Journal of Clinical Oncology, Vol 22, No 13 (July 1), 2004: pp. 2610-2616
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.12.040
Cetuximab, a Monoclonal Antibody Targeting the Epidermal Growth Factor Receptor, in Combination With Gemcitabine for Advanced Pancreatic Cancer: A Multicenter Phase II Trial
Henry Q. Xiong,
Arthur Rosenberg,
Albert LoBuglio,
William Schmidt,
Robert A. Wolff,
John Deutsch,
Michael Needle,
James L. Abbruzzese
From the Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Greenwich Hospital/Bendheim Cancer Center, Greenwich, CT; Comprehensive Cancer Center, Clinical Studies Unit, University of Alabama, Birmingham, AL; University of Colorado Health Sciences Center, Denver, CO; Trident Palmetto Hematology/Oncology Group, Charleston, SC; and ImClone Systems Inc, Somerville, NJ
Address reprint requests to James L. Abbruzzese, MD, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jabbruzz{at}mdanderson.org
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ABSTRACT
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PURPOSE: To determine the response rate, time to disease progression, survival duration and rate, and toxicity with the combination of cetuximab and gemcitabine in patients with epidermal growth factor receptor (EGFR)-expressing advanced pancreatic cancer.
PATIENTS AND METHODS: Patients with measurable locally advanced or metastatic pancreatic cancer who had never received chemotherapy for their advanced disease and had immunohistochemical evidence of EGFR expression were eligible for the multicenter phase II trial. Patients were treated with cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly for 7 weeks. Gemcitabine was administered at 1,000 mg/m2 for 7 weeks, followed by 1 week of rest. In subsequent cycles, cetuximab was administered weekly, and gemcitabine was administered weekly for 3 weeks every 4 weeks.
RESULTS: Sixty-one patients were screened for EGFR expression, 58 patients (95%) had at least 1+ staining, and 41 were enrolled onto the trial. Five patients (12.2%) achieved a partial response, and 26 (63.4%) had stable disease. The median time to disease progression was 3.8 months, and the median overall survival duration was 7.1 months. One-year progression-free survival and overall survival rates were 12% and 31.7%, respectively. The most frequently reported grade 3 or 4 adverse events were neutropenia (39.0%), asthenia (22.0%), abdominal pain (22.0%), and thrombocytopenia (17.1%).
CONCLUSION: Cetuximab in combination with gemcitabine showed promising activity against advanced pancreatic cancer. Further clinical investigation is warranted.
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INTRODUCTION
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Pancreatic cancer remains a devastating health problem, with an estimated 28,900 deaths in 2001 and a 5-year survival rate of 4% in the United States.1 The disease is characterized by early locoregional spread and distant metastasis. As a consequence, the majority of patients present with advanced disease that is not resectable. For these patients, systemic chemotherapy has been largely ineffective,2,3 although gemcitabine has demonstrated a modest clinical benefit and has become standard chemotherapy for advanced pancreatic cancer.4,5 The median survival of patients with advanced disease continues to be less than 6 months, and evaluation of novel therapeutic targets is needed to improve the outcome for these patients.
Recent advances in molecular biology have provided a detailed understanding of the molecular events in pancreatic carcinogenesis and may now offer new approaches to the treatment of pancreatic cancer. The development, progression, and metastasis of pancreatic cancer are determined by the accumulation of multiple genetic and epigenetic changes, including inactivation of tumor-suppressor genes and activation or overexpression of proto-oncogenes. The epidermal growth factor receptor (EGFR) seems to play a particularly important role in carcinogenesis of human cancers, including pancreatic cancer.6-8 Increased expression of EGFR and its ligand has been detected in human pancreatic cancer tissue.9 Moreover, coexpression of EGFR and its ligand has been proven to predict poor prognosis in pancreatic cancer,10,11 and it has been proposed that coexpression of EGFR and its ligand functions as an autocrine loop to constantly stimulate cell proliferation. Therefore, blockade of EGFR activity would interrupt EGFR-mediated signal transduction pathways and result in suppression of tumor growth. In addition to EGFR's role in regulating cell proliferation, EGFR-mediated signaling pathways are potent stimulators of vascular endothelial growth factor (VEGF) production.12,13
Cetuximab is a chimeric monoclonal antibody generated from fusion of the variable region of the murine anti-EGFR monoclonal antibody M225 and the human IgG1 constant region. The resulting antibody retains high affinity and specificity to EGFR and reduces immunogenicity.14-16 Preclinical studies have demonstrated that cetuximab effectively inhibits the proliferation of a variety of EGFR-expressing cancer cells in vitro and that it inhibits tumor growth in xenograft models.17,18 Combining cetuximab with various chemotherapeutic agents has been shown to markedly enhance antitumor effects. In an orthotopic pancreatic cancer model,19 cetuximab significantly suppressed the growth of orthotopically implanted pancreatic tumors, and this effect was enhanced by the addition of gemcitabine. Histologic analysis of tumor specimens revealed that cetuximab induced apoptosis and suppressed proliferation of tumor cells. Interestingly, cetuximab also induced apoptosis of endothelial cells, which are not believed to be direct targets of EGFR inhibition. Moreover, an antiangiogenic effect, characterized by decreased microvascular densities associated with reduced expression of tumor-related VEGF and interleukin-8, was observed. These data suggest that, in addition to direct antiproliferative activity, antiangiogenic activity contributes significantly to the antitumor effect of EGFR inhibitors.
Phase I studies of cetuximab alone and in combination with chemotherapeutic agents have demonstrated cetuximab to be well tolerated,20 with acne-like rash among the most common side effects. While the maximum-tolerated dose was not reached in those studies, the recommended dose for phase II study was determined using a combination of pharmacologic and pharmacodynamic parameters. Cetuximab doses in the range of 200 to 400 mg/m2 were associated with complete saturation of EGFR and systemic clearance. In vivo studies suggested that saturation of EGFR with cetuximab is required to achieve optimal antitumor activity.21
We report the results of a multicenter phase II trial of cetuximab in combination with gemcitabine for patients with EGFR-expressing advanced pancreatic cancer. The objectives of the trial were to determine the objective tumor response rate, time to disease progression, survival, and safety profile.
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PATIENTS AND METHODS
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Patients
Patients with pathologically confirmed locally advanced, metastatic, or recurrent pancreatic cancer who had received no previous chemotherapy for their advanced disease were screened for intratumoral EGFR expression by immunohistochemical staining. Patients who had measurable disease and evidence of EGFR expression were eligible for the study. Other eligibility criteria included Karnofsky performance status  60, age 18 years, at least 6 months since completion of any adjuvant therapy, at least 4 weeks since completion of any radiation therapy (measurable tumor mass had to be outside the radiation field), and adequate organ function, as indicated by a WBC count 3,000/µL, hemoglobin level 9 g/dL, platelet count 100,000/µL, alkaline phosphatase level  5 times the upper limit of normal (ULN), total bilirubin level 2 times ULN, serum transaminase level 5 times ULN, and creatinine level 1.5 mg/dL. Before treatment, all patients provided written informed consent according to each institutional standard.
Detection of EGFR
The intratumoral EGFR expression levels from previous biopsy specimens were detected by immunohistochemical staining (ImPath, Los Angeles, CA). An EGFR status of 1+ indicated faint or barely perceptible membrane staining, an EGFR status of 2+ indicated weak to moderate staining of the complete cell membrane, and an EGFR status of 3+ indicated a strong staining of the complete cell membrane. Sixteen tumor specimens were collected from the pancreas, 16 from liver metastasis, one each from omentum, uterus, and ampulla, and the biopsy sites for six specimens were not recorded.
Treatment
All patients received diphenhydramine hydrochloride and a 20mg cetuximab test dose before the initial dose of cetuximab. Patients received cetuximab at an initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2. Patients were then observed for 30 minutes for signs of anaphylaxis or other allergic reactions. If a patient experienced an allergic reaction, the infusion time was increased, and the increase was maintained for subsequent infusions. Patients continued to receive additional courses of cetuximab and gemcitabine until disease progression or appearance of an unacceptable toxic reaction.
If a patient experienced a grade 3 skin toxicity, the next dose of cetuximab was delayed for up to 2 consecutive weeks with no change of dose level. If the toxicity resolved to grade 2 or less within 2 weeks, treatment resumed. If a patient experienced a second or third occurrence of grade 3 skin toxicity, cetuximab therapy was again delayed for up to 2 consecutive weeks, with concomitant dose reductions to 200 mg/m2 and 150 mg/m2, respectively. Patients were taken off the study if more than two consecutive infusions had been canceled or grade 3 skin toxicity recurred despite two dose reductions.
Sixty minutes following the cetuximab dose, gemcitabine was administered at a dose of 1,000 mg/m2 over 30 minutes for up to 7 weeks, followed by a week of rest. During subsequent courses, gemcitabine was administered once weekly for 3 weeks followed by a week of rest. Dose modifications of gemcitabine were based on absolute neutrophil counts (ANC) and platelet counts. The gemcitabine dose was reduced by 25% if the ANC nadir was between 500 and 999/µL or the platelet count nadir was between 50,000 and 99,000/µL. Gemcitabine was held if the ANC nadir was less than 500/µL or the platelet count nadir was less than 50,000/µL. The missed dose of gemcitabine was not administered and gemcitabine was restarted when platelet count was 100,000/µL and ANC was 1000/µL. Gemcitabine therapy was not withheld if the cetuximab infusion was suspended because of skin toxicity.
Study Evaluations
Evaluations before and during treatment consisted of a complete medical history and physical examination, assessment of Karnofsky performance status, laboratory studies, including hematologic and biochemical profiles, computed tomography or magnetic resonance imaging of the abdomen or other body areas with disease involvement, and chest x-ray. Imaging studies were performed every 8 weeks to assess tumor response and at the follow-up visit (unless the patient discontinued for disease progression).
Response Criteria and Toxicity
The WHO response criteria were used.22 A complete response was defined as the disappearance of all measurable and evaluable disease for at least 4 weeks. A partial response (PR) was at least a 50% decrease in the sum of the products of the maximum diameter and a perpendicular diameter of all measurable lesions for at least 4 weeks with no new lesions and no simultaneous increase of greater than 25% in any lesion. Progressive disease was defined as a more than 25% increase in the sum of the products of the perpendicular diameters of all measurable lesions, the appearance of new lesions, or the reappearance of any lesion that had previously disappeared. Stable disease (SD) was a 25% increase or decrease in the summed products of the perpendicular diameters of measurable lesions or a response that did not meet the criteria for complete response, PR, or progressive disease. Time to disease progression was defined as the interval between the initiation of therapy and the occurrence of disease progression. Survival duration was measured from the initiation of therapy to death or to the last follow-up assessment. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2.
Statistical Analysis
Tumor response rates in pancreatic cancer have typically not exceeded 10% in gemcitabine-treated patients, and tumor progression is usually observed in 4 months or less. Therefore, a response rate of at least 15% or a median time to progression of greater than 4 months in patients treated with cetuximab and gemcitabine would suggest a potential benefit in this population.
A total of 40 patients would allow for estimation of the targeted response rate of 15% with reasonable precision. For example, if at least six patients responded, the lower limit of the 95% CI would be no less than 5.7%; if 20% of patients responded, the exact binomial 95% CIs would range from 9.1% to 35.7%. Overall survival and progression-free survival (PFS) curves were generated using the Kaplan-Meier method. A P value .05 was considered statistically significant.
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RESULTS
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A total of 61 patients were screened for EGFR expression. Fifty-eight patients (95%) had at least 1+ staining for EGFR. Forty-one of these patients were enrolled in the study between January 21, 2000, and August 30, 2000, and the remaining 17 patients did not meet other eligibility criteria. Table 1 depicts their baseline characteristics. Most patients (85.4%) had metastatic disease.
The objective response data for all 41 patients are shown in Table 2. Although there were no CRs, five patients (12.2%) achieved a PR. The median time to best response was 1.7 months, and the median duration of response was 3.8 months. All five responders developed a rash. Four of these patients had 2+ staining for EGFR, and one had 1+ staining. The relationship between EGFR expression level and tumor response was not analyzed owing to the small number of responders. An additional 26 patients (63.4%) had SD at their first assessment. The duration of disease control was 5.4 months for the 31 patients who had disease control (SD + PR). The median time to disease progression was 3.8 months. Figures 1 and 2 show the overall survival and PFS curves. The median survival duration was 7.1 month, the 1-year overall survival rate was 31.7%, and the 1-year PFS rate was 12%. Interestingly, the development of a skin rash was associated with longer survival (Fig 3). There was no correlation between carbohydrate antigen 19-9 level and tumor response (data not shown).
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Fig 2. Kaplan-Meier progression-free survival curve. The median progression-free survival was 3.8 months. d, days.
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Fig 3. Overall survival by degree of acne rash. Leftmost line, no toxicity; solid line, grade 1 toxicity; second line from right, grade 2 toxicity; rightmost line, grade 3 toxicity. Differences between the groups were statistically significant (P[r] = .0007 by log-rank). Tox, toxicity; Gr, grade.
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The combination of cetuximab and gemcitabine was generally well tolerated. The most commonly reported adverse events of all grades were acne-like rash (87.8%), asthenia (85.4%), nausea (61.0%), weight loss (58.5%), diarrhea (53.7%), abdominal pain (53.7%), and vomiting (51.2%). Table 3 summarizes the clinically relevant adverse events. Many adverse events were judged to be complications of advanced disease. There were no grade 3 or 4 allergic reactions, but 3 patients (7.3%) developed grade 2 allergic reactions. Hematologic toxicities (all grades) included anemia (39.0%), neutropenia (51.2%), and thrombocytopenia (48.8%). Grade 3 or 4 neutropenia was common (39.0%).
Almost all patients developed acne-like rashes (87.8%). Among them, 28 patients had typical acne (68.3%). Other skin-specific toxic effects included dry skin, pruritus, alopecia, and skin ulcer (Table 4). Skin toxicities were usually mild (grade 1 or 2); only five patients developed a grade 3 acne-like rash. No patients discontinued therapy because of a rash. Acne-like skin rashes typically developed within 2 weeks after treatment and were commonly distributed over the face, scalp, chest, and upper back. In most cases, the rash persisted, but in some cases, it improved despite continued therapy with gemcitabine and cetuximab. Numerous dermatologic interventions were tried including oral and topical antibiotics and topical steroids, but no single treatment resulted in consistent or convincing improvement.
There were no treatment-related deaths, but 11 patients died during the study or within 30 days of study discontinuation because of disease progression or disease-related complications. Seven patients discontinued treatment as a result of adverse events: pulmonary infiltrates, pulmonary embolism, osteomyelitis and nail disorder, vomiting, hypertension and acute renal failure, disseminated intravascular coagulation, or cognitive impairment.
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DISCUSSION
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EGFR has long been hypothesized to be a strategic target in the development of novel therapies for the treatment of cancer.23 The chimeric monoclonal antibody cetuximab has provided an ideal tool for testing this hypothesis in the clinical setting. Numerous preclinical studies demonstrated that cetuximab is active against a variety of EGFR-expressing tumor xenografts, including pancreatic cancers. Further studies showed that blockade of EGFR results in inhibition of both cell proliferation and angiogenesis. This study was designed to evaluate the antitumor activity of cetuximab in combination with gemcitabine. Our results suggest that the combination of weekly cetuximab and gemcitabine has promising activity against advanced pancreatic cancer. At 1 year, patients who received gemcitabine and cetuximab had an overall survival rate of 31.7% and a PFS rate of 12%. These data compare favorably with respective values of 18% and 9% reported from a previous phase III trial of gemcitabine monotherapy.5 In addition, the median time to disease progression of 3.8 months and the median survival duration of 7.1 month were significantly longer than those typically seen with gemcitabine monotherapy (2.1 and 5.7 months, respectively).
A significant number of patients (76%) in our study experienced disease control, mostly SD. This observation may reflect an additive, or even supra-additive, effect from the use of cetuximab and gemcitabine. The binding of cetuximab to EGFR blocks activation of its intrinsic tyrosine kinase activity and results in downregulation of EGFR from the cell surface, thus effectively abrogating mitogenic signals from autocrine or paracrine growth factors. The result is arrest of cell cycle progression but not active cell killing. In some cases, cell cycle arrest leads to apoptosis, such as observed in the DiFi human colon cancer cell line and A431 cells.24-26 However, this may not be true for pancreatic cancer cells. Consistent with this notion, in vitro studies have shown that the cytotoxic effect of cetuximab on pancreatic cancer cells is minimal.19,27,28 In addition, a study of human tumor xenografts showed that cetuximab decreases the growth of established tumors but does not eradicate them. Moreover, the antiangiogenic effect of cetuximab contributes significantly to its antitumor activity,19,29 and there is an expected delay in the antiangiogenic effect on tumor size. Thus, the clinical outcome of inhibition of cell proliferation and angiogenesis is disease stabilization instead of tumor shrinkage. Our observation was in agreement with this notion. Alternatively, this observation may simply reflect the fact that accurate assessment of objective tumor response in pancreatic cancer is notoriously difficult because of the anatomic location of the primary tumor and associated desmoplastic changes. The results of this study indicate that traditional measurement of tumor size may not fully assess the antitumor effect of EGFR-targeted therapy, especially for pancreatic cancer. Time to disease progression, which measures the combined impact of SD and objective response, and survival may be better clinical variables for assessment of the antitumor activity of EGFR-targeted therapy and should be considered in future clinical trials.
Skin toxicities, especially acne rash, are among the most commonly reported side effects of EGFR blockade.30,31 Tissue correlative studies have suggested that the pathologic changes are likely a direct consequence of inhibition of EGFR-mediated signaling pathways, including accumulation of p27 in epidermal keratinocytes.32 Previous reports have indicated a possible correlation between response and the presence of acne-like rash but no correlation between tumor response and the levels of EGFR expression in tumor cells.33,34 Consistent with this notion, we found that more severe acne rash was associated with prolonged survival. Therefore, acne rash may provide a surrogate marker of the efficacy of EGFR inhibition.
In conclusion, the combination of cetuximab and gemcitabine shows promising activity against advanced pancreatic cancer: a significant number of patients experienced disease control, and the median overall survival and 1-year overall survival and PFS rates of patients in this study were favorable compared to previously reported data for gemcitabine monotherapy. Moreover, the addition of cetuximab did not seem to exacerbate toxic reactions. However, the relative contribution of each agent was not evaluated. It is conceivable that the antitumor activity observed in this trial can be attributed to the combination. Since gemcitabine monotherapy has demonstrated moderate improvement of tumor-related symptoms but only marginal effects on survival and objective tumor response, one may question the importance of the addition of gemcitabine to cetuximab. However, preclinical studies have consistently demonstrated that the combination of cetuximab with cytotoxic agents is more active than cetuximab alone,35,36 and since gemcitabine is the only registered agent for advanced pancreatic cancer, it is reasonable to combine cetuximab with gemcitabine. The individual agents' activities and the effectiveness of the combination may be best addressed in a future phase III, randomized comparative study of cetuximab in combination with gemcitabine versus gemcitabine alone in patients with advanced pancreatic cancer.
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Authors' Disclosures of Potential Conflicts of Interest
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The following authors or their immediate family members have indicated a finanical interest. No conflicts exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: James L. Abbruzzese, ImClone.
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Acknowledgment
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We thank Diane Gravel for her expert research nursing.
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NOTES
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Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Submitted December 8, 2003;
accepted February 24, 2004.
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R. L. Mahtani and J. S. Macdonald
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Oncologist,
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Oncologist,
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TOP
ABSTRACT
INTRODUCTION
