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Phase II Study of Erlotinib in Patients With Advanced Biliary Cancer

Philip A. Philip, Michelle R. Mahoney, Cristine Allmer, James Thomas, Henry C. Pitot, George Kim, Ross C. Donehower, Tom Fitch, Joel Picus, Charles Erlichman

From the Karmanos Cancer Institute, Wayne State University, Detroit, MI; University of Wisconsin Comprehensive Cancer Center, Madison, WI; Howard University College of Medicine, Washington, DC; Bunting Blaustein Cancer Research Bldg, Baltimore, MD; Mayo Clinic Jacksonville, Jacksonville, FL; Mayo Clinic Scottsdale, Scottsdale, AZ; Washington University School of Medicine, St Louis, MO; and the Mayo Clinic, Rochester, MN

Address reprint requests to Philip Agop Philip, MD, PhD, Karmanos Cancer Institute, 4-HWCRC, 4100 John R St, Detroit, MI 48201; e-mail: philipp{at}karmanos.org

	ABSTRACT

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PURPOSE: Epidermal growth factor receptor/human epidermal growth factor receptor 1 and ligand expression is common in biliary cancers (BILI) and may be associated with worse outcome. The primary objective of this study was to determine the proportion of patients with advanced BILI who were progression-free at 6 months.

METHODS: Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was administered continuously at a dose of 150 mg per day orally.

RESULTS: Forty-two patients with BILI were enrolled. The median age was 67 years (range, 33 to 82 years). Fifty-two percent of patients had Eastern Cooperative Oncology Group performance status of 1. Fifty-seven percent of patients had received prior chemotherapy for advanced BILI. HER1/EGFR expression by immunohistochemistry in tumor cells was detected in 29 (81%) of the 36 assessable patients. Seven of the patients (17%; 95% CI, 7% to 31%) were progression free at 6 months. Three patients had partial response by Response Evaluation Criteria in Solid Tumors Group classification of duration 4, 4, and 14 months, respectively. All responding patients had mild (grade 1/2) skin rash and two patients had positive tumoral HER1/EGFR expression. Three patients (7%) had toxicity-related dose reductions of erlotinib due to grade 2/3 skin rash.

CONCLUSION: Results suggest a therapeutic benefit for EGFR blockade with erlotinib in patients with biliary cancer. Additional studies with erlotinib as a single agent and in combination with other targeted agents are warranted in this disease.

	INTRODUCTION

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Patients with biliary cancers (BILI) usually present with advanced disease. Treatment of advanced disease is by systemic drug therapy with or without radiation therapy. There currently is no therapy that is considered standard in this situation.^1,2 A number of cytotoxic agents have been investigated but none has shown a significant improvement in the outcome of this disease.³

The epidermal growth factor receptor/human epidermal growth factor receptor 1 (EGFR/HER1) and its ligands EGF and transforming growth factor alpha (TGF-) are important in cell proliferation, as well as motility, adhesion, invasion, survival, and angiogenesis.^4,5 EGFR expression is increased in the majority of gall bladder and bile duct cancers.⁶ The ligand TGF- frequently is increased in gall bladder cancers.⁶ Sustained EGFR activation was demonstrated in cholangiocarcinoma cells.⁷ Bile acids activate EGFR and cellular proliferation via a TGF-–dependent mechanism in human cholangiocarcinoma cells.⁸ Blockade of the EGFR tyrosine kinase activity reduced the proliferation of cholangiocarcinoma cells in vitro.⁷ These findings support a potential role for EGFR blockade in the therapy of human biliary cancers.

Erlotinib (Tarceva, OSI-774; OSI Pharmaceuticals, Melville, NY) is an orally active, potent, selective inhibitor of the EGFR/HER1 tyrosine kinase. Erlotinib inhibits the tyrosine kinase activity with a concentration that inhibits 50% of 2 nmol/L in an in vitro enzyme assay and reduces EGFR/HER1 autophosphorylation in intact tumor cells with a concentration that inhibits 50% of 20 nmol/L. Erlotinib inhibits EGF-dependent proliferation of cancer cells at submicromolar concentrations and blocks cell cycle progression in the G₁ phase.

We hypothesized that an EGFR blockade in patients with BILI will reduce the growth of these tumors and therefore delay the progression of the disease. The primary objective of this study was to determine the progression-free survival of patients with BILI treated with erlotinib 150 mg per day. Secondary end points included adverse event profile, objective response assessment, and overall survival.

	METHODS

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Eligibility Criteria
Patients eligible for the study had histologically or cytologically confirmed BILI that was surgically unresectable or metastatic. Measurable disease was required. Other eligibility criteria included an Eastern Cooperative Group performance status (PS) of 0 to 2; an estimated life expectancy of at least 3 months; adequate bone marrow, hepatic, and renal function indicated by an absolute neutrophil count 1,500/µL, platelets 75,000/µL, total bilirubin 2x the upper normal limit of normal; serum AST or ALT levels 3x the upper normal limit of normal; serum creatinine 2 mg/dL; serum albumin 2.5 g/dL; and an international normalized ratio 1.5 (unless the patient was taking anticoagulation medication). For patients having prior cryotherapy, radiofrequency ablation, ethanol injection, or photodynamic therapy, the following criteria were required: more than 6 weeks elapsed since that therapy; indicator lesion(s) was/were outside the area of prior treatment, or if the only indicator lesion was inside the prior treatment area, there was clear evidence of disease progression in that lesion. Patients with more than one prior systemic anticancer therapy were excluded. Other exclusions included a history of other malignancy within the previous 3 years (except for adequately treated basal cell or squamous cell skin cancer, or cervical cancer). Patients were also excluded on the basis of known abnormalities of the cornea, CNS metastases, and HIV infection.

Erlotinib Administration
All patients received erlotinib 150 mg orally once daily. Erlotinib was supplied by the Division of Cancer Treatment and Diagnosis, National Cancer Institute (Bethesda, MD). Treatment was administered on a continuous daily basis and a treatment cycle was 28 days (ie, defined as the time between adverse event assessments and replenishing of erlotinib). Treatment was held up to 14 days for grade 3 or 4 toxicity until resolution of toxicity to grade 1. Erlotinib was then reinitiated at a reduced dose. The erlotinib dose was reduced according to criteria defined prestudy to 100 or 50 mg per day. Patients requiring dose reductions to less than 50 mg were taken off study.

Disease Assessment
Objective response was assessed using the Response Evaluation Criteria in Solid Tumors Group classification. ⁹ Measurable disease was defined as at least one lesion for which the longest diameter could be accurately measured as 2.0 cm. Computed tomography or magnetic resonance imaging evaluation was the measurement of choice for such lesions. All other lesions (or sites of disease), including small lesions (longest diameter < 2.0 cm) were considered nonmeasurable. All identified sites of disease at baseline were followed on re-evaluation.

Patients who met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks were considered to have achieved disease stabilization. The duration of disease stabilization was calculated from study registration date to the last evaluation. Time to disease progression (TTP) was calculated from study entry to disease progression. Time to death (ie, survival) was calculated from the date of study entry to death or last contact. Duration of response was calculated from the date of the patient's first best objective status of complete response or partial response to the date of progression. Patients who died (or were lost to follow-up) without progression were considered to have experienced progression at the date of death (or last contact) unless documentation proved otherwise, in which case they would be considered as having no progression at the date of last tumor evaluation. Patients were observed until death or a maximum of 3 years after registration.

Toxicity Assessment
Patients were evaluated for treatment-related toxicity at a minimum of every 28 days as per the National Cancer Institute Common Toxicity Criteria version 2.0. The worst grade of toxicity per patient was recorded.

Determination of EFGR/HER1 Expression
Tissue from diagnostic biopsies, when available, was collected prospectively on entry to the study. Immunostaining of unstained sections was performed to semiquantify the expression of EGFR/HER1 in the histologically identified tumor tissues. Immunohistochemistry using EGFR/HER1 pharmDx monoclonal antibody (Dako Corp, Carpinteria, CA) was used. A scale of 0 to 3 was used to indicate the following: 0, no staining; 1, few stained cells; 2, more than 10% of cells stained; 3, majority of cells stained with intense color.

Statistical Considerations
The primary end point of this trial was the proportion of patients who are progression free at 24 weeks. All eligible patients who began treatment were considered assessable for the primary end point. The estimated 24-week progression-free rate was calculated as a binomial proportion, by dividing the number of patients who have not experienced progression within 24 weeks by the total number of assessable patients. A two-stage Simon-Optimal design¹⁰ was used to evaluate the 24-week progression-free rate. Here, patients were enrolled without suspension between stages, yet an interim analysis was performed when enrollment onto the first stage was completed. Erlotinib was considered inactive if none of the initial 15 patients were progression free at 24 weeks. Four or more of 35 assessable patients who were progression free at 24 weeks were required to declare promising activity. Using this design, the study had 92% power (at .09 level of significance) to detect a 24-week progression-free rate of at least 20%. The CI for the estimate of the 24-week progression-free rate was calculated by the method of Duffy and Santner.¹¹

Secondary end points included overall response rate, toxicity profile, TTP, survival, and association between EGFR/HER1 expression and clinical outcome. All toxicity was summarized as a maximum grade for a given type of event. Kaplan-Meier methodology¹² was used to describe the distribution of TTP and survival, which took into account the censoring of events in the calculation of an estimate of a rate at a specific time point (eg, 1 year). Cox proportional hazards¹³ modeling was used to identify factors (ie, age, sex, PS) significantly associated with positive EGFR/HER1 expression. P values of at least .05 were considered statistically significant. All analyses were performed using SAS version 8.0 (http://www.sas.com; SAS Institute, Cary, NC).

	RESULTS

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Patient Characteristics
A total of 42 patients from seven institutions affiliated with the phase II consortium (Mayo Clinic Rochester, Rochester, MN; Mayo Clinic Scottsdale, Scottsdale, AZ; Mayo Clinic Jacksonville, Jacksonville, FL; Johns Hopkins, Baltimore, MD; Karmanos Cancer Institute, Detroit, MI; University of Wisconsin, Madison, WI; and Washington University, St Louis, MO) were enrolled between March 2002 and January 2003 (Table 1). All were eligible, white, and 52% (n = 22) were female. Patients ranged in age from 33 to 82 years (median, 67 years) and 52% (n = 22) had PS of 1 (v 0 or 2). Fifty-seven percent (n = 24) of patients had received prior systemic therapy for BILI. Eighty-one percent (29 of the 36 patients with assessable tumor samples) were EGFR/HER1 positive (ie, 1, 2, or 3 levels of EGFR expression). Tissue was not available in sufficient quantity to provide information on EGFR/HER1 status for the remaining six patients.

Toxicity
All patients were assessable for toxicity (Table 2). Forty-eight percent of the patients experienced grade 3 or 4 adverse events. Overall, leukopenia, anemia, and thrombocytopenia were minimal (ie, grade 2). Seven patients (17%) experienced a grade 3 nonhematologic toxicity (ie, at least possibly related to erlotinib). Most frequent grade 3 toxicities were vomiting (7%), skin rash (5%), and nausea (5%). In addition, the following three patients died as a result of events considered to be unrelated to study treatment and were not reflected in Table 2: one patient experienced a septic shock after three cycles of treatment, and two patients died as a result of disease-related causes after one and three cycles of treatment, respectively.

View larger version (10K): [in this window] [in a new window]   Fig 1. Kaplan and Meier survival curves for the overall and progression-free survival of 42 patients with biliary carcinoma treated with erlotinib.

	DISCUSSION

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BILIs are increasing in worldwide incidence and mortality. Unfortunately, the vast majority of the patients who are newly diagnosed have advanced stage at diagnosis.¹⁴ The frequent presence of metastatic disease coupled by the modest benefits of the currently used conventional cytotoxic therapies underlie their poor prognosis.³ Commonly used agents in advanced BILI include the fluoropyrimidines and gemcitabine, as single agents or in combination. A recent study with locally advanced and metastatic BILI without prior therapy showed disease control in 73% of patients with a combination of gemcitabine and capecitabine.¹⁵ The median TTP and survival were 7 and 14 months, respectively. There is therefore a need to develop better systemic therapies based on the advances in our knowledge of the molecular biology of these cancers. This study is the first report of a targeted-therapy approach in the therapy of patients with biliary cancers.

A predominant genetic aberration has not been identified in biliary cancer. Therefore, systematic and stepwise interrogation of various pathways is warranted with the goal of identifying agents that can influence the natural history of the disease. Ultimately, combination therapies with multiple targets can be developed based on the clinical information from studies using blockade of individual targets in the tumor cells. The choice of EGFR as a therapeutic target in this study was based on the known role of the EGF and TGF- activated signaling in carcinogenesis and tumor progression.¹⁶ In addition, erlotinib has shown significant antitumor activity in a number of other epithelial cancers, including non–small-cell lung,¹⁷ pancreatic,¹⁸ and primary liver cancer.¹⁹ The toxicity profile of erlotinib in this study confirmed the safety of a starting dose of 150 mg per day.

The primary objective of this study was to estimate the efficacy of erlotinib as a single agent in patients with advanced biliary cancer. The choice of disease control as a primary end point (rather than objective response guided by Response Evaluation Criteria in Solid Tumors Group classification) of this study was based on its clinical usefulness and the difficulty in evaluating responses objectively in some of these patients. Moreover, delays in disease progression using cytostatic agents such as erlotinib will have a clinical significance. The prestudy threshold for additional clinical interest was set at 20% for 24-week freedom from progression. The eligibility criteria for this study included patients with no or only one prior systemic therapy. The inclusion of tumors that did not express EGFR was based on the lack of correlation between EGFR expression level and treatment outcome in other types of cancer (eg, colon) treated with EGFR-blocking drugs.

Results of this study demonstrated a modest activity for erlotinib in this selected population of patients. Objective partial responses were seen in three patients that lasted 4, 4, and 14 months, respectively. The control of disease defined as stabilization for at least 24 weeks was seen in 17% (95% CI, 27% to 59%) of the patients. It is noteworthy that based on historical data, the vast majority of untreated patients of a similar population with advanced BILI would have also experienced objective disease progression by 24 weeks. Whether erlotinib delays progression of disease can only be determined in a randomized study using untreated controls.

The role of EGFR expression in the response to erlotinib was not determined formally in this study. The final number of patients with tumoral EGFR-negative cancer precluded any meaningful conclusions because of the lack of any statistical power. A significantly larger number of patients will be required for such an analysis. However, there did not appear to be a significant association between the level of expression of EFGR and treatment outcome within the small patient population.

Results of this study, in particular the overall survival, should be interpreted taking into account the study population. It is noteworthy that more than 50% of patients in this study were treated previously for their advanced BILI. This, together with eligibility criteria permitting some degree of organ dysfunction, allowed for a population of patients with worse characteristics than those eligible for the average phase II trials using cytotoxic agents. Conversely, such selection criteria (eg, previous therapy) may not influence the outcome of testing targeted drugs such as erlotinib, which have different mechanisms of action than cytotoxic drugs and therefore are less likely to be affected by the common drug resistance mechanisms. We note that five of the 24 patients who received erlotinib in the chemotherapy-refractory setting were progression free at 24 weeks. If this study had been designed initially to evaluate erlotinib in second-line patients and used the same decision rule for declaring the agent promising (ie, five of 35; 17%), we would have concluded that the agent was promising despite enrolling only 24 (of 35) patients required for by the study design. The same was not true for first-line patients, given that enrollment would have had to continue to 35 patients. As such, erlotinib may offer a treatment option for patients experiencing treatment failure after cytotoxic therapy, similar to its use in non–small-cell lung cancer.

Future development of erlotinib in BILI is of interest based on results of this study. However, at least two strategies of research are needed to produce a major impact on the disease by erlotinib or similar agents. The identification of molecular signatures that predict benefit from erlotinib will also identify patients who will not benefit from such therapy. The inclusion of erlotinib in combinations with other targeted agents should also be pursued in the preclinical and clinical setting to define the best combination with respect to efficacy and tolerability. Suggested combinations of interest would include blockade of the Akt survival pathway or the angiogenesis-related signaling pathways.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Philip A. Philip, Michelle R. Mahoney, Cristine Allmer Administrative support: Philip A. Philip, Cristine Allmer Provision of study materials or patients: Philip A. Philip, James Thomas, Henry C. Pitot, George Kim, Ross C. Donehower, Tom Fitch, Joel Picus, Charles Erlichman Collection and assembly of data: Michelle R. Mahoney, Cristine Allmer, James Thomas, Henry C. Pitot, George Kim, Ross C. Donehower, Tom Fitch, Joel Picus, Charles Erlichman Data analysis and interpretation: Philip A. Philip, Michelle R. Mahoney, Cristine Allmer Manuscript writing: Philip A. Philip, Michelle R. Mahoney, Cristine Allmer, James Thomas, Henry C. Pitot, George Kim, Ross C. Donehower, Tom Fitch, Joel Picus, Charles Erlichman Final approval of manuscript: Philip A. Philip, Michelle R. Mahoney, Cristine Allmer

 

	NOTES

 
Supported by Grant No. NO-1 CM17104 from the National Cancer Institute.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
1. Rajagopalan V, Daines WP, Grossbard ML, et al: Gallbladder and biliary tract carcinoma: A comprehensive update—Part 1. Oncology 18:889-896, 2004[Medline]

2. Daines WP, Rajagopalan V, Grossbard ML, et al: Gallbladder and biliary track carcinoma: A comprehensive update—Part 2. Oncology 18:1049-1054, 2004[Medline]

3. Olnes MJ, Erlich R: A review and update on cholangiocarcinoma. Oncology 66:167-179, 2004[CrossRef][Medline]

4. Woodburn J: The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 82:241-250, 1999[CrossRef][Medline]

5. Gibbs J: Anticancer drug targets: Growth factors and growth factor signaling. J Clin Invest 105:9-13, 2000[Medline]

6. Lee CS, Pirdas A: Epidermal growth factor receptor immunoreactivity in gallbladder and extrahepatic biliary tract tumors. Pathol Res Pract 191:1087-1091, 1995[Medline]

7. Yoon JH, Gwak GY, Lee HS, et al: Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells. J Hepatol 41:808-814, 2004[CrossRef][Medline]

8. Werneburg NW, Yoon JH, Higuchi H, et al: Bile acids activate EGF receptor via a TGF-alpha-dependent mechanism in human cholangiocyte cell lines. Am J Physiol Gastrointest Liver Physiol 285:G31-G36, 2003

9. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

10. Simon R: Optimal two-stage design for phase II clinical trials. Control Clin Trials 10:1-10, 1989[Medline]

11. Duffy DE, Santer TJ: Confidence intervals for a binomial parameter based on multistage tests. Biometrics 43:81-93, 1987[CrossRef]

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13. Cox D: Regression models and life tables (with discussion). J R Stat Soc B 74:187-220, 1972

14. Shaib Y, El-Serag HB: The epidemiology of cholangiocarcinoma. Semin Liver Dis 24:115-125, 2004[CrossRef][Medline]

15. Knox JJ, Hedley D, Oza A, et al: Combining gemcitabine and capecitabine in patients with advanced biliary cancer: A phase II trial. J Clin Oncol 23:2332-2338, 2005[Abstract/Free Full Text]

16. Sirica A: Cholangiocarcinoma: Molecular targeting strategies for chemoprevention and therapy. Hepatology 41:5-15, 2005[CrossRef][Medline]

17. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132,2005[Abstract/Free Full Text]

18. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic caner: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. J Clin Oncol 24:1s, 2005 (suppl; abstr 1)

19. Philip PA, Mahoney MR, Allmer C, et al: Phase II study of erlotinib (OSI0774) in patients with advanced hepatocellular cancer. J Clin Oncol 23:6657-6663, 2005[Abstract/Free Full Text]

Submitted December 22, 2005; accepted April 7, 2006.

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