of Clinical Oncology, National University Hospital
Cancer Therapeutics Research Group, Johns Hopkins-National University Hospital International Medical Center, Singapore
Cancer Therapeutics Research Group, Sydney Cancer Center, Sydney, Australia
Merck KGaA, Darmstadt, Germany
ABSTRACT
PURPOSE: To evaluate efficacy and toxicity of cetuximab plus carboplatin in recurrent or metastatic nasopharyngeal carcinoma (NPC) resistant to platinum treatment.
PATIENTS AND METHODS: A multicenter, open-label, single-arm, phase II study in patients with epidermal growth factor receptor–expressing NPC who progressed on or within 12 months after termination of platinum-based chemotherapy for recurrent or metastatic disease. Cetuximab was administered at an initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2. Carboplatin area under the curve 5 was administered every 3 weeks up to a maximum of eight cycles.
RESULTS: Sixty patients were enrolled (46 males, 14 females; median age, 44.5 years; range, 23 to 64 years), and all patients were included in the intent-to-treat and safety analyses. Of the 59 patients assessable for efficacy, there were seven partial responses (11.7%), 29 patients (48.3%) with stable disease, and 23 patients (38.3%) with progressive disease, giving an overall response rate of 11.7% (95% CI, 4.8% to 22.6%). The median time to progression was 81 days in all patients and was longest in the group of patients with a confirmed response (173 days). The median overall survival time was 233 days in all patients. Six patients (10%) experienced serious treatment-related adverse events. Grade 3 or 4 toxicities occurred in 31 patients (51.7%); of these patients, only 19 (31.7%) were considered to have toxicity related to cetuximab.
CONCLUSION: Cetuximab in combination with carboplatin demonstrates clinical activity and an acceptable safety profile in heavily pretreated patients with recurrent or metastatic NPC who had previously experienced treatment failure with platinum-based therapy.
INTRODUCTION
In many parts of Asia, including Southern China and Southeast Asia, nasopharyngeal carcinoma (NPC) is the most common head and neck cancer, with an incidence of between 15 and 50 cases per 100,000 people. The primary treatment for American Joint Committee on Cancer stage T1-4N1-3M0 nonmetastatic NPC is a course of radical external-beam radiotherapy (RT) for early-stage disease and concurrent cisplatin-RT for locally advanced disease.1 More accurate treatment planning through tumor localization by computed tomography (CT) and better RT technique have contributed to improvement in local control of this disease, with a local failure-free rate of approximately 80%.2 However, patients with advanced disease (International Union Against Cancer stage III and IV) have significant rates of local relapse or distant metastasis after primary treatment. For patients who relapse with distant metastasis, the prognosis is poor, with reported median survival times ranging from only 5 to 11 months.3-7
Epidermal growth factor receptor (EGFR) represents a promising new therapeutic target in cancer. EGFR is highly expressed in most human epithelial carcinomas and has been correlated with a more aggressive phenotype, resistance to treatment, and a poor prognosis.8,9 EGFR expression in NPC has been previously reported.10-15 Our recent prospective study has demonstrated that EGFR was expressed in more than 85% of NPC.16 Furthermore, high EGFR expression has been shown to be an independent predictor of poor clinical outcome in NPC.16,17
The use of monoclonal antibodies to inhibit EGFR was the first approach to target the aberrant signaling of EGFR in malignant cells. Cetuximab (Erbitux; ImClone Systems Inc., New York, NY) was the first chimeric human-mouse monoclonal antibody to be explored in clinical studies.18 Several preclinical studies demonstrated the antitumor effect of cetuximab in a variety of cell types and mouse xenografts either as single agent or in combination with chemotherapeutic agents or RT.19-23 Although cetuximab has modest activity as monotherapy in some systems, it consistently demonstrated better activity when administered in conjunction with cytotoxic chemotherapy. A phase II study demonstrated that cetuximab achieved nearly complete saturation of EGFR in tumor tissue and a high percentage of tumor response in combination with cisplatin, when an initial dose of 400 mg/m2 and a weekly dose of 250 mg/m2 were administered to patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).24 This suggested the need for additional concurrent chemotherapy if receptor-targeting therapy with a monoclonal antibody was to be useful against cancer in the clinical setting.
Clinical studies of cetuximab in a variety of indications and settings have provided further support to the theory that the response of a tumor to standard chemotherapy is improved by combination of the usual regimen with cetuximab.25 Indeed, cetuximab’s first marketing approval in the European Union was based on the positive results of a pivotal phase II study looking at cetuximab in combination with irinotecan in metastatic colorectal cancer after failure with an irinotecan-based regimen.26 In addition, several studies in head and neck cancer patients suggested that the addition of cetuximab to platinum analogs may be able to overcome resistance against these drugs.27,28
Further indications for EGFR as a possible target to treat NPC were suggested by the anti-NPC activity observed in preclinical models with specific inhibitors of the EGFR family of tyrosine kinases.29 Given this scientific background and early clinical data, we conducted a phase II study formally to evaluate the activity and safety of cetuximab plus carboplatin in patients with recurrent and/or metastatic NPC who had experienced treatment failure with platinum-based chemotherapy. Because there is a high rate of initial response to first-line platinum-based regimens, most patients would have received six to eight cycles of treatment. Hence, on subsequent progression of disease, further treatment with cisplatin would be associated with a higher risk of occurrence of cumulative toxicities such as nephrotoxicity, ototoxicity, and neurotoxicity. Carboplatin is less toxic to nerves and kidneys than cisplatin and likely to be better tolerated by this patient population; therefore, the combination of cetuximab and carboplatin was selected for the study.
PATIENTS AND METHODS
Study Design and Entry Criteria
We conducted a multicenter, open-label, single-arm phase II study, which was planned to enroll up to 60 patients with recurrent or metastatic NPC. The study was performed in six centers in the Asia-Pacific region. Patients were eligible if they had disease progression on or within 12 months after the end of treatment with a platinum-based chemotherapy for recurrent or metastatic disease. Additionally, patients had to have a confirmed histologic diagnosis of NPC, recurrent or metastatic disease, EGFR expression in the target tumor, and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)30 either by CT scan or magnetic resonance imaging. Patients had to be aged 18 years or older and had to have a Karnofsky performance status of at least 60%. Patients were required to have hemoglobin 9 g/dL, WBC count 3,000/μL, platelet count 100,000/μL, ALT or AST 3 x the upper limit of normal, bilirubin 2 x the upper limit of normal, and serum creatinine 1.5 x the upper limit of normal.
Ethics
The study protocol was reviewed and approved by the institutional review board of each participating center, and all patients gave written informed consent before participation.
EGFR Expression
The EGFR assessment on tumor specimen was performed locally at each study site and also centrally at the Prince of Wales Hospital at the Chinese University of Hong Kong to avoid any discrepant assessment caused by, for instance, the quality of tumor specimens or heterogeneity of tumors. The assessment was performed using the EGFR pharmDX kit system (DakoCytomation, Copenhagen, Denmark). The results of immunohistochemical examination of EGFR expression in tumor tissue specimens was graded as a score of 0, 1+, 2+, or 3+. The extent of stained cells per section was defined and scored as 0 for no staining or less than 10% staining of the tumor cells, 1+ for faint staining in more than 10% of the tumor cells, 2+ for weak to moderate complete membrane staining in more than 10% of the tumor cells, and 3+ for strong complete membrane staining in more than 10% of the tumor cells. A tissue was declared to be an EGFR-expressing tissue when it could be classified as at least 1+. Patients whose tumors were classified as expressing EGFR by either the local or central test were permitted to be enrolled onto this study. The EGFR results of the central test were used in this report.
Therapy
Cetuximab was administered at an initial dose of 400 mg/m2 over 120 minutes and was subsequently administered as weekly doses of 250 mg/m2 over 60 minutes. All patients were pretreated with an antihistamine. Carboplatin with a targeted area under the curve of 5 (according to the Calvert formula) was administered after the cetuximab infusion on day 1 of a 21-day treatment cycle. The duration of treatment with cetuximab in combination with carboplatin was planned until progressive disease (PD) or unacceptable toxicity or a maximum of eight cycles. If patients had still not progressed at this stage, treatment with cetuximab as monotherapy could be administered until PD. In the case of carboplatin-associated toxicity, dosage reduction and delays were permitted. If carboplatin discontinuation was required because of unacceptable toxicity but the patient was still experiencing benefit from therapy with cetuximab, treatment with cetuximab as monotherapy was continued until PD was diagnosed.
Dose Modifications for Cetuximab
If a patient experienced grade 3 skin toxicity, cetuximab therapy could be interrupted for up to two consecutive infusions with no change in the dose level. If toxicity resolved to grade 2 or less after up to 2 weeks of interruption, treatment could be resumed. On the second and third occurrence of grade 3 skin toxicity, cetuximab therapy could be interrupted again for up to 2 consecutive weeks, with subsequent dose reductions to 200 and 150 mg/m2, respectively. Patients had treatment discontinued if more than two consecutive infusions were withheld or if a fourth occurrence of grade 3 skin toxicity occurred. The chemotherapy was continued independently of temporary interruption of cetuximab. Cetuximab was not withheld for carboplatin-related toxicities, unless the patient developed a concomitant illness that, in the opinion of the investigator, mandated interruption of therapy. Study treatment was terminated on discontinuation of cetuximab therapy.
Evaluation of Patients
Routine evaluation of patients was performed at pretreatment and then weekly for the duration of the study. These evaluations included a physical examination, vital signs, laboratory hematologic and biochemical results, and the recording of concomitant medication and adverse events (AEs). All AEs were documented and coded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Blood sampling for routine laboratory tests was performed twice per cycle. Human antichimeric antibody was assessed every second treatment cycle.
Patients were evaluated for response every other treatment cycle with an assessment of Karnofsky performance status. The response evaluation of the tumor to therapy was based on CT scan or magnetic resonance imaging, and patients were classified by the investigator according to the Response Evaluation Criteria in Solid Tumors criteria as having a complete response (CR), partial response (PR), stable disease (SD), or PD or as not assessable. To be assigned a status of PR or CR, a confirmation assessment was required no less than 4 weeks after the criteria for response were first met.
Statistical Analysis
The primary objective was to determine the response rate. Secondary objectives were to evaluate time to response, duration of response, time to progression (TTP), and overall survival and to collect safety data. The sample size was fixed at 60 patients without a formal sample size calculation. Because of the explorative nature of the study, no formal sample size estimation was performed. Assuming a response rate of 30%, observation of 14 or more responders out of 60 patients with a probability of approximately 90% was expected. Alternatively, assuming a response rate of 15%, the probability of observing 14 or more responders was only approximately 5%. Therefore, a sample size of 60 patients was regarded as appropriate for this study. The intent-to-treat and safety population included all patients who received any dose of cetuximab. The primary efficacy variable was the response rate based on each patient’s best response during the study. The response rate and its 95% CI (using the method of Pearson and Clopper) were calculated. TTP and survival time were estimated using the Kaplan-Meier method. Descriptive statistics were used for safety evaluations.
RESULTS
Patients Characteristics
All of the 60 enrolled patients were included in the intent-to-treat and safety population, which included 46 male patients (77%) and 14 female patients (23%). The median age of the patients was 44.5 years (range, 23 to 64 years), and the majority of patients (n = 56, 93%) was Chinese. The demographic and baseline characteristics of the 60 patients are listed in Table 1. At the baseline of the study, four patients (6.7%) had stage III disease, and 56 patients (93.3%) had stage IV disease, and among these patients, 51 (85%) had distant metastasis.
Prior Treatment
The study protocol did not restrict the number of previous palliative chemotherapy lines; the patients only had to be progressive after platinum-based chemotherapy. Cetuximab plus carboplatin was administered in this study as second-line therapy in 40 patients (70%) and as third- to seventh-line therapy in the remaining 18 patients (30%; Table 1). The median time from the start of recent platinum-based chemotherapy to PD was 203 days (range, 50 to 414 days). The median time from the date PD was diagnosed to the first dose of cetuximab was 29 days (range, 9 to 232 days), whereas the median time from the end of recent platinum-based chemotherapy to the first dose of cetuximab was 116 days (range, 2 to 407 days).
Besides prior platinum agents and FU, several other agents had been used, such as paclitaxel in 12 patients (20%), gemcitabine in nine patients (15%), vinorelbine in four patients (7%), and docetaxel in one patient (2%; Table 1). In total, most patients had received between two and five different agents, with some patients having had exposure to eight different compounds. In addition, 55 patients (92%) had other prior therapy administered either before or after the recent platinum-based therapy. In total, 46 patients (77%) had received other prior chemotherapies (of whom, 28 patients, or 47%, were treated with platinum-based chemotherapy), whereas 53 patients (88%) had received RT.
Treatment With Cetuximab and Carboplatin
The median number of infusions of cetuximab was 10 (range, one to 30 infusions). Twenty-one patients (35%) received six to 10 infusions, which was the biggest proportion. This was followed by 16 patients (27%) who received 11 to 20 infusions. The relative dose-intensity of cetuximab was 90% in 55 patients (91.75%) and 80% in 58 patients (97%; Table 2). A total of 25 patients had minor dose reductions that resulted from small variations in body surface area. No patients required dose modification of cetuximab as a result of skin toxicity as defined in the study protocol.
The numbers of carboplatin infusions in this population are listed in Table 2. Approximately half of the patients (n = 32, 53.3%) received at least three infusions, and 10 patients (16.7%) received the maximum of eight infusions. The dose-intensity of carboplatin was 80% of the planned dose in 45 patients (75%).
EGFR Expression
Of 66 patients screened for tumor EGFR expression, 61 (92.4%) were assessed as expressing EGFR. In 60 enrolled patients, compatible assessments concerning the grade of positivity from both laboratories were seen in 51 patients (85%), whereas a difference of one grade was measured in six patients (10%), and a difference of two grades was measured in one patient (1.6%). In addition, two patients (3.3%) were not evaluated as expressing EGFR by the central lab. In just over half of the patients (55%), the tumors were assessed as 3+. EGFR expression as determined by the central laboratory is listed in Table 3.
Efficacy
No patient achieved a CR, seven patients (11.7%) achieved a PR, 29 patients (48.3%) had SD, and 23 patients (38.3%) had PD. One patient had no postbaseline assessment and was, therefore, not assessable. The confirmed response rate was 11.7% (95% CI, 4.8% to 22.6%), and the disease control rate (CR + PR + SD) was 60% (95% CI, 46.5% to 72.5%). There was no obvious association between the level of EGFR expression and best response (Table 3). Responses were seen in six (13.0%) of 46 patients with undifferentiated carcinoma, and one (7.1%) of 14 patients with other histologic types of tumor.
In the seven patients with a confirmed response, the median time to response after the beginning of treatment with cetuximab was 42 days (range, 39 to 82 days). Of these seven patients, two were still in confirmed response (PR) at the cutoff date of the study. The median duration of response was 99 days. The median TTP was 81 days in all patients; it was longest in the group of patients with confirmed response (173 days), followed by the groups of patients with disease control (127 days) and SD (106 days). Patients with PD had a median TTP of 41.5 days. No association was found between TTP and skin toxicities (Fig 1).
Survival and Subgroup Analysis
The median survival time was 233 days in all patients. In the groups with disease control and SD, the median survival times were equal (241 days). The shortest survival time occurred in the group of patients with PD (114 days).
The following factors seem to be associated with a prolonged survival time: sex (male compared with female), a Karnofsky performance status 80% at baseline compared with one of less than 80%, setting of cetuximab plus carboplatin as second-line therapy compared with a setting of third-line therapy or higher, and an interval of more than 90 days between recent platinum-based chemotherapy and the start of cetuximab plus carboplatin compared with an interval of 90 days. No noticeable impact on survival time could be detected for the following factors evaluated: age, baseline tumor staging, metastasis stage at screening, and prior RT.
There was no obvious association between the level of EGFR expression and survival time (Table 4). However, the median survival time seemed to be longest in patients who developed grade 3 and 4 early skin reaction or acne-like rash, but this result is inconclusive because this group consisted of only two patients (Fig 2).
AEs
AE frequencies in this patient population are listed in Table 5. All of the 60 patients in this study experienced AEs. The most common AEs were (in order of decreasing frequency) rash, nausea, and vomiting (frequency 40% of the patients); fever, asthenia, dry skin, cough, and anorexia (frequency 30% and < 40% of the patients); nail disorder, dyspnea, anemia, constipation, insomnia, stomatitis, diarrhea, and thrombocytopenia (frequency 20% and < 30% of the patients); and epistaxis, pain, pruritus, acne, headache, infection, leukopenia, neuropathy, rhinitis, and increased sputum (frequency 15% and < 20% of the patients). The most common grade 3 and 4 AEs were (in order of decreasing frequency): anemia, dyspnea, and thrombocytopenia (frequency 10% of the patients); and rash, asthenia, hypochromic anemia, vomiting, and neuralgia (frequency > 5% of the patients). Fifty-eight patients (97%) experienced AEs that were considered by the investigator to be related to cetuximab. A total of 11 patients (18.3%) experienced AEs that led to discontinuation of study medication. However, cetuximab-related AEs that caused discontinuation of cetuximab were experienced by five patients (8%). Grade 3 or 4 toxicity occurred in 31 patients (51.7%), and in 19 of these patients (31.7%), these AEs were assessed as cetuximab-related events. No cetuximab-related hypersensitivity reaction was reported. The hypersensitivity reaction (grade 1) in one patient was associated with carboplatin by the investigator. Seven patients (11.7%) died while enrolled on the study or within 30 days after their last dose of cetuximab. None of the deaths were considered as being related to treatment with cetuximab.
Because of the underlying recurrent and/or metastatic malignant disease and because of previously received chemotherapy, most patients already had abnormal laboratory findings before inclusion onto the clinical study. During the course of this study, grade 3 and 4 on-treatment hematologic toxicities (laboratory value) were reported in 40 patients (66.7%), and hematologic grade 4 toxicities were only reported for hemoglobin (four patients, 6.7%) and neutrophils (one patient, 1.7%). Grade 3 and 4 on-treatment blood chemistry toxicities (laboratory value) were reported in 19 patients (31.7%) and exceeded 5% only for alkaline phosphatase (nine patients, 15.0%), sodium (seven patients, 11.7%), and gamma-glutamyltransferase (six patients, 10.0%). Only three clinically relevant urine analysis values were reported. One patient had increased protein and blood levels in urine at the end-of-study visit, which was a result of a urinary tract infection. Another patient had an increased protein level in urine at the end-of-study visit. None of the serum samples showed a positive human antichimeric antibody response.
DISCUSSION
A wide range of chemotherapeutic agents has been used in the treatment of locally recurrent or metastatic NPC. Although the activity of platinum-based chemotherapy in patients with recurrent or metastatic NPC is high, with response rates greater than 50%, the duration of response and survival time are limited, and palliative second-line chemotherapy is only reserved for good-performance patients.31 A small number of publications have reported the outcome of treatments administered to recurrent or metastatic NPC patients who progressed after palliative platinum-based chemotherapy. Airoldi et al32 reported a small series of 12 patients with recurrent NPC treated with carboplatin and paclitaxel as third-line therapy (after cisplatin and fluorouracil). Three patients (25%) obtained a PR, one patient (8.3%) had a minimal response, and three patients (25%) showed no change. The median survival time was 14 months for patients who had a PR or minimal response or no change and 5 months for nonresponders. Median overall survival time was 9.5 months. The treatment was reported to be well tolerated, with manageable toxicity.32 Similarly, Chua et al33 reported a small phase II study in which 17 patients with recurrent or metastatic NPC received oral capecitabine as second-line therapy after platinum-based chemotherapy administered either as adjuvant or as first-line therapy. The overall response rate was 23.5%, and the median survival time was 7.6 months. Treatment-related AEs were reported to be generally mild, except for hand-foot syndrome, which occurred in 58.8% of patients.33
Cetuximab is the first monoclonal antibody targeting the EGFR approved for biologic therapy to treat colorectal cancer. This study demonstrated that the combination therapy of cetuximab (250 mg/m2/wk) with carboplatin (area under the curve 5) has clinical efficacy, even in heavily pretreated NPC patients, of whom approximately 30% had received more than two and up to six prior chemotherapy regimens. This combination exhibited an 11.7% response rate, and nearly 50% of the patients had stabilization of their disease, resulting in a disease control rate of 60% in the study. Moreover, a median TTP of 3 months and a median survival time of 8 months were observed and are comparable to the results in the study reported by Chua et al,33 in which patients with metastatic or recurrent NPC received chemotherapy regimens as second-line treatment. In view of the intensely pretreated patients, the results from this study look promising. The inclusion and exclusion criteria of this study resulted in a clearly refractory patient population, which makes comparison with literature data somewhat difficult because most published studies consisted of metastatic or recurrent patient populations who received mainly first-line chemotherapy with probably better prognosis. Our study is also consistent with results reported from clinical studies of cetuximab in platinum-refractory SCCHN.28,34
Because the patients enrolled onto this study had advanced disease and were heavily pretreated, it was expected that many AEs would be observed in this setting of combination. The typical side effects associated with cetuximab are skin reactions, whereas the other side effects were either associated with the underlying disease or the well-described toxicities of carboplatin that were not aggravated by cetuximab. The combination of cetuximab with carboplatin demonstrated acceptable tolerability, and no dose modifications were necessary. Therefore, the favorable benefit to risk ratio of cetuximab plus carboplatin justifies the use of this combination as treatment for patients who experienced treatment failure with standard chemotherapy for NPC. Cetuximab in combination with standard cytotoxic therapies has now shown consistent anticancer activity across a wide range of EGFR-expressing tumors, including NPC, SCCHN, colorectal cancer, and non–small-cell lung cancer.
Previous studies have shown that cetuximab seems to be able to overcome resistance to previously administered chemotherapy.26 The present study supports this finding, with the combination of cetuximab with carboplatin showing activity in tumors that would otherwise be expected to have no or minimal response to carboplatin monotherapy. The mechanism by which cetuximab is able to overcome resistance is as yet unclear.
Subgroup analysis also showed that there does not seem to be a correlation between the level of EGFR expression in the target tumor and the activity of treatment. This is similar to the results of another study using cetuximab or cetuximab in combination with irinotecan to treat patients with metastatic colorectal cancer.26 Whether this is because the amount of activated EGFR in a tumor cell does not affect the rate of tumorigenesis or, instead, because of an inherent problem with the immunohistochemical visualization system used has yet to be determined. A clinical study of cetuximab in EGFR nondetectable patients will show whether the presence of EGFR in a tumor is a prerequisite for activity. Simultaneously, efforts are ongoing in an attempt to find molecular markers other than EGFR that could be used to select patients for cetuximab treatment with greater success in terms of the clinical response and survival; candidates include MAPK, Akt, p67, and phosphorylated EGFR activities. In the meantime, there may be a practical alternative because we did observe a link (albeit inconclusive) between treatment activity and the severity of cetuximab-induced skin reactions, as reported in the other study with cetuximab-based therapy.25 The potential use of skin reaction as a predictor of cetuximab treatment efficacy and patient selection is currently being investigated in a titrate to rash clinical study, which evaluates the tumor response to a dose escalation of cetuximab until skin reaction occurs in patients without tumor response to the current regimen.
Several studies are ongoing looking at the combination of cetuximab and chemotherapy as first-line treatment in SCCHN, with promising interim results.35,36 In addition, Bonner et al37 recently released data showing a significant survival benefit when cetuximab was added to RT in the same setting. On the basis of these and the present results, evaluation of the potential for cetuximab in earlier lines of treatment for NPC is justified.
Authors' Disclosures of Potential Conflicts of Interest
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. Employment: Matthias Mueser, Merck Pte Ltd Singapore; Nadia Amellal, Merck KGaA; Xiao Lin, Merck Pte Ltd Singapore. Consultant/Advisory Role: Michael J. Millward, Merck KGaA; Alex Y. Chang, AstraZeneca, Bristol-Myers Squibb. Honoraria: Michael J. Millward, Merck KGaA; Alex Y. Chang, Bristol-Myers Squibb. Research Funding: Michael J. Millward, Merck KGaA; Alex Y. Chang, AstraZeneca, Aventis, Bristol-Myers Squibb, Pfizer. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Supported by Merck KGaA.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2003, and at the 12th Annual European Cancer Conference Meeting, Copenhagen, Denmark, September 19-25, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Chan AT, Teo PM, Johnson PJ: Nasopharyngeal cancer. Cancer Treat Res 114 : 275 -293, 2003
Teo P, Yu P, Lee WY, et al: Significant prognosticators after primary radiotherapy in 903 nondisseminated nasopharyngeal carcinoma evaluated by computer tomography. Int J Radiat Oncol Biol Phys 36 : 291 -304, 1996
Teo PM, Kwan WH, Lee WY, et al: Prognosticators determining survival subsequent to distant metastasis from nasopharyngeal carcinoma. Cancer 77 : 2423 -2431, 1996
Vikram B, Mishra UB, Strong EW, et al: Patterns of failure in carcinoma of the nasopharynx: Failure at distant sites. Head Neck Surg 8 : 276 -279, 1986
Leung SF, Teo PM, Shiu WW, et al: Clinical features and management of distant metastases of nasopharyngeal carcinoma. J Otolaryngol 20 : 27 -29, 1991
Geara FB, Sanguineti G, Tucker SL, et al: Carcinoma of the nasopharynx treated by radiotherapy alone: Determinants of distant metastasis and survival. Radiother Oncol 43 : 53 -61, 1997
Hui EP, Leung SF, Au JS, et al: Lung metastasis alone in nasopharyngeal carcinoma: A relatively favorable prognostic group—A study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Cancer 101 : 300 -306, 2004
Ciardiello F, Tortora G: A novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor. Clin Cancer Res 7 : 2958 -2970, 2001
Mendelsohn J: Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 20 : 1S -13S, 2002 (suppl)
Zheng X, Hu L, Chen F, et al: Expression of Ki67 antigen, epidermal growth factor receptor and Epstein-Barr virus-encoded latent membrane protein (LMP1) in nasopharyngeal carcinoma. Eur J Cancer B Oral Oncol 30B : 290 -295, 1994
Roychowdhury DF, Tseng A Jr, Fu KK, et al: New prognostic factors in nasopharyngeal carcinoma: Tumor angiogenesis and C-erbB2 expression. Cancer 77 : 1419 -1426, 1996
Sheen TS, Huang YT, Chang YL, et al: Epstein-Barr virus-encoded latent membrane protein 1 co-expresses with epidermal growth factor receptor in nasopharyngeal carcinoma. Jpn J Cancer Res 90 : 1285 -1292, 1999
Fujii M, Yamashita T, Ishiguro R, et al: Significance of epidermal growth factor receptor and tumor associated tissue eosinophilia in the prognosis of patients with nasopharyngeal carcinoma. Auris Nasus Larynx 29 : 175 -181, 2002
Leong JL, Loh KS, Putti TC, et al: Epidermal growth factor receptor in undifferentiated carcinoma of the nasopharynx. Laryngoscope 114 : 153 -157, 2004
Putti TC, To KF, Hsu HC, et al: Expression of epidermal growth factor receptor in head and neck cancers correlates with clinical progression: A multicentre immunohistochemical study in the Asia-Pacific region. Histopathology 41 : 144 -151, 2002
Ma BB, Poon TC, To KF, et al: Prognostic significance of tumor angiogenesis, Ki 67, p53 oncoprotein, epidermal growth factor receptor and HER2 receptor protein expression in undifferentiated nasopharyngeal carcinoma: A prospective study. Head Neck 25 : 864 -872, 2003
Chua DT, Nicholls JM, Sham JS, et al: Prognostic value of epidermal growth factor receptor expression in patients with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys 59 : 11 -20, 2004
Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21 : 2787 -2799, 2003
Fan Z, Baselga J, Masui H, et al: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53 : 4637 -4642, 1993
Huang SM, Bock JM, Harari PM: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59 : 1935 -1940, 1999
Ciardiello F, Bianco R, Damiano V, et al: Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res 5 : 909 -916, 1999
Inoue K, Slaton JW, Perrotte P, et al: Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma. Clin Cancer Res 6 : 4874 -4884, 2000
Prewett MC, Hooper AT, Bassi R, et al: Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 8 : 994 -1003, 2002
Shin DM, Donato NJ, Perez-Soler R, et al: Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res 7 : 1204 -1213, 2001
Humblet Y: Cetuximab: An IgG(1) monoclonal antibody for the treatment of epidermal growth factor receptor-expressing tumours. Expert Opin Pharmacother 5 : 1621 -1633, 2004
Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351 : 337 -345, 2004
Baselga J, Trigo J, Bourhis J, et al: Cetuximab (C225) plus cisplatin/carboplatin is active in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on a same dose and schedule platinum-based regimen. Proc Am Soc Clin Oncol 21 : 226 , 2002 (abstr 900)
Trigo J, Hitt R, Koralewski P, et al: Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN): Results of a phase II study. Proc Am Soc Clin Oncol 23 : 488 , 2004 (abstr 5502)
Sun Y, Fry DW, Vincent P, et al: Growth inhibition of nasopharyngeal carcinoma cells by EGF receptor tyrosine kinase inhibitors. Anticancer Res 19 : 919 -924, 1999
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92 : 205 -216, 2000
Chan AT, Teo PM, Leung TW, et al: The role of chemotherapy in the management of nasopharyngeal carcinoma. Cancer 82 : 1003 -1012, 1998
Airoldi M, Pedani F, Marchionatti S, et al: Carboplatin plus Taxol is an effective third-line regimen in recurrent undifferentiated nasopharyngeal carcinoma. Tumori 88 : 273 -276, 2002
Chua DT, Sham JS, Au GK: A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol 39 : 361 -366, 2003
Kies MS, Arquette MA, Nabell L, et al: Final report of the efficacy and safety of the anti-epidermal growth factor antibody Erbitux (IMC-C225), in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) refractory to cisplatin containing chemotherapy. Proc Am Soc Clin Oncol 21 : 232 , 2002 (abstr 925)
Humblet Y, Vega-Villegas E, Mesia R, et al: Phase I study of cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil (5-FU) in patients (pts) with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 23 : 491 , 2004 (abstr 5513)
Burtness BA, Li Y, Flood W, et al: Phase III trial comparing cisplatin (C) + placebo (P) to C + anti-epidermal growth factor antibody (EGF-R) C225 in patients (pts) with metastatic/recurrent head and neck cancer (HNC). Proc Am Soc Clin Oncol 21 : 226 , 2002 (abstr 901)
Bonner JA, Giralt J, Harari PM, et al: Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. Proc Am Soc Clin Oncol 23 : 489 , 2004 (abstr 5507)(Anthony T.C. Chan, Mow-Mi)