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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4787-4792 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.8521 Capecitabine Plus Erlotinib in Gemcitabine-Refractory Advanced Pancreatic Cancer
From the Department of Medical Oncology, Dana-Farber Cancer Institute; Division of Hematology/Oncology, Massachusetts General Hospital; Department of Biostatistics, Massachusetts General Hospital; and the Channing Laboratory, Brigham and Women's Hospital, Boston MA Address reprint requests to Matthew Kulke, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: Matthew_Kulke{at}dfci.harvard.edu
Purpose The addition of either capecitabine or erlotinib to gemcitabine in the first-line treatment of advanced pancreatic cancer is associated with modest improvements in overall survival. We evaluated an oral regimen of capecitabine and erlotinib in patients with advanced pancreatic cancer who had experienced treatment failure with standard first-line therapy with gemcitabine. Patients and Methods Thirty patients with gemcitabine-refractory metastatic pancreatic cancer were treated with capecitabine, administered at a dose of 1,000 mg/m2 twice daily for 2 weeks, followed by a 1-week break. All patients also received erlotinib 150 mg daily. Patients were observed for evidence of response, toxicity, and survival. EGFR mutational status was assessed in available tumor blocks. Results Treatment with capecitabine and erlotinib in gemcitabine-refractory patients was associated with an overall objective radiologic response rate of 10% and a median survival duration of 6.5 months. In addition, 17% of the treated patients experienced decreases in tumor marker (CA 19-9) levels of more than 50% from baseline. Common toxicities included diarrhea, skin rash, fatigue, and hand-foot syndrome. EGFR mutations were detected in two of five available tumors; no association between treatment response and EGFR mutational status was evident. Conclusion The combination of capecitabine and erlotinib is active in patients with gemcitabine-refractory pancreatic cancer. This regimen may represent an acceptable treatment option in patients who experience treatment failure with standard first-line therapy with gemcitabine or for whom gemcitabine may not be an appropriate first-line treatment option.
Pancreatic cancer remains a leading cause of cancer-related death in North America and Europe.1 Although the systemic administration of gemcitabine has been associated with both clinical benefit and prolongation of survival in patients with advanced disease, objective tumor responses occur in fewer than 10% of patients, and survival times are generally less than 6 months.2 Gemcitabine-based combination chemotherapy regimens have been associated with promising activity in phase II studies.3-6 When subsequently compared with single-agent gemcitabine in randomized trials, however, treatment with many of these regimens has failed to translate into significant improvements in overall survival. Survival times associated with combinations of gemcitabine/fluorouracil, gemcitabine/irinotecan, gemcitabine/cisplatin, and gemcitabine/oxaliplatin appear to be either equivalent or only marginally superior to those associated with single-agent gemcitabine.7-10 Treatment with the oral fluoropyrimidine capecitabine was associated with an overall objective response rate of 7.3% in a 42-patient phase II study of treatment-naive patients with advanced pancreatic cancer.11 Phase II studies of capecitabine administered in combination with gemcitabine demonstrated reasonable tolerance and evidence of activity, leading to the development of large phase III randomized trials.12,13 An initial randomized study, involving 319 patients, compared gemcitabine alone with a combination of gemcitabine and capecitabine and failed to demonstrate significant survival differences between the two arms.14 However, in a second, larger study involving 533 patients, the gemcitabine/capecitabine combination was associated with both an enhanced overall response rate (14.2% v 7.1%) and a modest improvement in median survival time (7.4 v 6 months) when compared with gemcitabine alone.15 The toxicities associated with the combination arm were also greater, and included an increased incidence of grade 3 or 4 neutropenia, thrombocytopenia, diarrhea, and hand-foot syndrome. Erlotinib is a small-molecule tyrosine kinase inhibitor that inhibits phosphorylation of the epidermal growth factor receptor (EGFR).16 Phase II studies of erlotinib administered alone have demonstrated activity in several epithelioid malignancies, including non–small-cell lung cancer, squamous cell carcinoma of the head and neck, and gastroesophageal adenocarcinoma.17-20 Notably, in non–small-cell lung cancer, response to oral tyrosine kinase inhibitors of EGFR appears greatest in tumors with selected somatic mutations in the EGFR gene.21,22 In a large, randomized phase III study, patients with advanced pancreatic cancer receiving a combination of gemcitabine/erlotinib experienced a significant, though modest, improvement in survival compared with those treated with gemcitabine alone (1-year survival: 23% v 17%, respectively).23 Patients in the erlotinib-containing arm experienced an increased incidence of rash, diarrhea, and hematologic toxicity. The relatively modest survival benefits, taken together with the increased potential for toxicity associated with the gemcitabine/erlotinib and gemcitabine/capecitabine combination regimens has tempered enthusiasm for their use in the first-line setting. Given the activity of both capecitabine and erlotinib in pancreatic cancer, we performed a phase II multicenter study evaluating the safety and efficacy of a combination of these two drugs in patients with advanced pancreatic cancer who had experienced treatment failure with first-line therapy with a gemcitabine-containing regimen. Patients were treated with capecitabine 1,000 mg/m2 twice daily, together with erlotinib 150 mg, using a regimen similar to that in a published study of colorectal cancer.24 Patients were observed for evidence of toxicity, radiologic response, and survival, and available tumor blocks were evaluated for mutations in EGFR.
Patient Population The study population consisted of patients with histologically confirmed metastatic pancreatic carcinoma who had experienced treatment failure with one prior gemcitabine-based chemotherapy regimen for metastatic disease. Patients may have also received prior fluorouracil-based adjuvant therapy. Patients who had received prior therapy with capecitabine or EGFR inhibitors, or who had received more than one prior chemotherapy treatment regimen for the treatment of metastatic disease, were excluded.
Patients were further required to have measurable disease (by Response Evaluation Criteria in Solid Tumors [RECIST]), Eastern Cooperative Oncology Group (ECOG) performance status of 1 or better; life expectancy of at least 12 weeks; adequate renal function (creatinine clearance Patients were excluded if they had clinically apparent CNS metastases or carcinomatous meningitis, clinically significant cardiac disease (eg, congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication, or myocardial infarction within the last 12 months), major surgery within 4 weeks of the start of study treatment, without complete recovery, or uncontrolled serious medical or psychiatric illness. Patients who were pregnant or lactating were excluded from study entry. All patients provided a signed, informed consent as required by the institutional review boards of their respective institutions.
Treatment Program On-study evaluation included toxicity assessments and measurement of hematologic, renal, and hepatic function weekly for the first 3 weeks of treatment and every 3 weeks thereafter. Patients were evaluated with computed tomography at 6 weeks, 12 weeks and subsequently every 9 weeks after treatment initiation. Response and progression were evaluated using RECIST.25
Statistical Methods
Patient Characteristics A total of 32 eligible patients were enrolled onto the study. Two patients withdrew from the study before receiving treatment. The remaining 30 received treatment and were included in subsequent analysis. Baseline characteristics of the treated patient population are shown in Table 1. Patients were recruited from two sites: Dana-Farber Cancer Institute and Massachusetts General Hospital (both Boston, MA). The median age of the patient population was 60 years; 43% were male and 57% female. As anticipated in a second-line study, nearly all patients were symptomatic from their disease. Only 23% had an ECOG performance status of 0, and 77% had a performance status of 1. Eight patients (27%) had undergone surgery and received prior adjuvant therapy; all 30 patients had received prior therapy with a gemcitabine-containing regimen for metastatic disease.
The treatment-related toxicities are summarized in Table 2. The most common toxicity was diarrhea, which developed in 77% of the patients. In five cases (17%), diarrhea was severe (grade 3). Rash developed in 67%; in four (13%), rash was graded as severe (grade 3). Other common toxicities included fatigue, hand-foot syndrome, and stomatitis. Hand-foot syndrome and stomatitis were severe (grade 3) in four (13%) and three (10%) cases, respectively. Hematologic toxicity was uncommon and generally mild, with only two (7%) cases of grade 3 neutropenia observed; thrombocytopenia was not observed as a treatment-related adverse event.
Twenty-one patients required dose modifications or delays of capecitabine. The most common reasons for dose modification were hand-foot syndrome, stomatitis, or diarrhea classified as grade 2 or greater. Twenty patients required dose modifications or delays for erlotinib-related toxicity. The most common reasons for modifying the erlotinib dose were diarrhea or skin rash classified as grade 2 or greater. Patients received a median of 2.5 3-week cycles of therapy, remaining on study for a median of 7.4 weeks. However, 25% of the treated patients remained on study for 4 or more months, and one patient remained on study for 21 months. The majority of patients (73%) treated on this study discontinued treatment for progressive disease, 10% of patients discontinued therapy for unacceptable toxicity, and the remaining patients discontinued therapy after withdrawing consent. The primary end point of the study was objective response rate, as measured by RECIST. Three patients (10%) experienced a partial response to therapy. In addition, five patients experienced biochemical responses, as defined by decreases in serum tumor marker CA 19-9 of more than 50%. Of the three patients who experienced partial radiologic responses, two also experienced biochemical responses. The median progression-free survival time was 3.4 months, and the median overall survival time was 6.5 months. One-year overall survival was 26% (Fig 1). We found no correlation between the development of skin rash and either response or survival.
EGFR and Ras mutation analysis was performed on archival tumor tissue from five patients enrolled onto the study, as previously described and reported.26 These patients had undergone prior pancreaticoduodenectomy at one of the participating institutions, and therefore had adequate tissue for analysis. Mutation analysis was not attempted in patients who had undergone only diagnostic needle biopsy or whose tumor blocks were not available. EGFR mutations were identified in two of the five available tumor specimens; both mutations occurred in exon 19 (Del 2235-2249), previously identified in patients with non–small-cell lung cancer (Table 3). 21,22 Mutations in Ras codon 12 were detected in three of the five specimens. Among the two patients with an EGFR mutation, one individual experienced a partial response to treatment; whereas among the three participants without a mutation in EGFR, one patient also experienced a partial response to treatment. Both tumors with EGFR mutations also contained Ras mutations. Within this small data set, EGFR mutational status did not appear to materially influence treatment response or overall survival. Survival times were 9.2 and 11 months in patients whose tumors contained EGFR mutations, and 4.1, 8.3, and 11.5 months in patients whose tumors had no mutations.
This phase II study demonstrated antitumor activity associated with the combination of capecitabine and erlotinib in patients with gemcitabine-refractory metastatic pancreatic cancer. The objective tumor response rate associated with this regimen was 10%, and OS 6 months. The toxicities observed were similar to toxicities previously known to be associated with the two agents when administered independently. Relatively few other studies have evaluated second-line treatments for patients with pancreatic cancer, and capecitabine alone has not been evaluated in this setting (Table 4). Direct comparisons between our results and those of the other studies listed are necessarily limited by the relatively small size of our patient cohort and our selected population. The tumor response rates associated with the regimens used in these second-line studies range, from 3.8% to 24%, and the median survival times range from 3.4 to 10.3 months. These broad ranges likely reflect not only variation in efficacy but also differences in patient selection.
The toxicity associated with our regimen reflects the known toxicities associated with both capecitabine and erlotinib. Diarrhea has been associated with both agents, and was the most common toxicity experienced by patients in this study; other common toxicities included rash, stomatitis, and hand-foot syndrome. The dose of erlotinib used in our study was 150 mg/m2, identical to the dose currently used in non–small-cell lung cancer, but higher than the 100 mg/m2 dose used in the majority of patients in the randomized trial of gemcitabine versus gemcitabine/erlotinib in pancreatic cancer.23 Among a small cohort of 23 patients in the randomized trial who were treated with 150 mg, 11 required dose reductions, suggesting that the higher dose level may be associated with more toxicity. The use of the 150- rather than the 100-mg dose of erlotinib in may well have contributed to the observed incidence of diarrhea and other adverse events in our study. Although the survival benefit associated with the addition of erlotinib to gemcitabine in the first-line setting clearly supports a role for EGFR inhibition in pancreatic cancer, the precise mechanisms by which EGFR inhibitors exert their clinical activity in this disease remain uncertain. In lung cancer patients, tumors with activating EGFR mutations have been shown to be particularly susceptible to therapy with EGFR tyrosine kinase inhibitors.21,22 Mutations in EGFR appear to be rare in pancreatic cancer. In one study evaluating 43 individual tumors, no mutations in EGFR were identified.27 In a second study, performed by Kwak et al,26 two tumors with EGFR mutations were identified among 55 pancreatic adenocarcinomas (3.6%). The study by Kwak et al included five available tumors from patients enrolled onto the current trial of capecitabine and erlotinib; both tumors with mutations were among these five specimens. The mutations identified in our patients were identical, and consisted of an in-frame deletion delE746-A750, previously described in non–small-cell lung cancer.21,22 The small number of tumors available for EGFR mutational analysis precluded a formal analysis correlating EGFR mutational status with clinical outcome in this study. The lack of available tumor specimens reflects the propensity for pancreatic cancer to be diagnosed by fine-needle biopsy at a late stage, and the consequent lack of resected tumor specimens with sufficient tissue to extract DNA. Among the patients with available tissue, one patient with an EGFR mutation experienced a radiologic partial response, and one experienced stable disease. Of the three assessable patients without EGFR mutations, one responded and two experienced stable disease. Survival times did not appear significantly different between patients with and without mutations. Although the limited number of assessable cases precludes drawing definitive conclusions, these results suggest that EGFR mutational status may not be a major predictor of response to capecitabine and erlotinib in patients with advanced pancreatic cancer. KRAS mutations are common in pancreatic cancer, and, in our study, were present in both patients with mutations in EGFR. KRAS functions downstream of EGFR, and, in non–small-cell lung cancer, the presence of KRAS mutations appears to diminish responsiveness to EGFR inhibition.28 The antitumor activity of cetuximab, a monoclonal antibody targeting the extracellular domain of EGFR, seems to be independent of EGFR mutation status.29 In a preliminary report, the addition of cetuximab to gemcitabine failed to improve the survival of patients with advanced pancreatic cancer, compared with gemcitabine alone.30 In conclusion, both the gemcitabine/erlotinib and gemcitabine/capecitabine combination regimens have been associated with improvements in overall survival when used as first-line therapy for patients with advanced pancreatic cancer. Our study demonstrates that a regimen containing two of these agents, capecitabine and erlotinib, can be safely administered and has activity in the second-line setting. The combination of capecitabine and erlotinib may represent a reasonable second-line treatment option for patients with advanced pancreatic cancer who experience treatment failure with single-agent gemcitabine, and may also be considered as a first-line option for patients in whom first-line gemcitabine is not appropriate.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Charles S. Fuchs, Roche (C), Sanofi-aventis (C), Pfizer (C), AstraZeneca (C), Brisol-Meyers Squibb Co (C), Amgen (C), Genentech (C) Stock Ownership: None Honoraria: Matthew H. Kulke, Novartis Pharmaceuticals; David P. Ryan, Genentech; Jeffrey A. Meyerhardt, Genentech; Peter C. Enzinger, Roche Pharmaceuticals Research Funding: Lawrence S. Blaszkowsky, Genentech Expert Testimony: None Other Remuneration: None
Conception and design: Matthew H. Kulke, Charles S. Fuchs Provision of study materials or patients: Matthew H. Kulke, Lawrence S. Blaszkowsky, David P. Ryan, Jeffrey W. Clark, Jeffrey A. Meyerhardt, Andrew X. Zhu, Peter C. Enzinger, Eunice L. Kwak, Charles S. Fuchs Collection and assembly of data: Matthew H. Kulke, Lawrence S. Blaszkowsky, David P. Ryan, Jeffrey W. Clark, Jeffrey A. Meyerhardt, Andrew X. Zhu, Peter C. Enzinger, Eunice L. Kwak, Alona Muzikansky, Colleen Lawrence, Charles S. Fuchs Data analysis and interpretation: Matthew H. Kulke, Alona Muzikansky, Charles S. Fuchs Manuscript writing: Matthew H. Kulke, Charles S. Fuchs Final approval of manuscript: Matthew H. Kulke, Lawrence S. Blaszkowsky, David P. Ryan, Jeffrey W. Clark, Jeffrey A. Meyerhardt, Andrew X. Zhu, Peter C. Enzinger, Eunice L. Kwak, Alona Muzikansky, Colleen Lawrence, Charles S. Fuchs
Supported by Roche Inc. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50 mL/min), adequate hepatic function (total bilirubin 
1.5x upper limit of normal [ULN]); AST 
