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Phase II Trial of Bevacizumab and Erlotinib in Carcinomas of Unknown Primary Site: The Minnie Pearl Cancer Research Network

John D. Hainsworth, David R. Spigel, Cindy Farley, Dana S. Thompson, Dianna L. Shipley, F. Anthony Greco

From the Sarah Cannon Research Institute; and Tennessee Oncology, PLLC, Nashville, TN

Address reprint requests to John D. Hainsworth, MD, Sarah Cannon Research Institute, 250 25th Ave North, Suite 220, Nashville, TN 37203; e-mail: jhainsworth{at}tnonc.com

	ABSTRACT

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Purpose Treatment remains poor for many patients with carcinoma of unknown primary site (CUP), and no effective second-line treatment has been identified. Combination inhibition of vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) with bevacizumab and erlotinib has proved efficacious and well tolerated in other solid tumors. We therefore have evaluated the efficacy and toxicity of this combination in patients with CUP.

Patients and Methods Patients with CUP who either had received previous chemotherapy or were previously untreated with poor-prognosis clinical features were eligible for this study. All patients received bevacizumab 10 mg/kg IV every 2 weeks, along with erlotinib 150 mg orally daily. Patients were re-evaluated after 8 weeks of treatment; those with objective response or stable disease continued treatment until disease progression.

Results Forty-seven (92%) of 51 patients received at least 8 weeks of treatment. Five patients (10%) had partial responses, and 29 patients (61%) had stable disease as the best response. The median survival for the entire group was 7.4 months, with 33% of patients alive at 1 year. This regimen was well tolerated by most patients.

Conclusion The combination of bevacizumab and erlotinib has substantial activity in the treatment of patients with CUP. The median survival is superior to survival previously reported with second-line chemotherapy, and is similar to the results of many first-line chemotherapy trials in this setting. This regimen merits further evaluation in patients with CUP.

	INTRODUCTION

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Carcinoma of unknown primary site is a relatively common clinical entity, accounting for approximately 3% of all cancer diagnoses. Although several clinicopathologic subsets with favorable prognosis have been identified, most patients do not fit into any of these subsets. Empiric chemotherapy with newer regimens (primarily taxane/platinum or gemcitabine/platinum) have produced response rates between 30% and 40%, with 1- and 2-year survivals of approximately 50% and 25%, respectively.^1-4 However, complete remissions with these regimens are unusual, and the remission durations are usually brief. In addition, several clinical features (liver metastases, multiple metastatic sites, high lactic dehydrogenase levels) have consistently predicted a poor outcome with empiric chemotherapy.^5-9 Empiric second-line treatment is also usually ineffective. Only a few second-line chemotherapy regimens for patients with carcinoma of unknown primary site have been evaluated, and these have produced low response rates.^10,11 Other agents have not been specifically evaluated; however, their low response rates as single agents and in combinations as first-line therapy makes effective second-line therapy extremely unlikely.

To make additional improvements in the treatment of patients with carcinoma of unknown primary site, agents with novel mechanisms of action are needed. Two of the most promising new classes of agents are the epidermal growth factor receptor (EGFR) inhibitors and the antiangiogenic agents. Overexpression of the EGFR is common in a variety of adult solid tumors, including adenocarcinomas. Similarly, vascular epithelial growth factor (VEGF) is overexpressed in many solid tumors, and is known to be vital for the development of tumor vasculature.¹² Although the frequency of VEGF and EGFR overexpression has not been investigated in patients with carcinoma of unknown primary site, most of these carcinomas probably arise from organs in which angiogenesis or EGFR signaling are known to contribute to cancer progression or survival.

The clinical utility of inhibiting these critical cellular pathways has now been demonstrated in a variety of cancer types. Bevacizumab, a monoclonal antibody targeting VEGF, has single-agent activity in patients with advanced renal cell carcinoma, and improves treatment efficacy when used with chemotherapy in patients with advanced colon, lung, or breast cancer.^13-16 Erlotinib, an intracellular EGFR tyrosine kinase inhibitor, prolongs survival when used as a single agent in refractory non–small-cell lung cancer, and extends survival in advanced pancreatic cancer when used with chemotherapy.^17,18

The combined blockade of VEGF and EGFR with bevacizumab and erlotinib, respectively, may improve efficacy when compared with the activity of either agent alone. Preclinical data suggest that inhibition of the EGFR also results in suppression of VEGF levels.^19,20 High levels of VEGF have also been considered a possible mechanism for acquired resistance to EGFR blockade.²¹ Clinically, the combination of bevacizumab and erlotinib has demonstrated efficacy in refractory non–small-cell lung cancer and advanced renal cell carcinoma.^22,23

In this multicenter, community-based phase II trial, we evaluate the efficacy of the combination of bevacizumab and erlotinib in the treatment of patients with carcinoma of unknown primary site. The majority of patients in this trial had received previous standard combination chemotherapy regimens and were considered refractory to further therapy.

	PATIENTS AND METHODS

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This multicenter, phase II trial was initiated in April 2004. The trial was conducted in the Minnie Pearl Cancer Research Network, a community-based clinical trials organization (Appendix).

Eligibility
To be eligible for this trial, patients were required to have histologically or cytologically confirmed carcinoma of unknown primary site. Eligible tumor histologies included adenocarcinoma, poorly differentiated adenocarcinoma, and poorly differentiated carcinoma. For the purposes of this study, patients were considered to have carcinoma of unknown primary site if the following diagnostic procedures were unrevealing of a primary site: complete history, physical examination, chemistry profile, computed tomography scans of the chest and abdomen, and directed radiologic work-up of the symptomatic areas. Patients previously treated with either one or two chemotherapy regimens were eligible. In addition, previously untreated patients were eligible if they had advanced liver metastases, predominant bone metastases, or three or more visceral sites of metastases (ie, clinical settings in which standard chemotherapy has had relatively little impact). Additional eligibility criteria included Eastern Cooperative Oncology Group performance status 0 or 1; measurable disease; absolute neutrophil count of 1,000/µL or more; platelet count of 75,000/µL or more; serum bilirubin 1.5x the institutional upper limits of normal or less; serum creatinine less than 2.0 mg/dL; ability to swallow oral medications; and age 18 years or older.

Patient exclusion criteria included the following: chemotherapy within 4 weeks of study entry; previous treatment with EGFR inhibitors or angiogenesis inhibitors; acute myocardial infarction within 6 months, or other clinically significant cardiovascular disease; history of stroke within 6 months; active brain metastases; concurrent infection; major surgical procedure within 28 days; indwelling percutaneous endoscopic gastrostomy or gastrostomy tubes; previous grade 4 thromboembolic event; clinical history of a bleeding diathesis or coagulopathy; and any other disease contraindicating the use of an investigational treatment. In addition, all patients were required to give written informed consent before entering the study. This study was approved by the TriStar institutional review board (Nashville, TN) and by the institutional review boards of all participating Network sites.

Pretreatment Evaluation
Before beginning therapy, all patients underwent complete history, physical examination, CBC, chemistry profile, prothrombin time, partial thromboplastin time, and urinalysis. Radiologic evaluation included computed tomography of the head, chest, and abdomen. Positron emission tomography was recommended but not required. Directed radiologic and endoscopic evaluation of other symptoms was performed as clinically indicated. Tumor measurements were performed in all patients before beginning therapy.

Routine pathologic evaluation included initial light microscopic evaluation; in patients with poorly differentiated tumors, biopsy specimens allowing histologic versus cytologic examination were obtained. Additional studies in adenocarcinomas were performed depending on clinical features: men with suggestive clinical features had immunostaining for prostate-specific antigen, whereas women had staining for hormone receptors and HER-2 expression. Poorly differentiated carcinomas routinely had additional immunohistochemical testing for neuroendocrine markers (synaptophysin, chromogranin), leukocyte common antigen, S-100 protein, and HMB-45. Additional pathologic evaluation was individualized on the basis of clinical and pathologic features.

Treatment
All patients received treatment with bevacizumab 10 mg/kg, administered by intravenous infusion on days 1 and 15 of each 28-day course. The initial dose of bevacizumab was infused over 90 minutes. If well tolerated, the second infusion was infused over 60 minutes, and if tolerated, all subsequent infusions were administered over 30 minutes. There were no regularly scheduled premedications administered with bevacizumab.

Erlotinib was administered orally at a daily dose of 150 mg. Patients took their dose of erlotinib each morning either at least 1 hour before or 2 hours after meals. No routine premedications were administered with erlotinib.

Before each dose of bevacizumab, patients had CBCs, chemistry profile, and urinalysis performed. Patients were seen and examined by their physicians on a monthly basis. After 8 weeks of treatment, patients were evaluated for response. At this time, computed tomography scans of all measured lesions were performed. On the basis of this evaluation, all patients were assigned a response category. Patients with objective response to treatment and those with stable disease continued to receive bevacizumab and erlotinib. Patients with tumor progression were removed from this study.

For patients continuing treatment, re-evaluations were performed at 2-month intervals. Treatment was continued until the time of tumor progression.

Dose Modifications
On the basis of previous clinical experience with bevacizumab, expected toxicities with this agent included hypertension, proteinuria, and hemorrhagic events. Before each dose of bevacizumab, patients were tested for proteinuria by urinary dipstick analysis. If the dipstick exam showed at least 2+ proteinuria, bevacizumab was held and a 24-hour urine collection was obtained. Bevacizumab was continued as long as the 24-hour urine protein remained less than 2,000 mg/24 hours. If proteinuria was more than 2,000 mg/24 hours, bevacizumab was held for 2 weeks, and 24-hour urine protein was remeasured. Bevacizumab was restarted when proteinuria decreased to less than 2,000 mg/24 hours. Bevacizumab was held if patients had evidence of grade 3 or 4 bleeding, and was discontinued if any life-threatening hemorrhagic events occurred. For bleeding events of grade 3 or less, bevacizumab could be restarted at the discretion of the treating physician after the bleeding episode had resolved. Patients who developed grade 3 hypertension on bevacizumab were treated using standard antihypertensives. If patients developed grade 4 hypertension, bevacizumab was interrupted and antihypertensive treatment was initiated. Bevacizumab could be restarted at the discretion of the treating physician only after satisfactory control of blood pressure was achieved.

Expected toxicities with erlotinib included acneiform skin rash and diarrhea. Patients experiencing grade 1 or 2 toxicities were continued on the same dose of erlotinib, and symptomatic treatment was administered. Patients developing grade 3 or 4 skin toxicity had erlotinib stopped for 1 week or until the toxicity improved to grade 2 or less. Erlotinib was then restarted at full dose. If grade 3 or 4 skin toxicity recurred, erlotinib was reduced to 100 mg daily. For grade 3 or 4 diarrhea not controlled by using standard schedules of loperamide, erlotinib was interrupted for 1 week or until diarrhea had improved to grade 2 or less. Erlotinib was then reinstituted at full dose. If grade 3 or 4 diarrhea recurred, the dose of erlotinib was decreased to 100 mg daily.

For other grade 3 or 4 toxicities caused by either of these agents or their combination, administration of the offending agent or agents was discontinued for 2 weeks or until the toxicity decreased to less than grade 2. Treatment was then reinstituted at full dose at the discretion of the treating physician. Patients who developed grade 3 or 4 toxicities that failed to improve after holding treatment for 2 weeks were removed from study.

Definition of Response
All patients were re-evaluated for response after completion of 8 weeks of treatment, and response categories were assigned by using Response Evaluation Criteria in Solid Tumors (RECIST).²⁴ All patients with major responses had confirmation of response on repeat scans performed at 8-week intervals. Patients with stable disease or minor response at 8 weeks were re-evaluated at 8-week intervals as treatment continued. The final response category assigned to these patients represented the best response obtained during their treatment course.

Statistical Considerations
This nonrandomized phase II study was designed to provide preliminary information regarding the efficacy of the combination of bevacizumab and erlotinib in the treatment of patients with carcinoma of unknown primary site. Second-line chemotherapy for patients with carcinoma of unknown primary site has been relatively ineffective, producing response rates of approximately 10%, and median overall survival of 3 to 4.5 months.^10,11 Therefore, we considered the achievement of a response rate more than 25% or a median survival more than 6 months to be a level of efficacy worthy of additional development of this combination regimen. The inclusion of 46 patients into this trial was considered sufficient to allow the determination of an increase from 30% to 50% in the proportion of patients alive at 6 months, with an level of .05 and a power of 0.9.

Progression-free survival was defined as the date of study entry until the date that tumor progression was documented. Overall survival was measured from the date of study entry until the date of death. Survival curves were constructed by using the method of Kaplan and Meier.²⁵ Toxicity was evaluated in all patients who received at least one dose of therapy. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria Version 3.0.

	RESULTS

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Patient Characteristics
Between April 2004 and July 2005, 52 patients were enrolled onto this clinical trial. One patient never received treatment because of a rapid downhill course related to tumor, and is not included in subsequent discussion. Characteristics of the 51 patients who received at least one dose of treatment are detailed in Table 1. The median age of 58 years is typical of the population of patients with carcinoma of unknown primary. The majority of patients (59%) had adenocarcinoma or poorly differentiated adenocarcinoma; 82% of patients had one or more visceral sites of metastases. Thirty-seven patients (73%) had received previous treatment with either one or two regimens. Thirty-five patients (69%) had received both a platinum agent and a taxane; additional cytotoxic agents previously administered included gemcitabine (15 patients), etoposide (12 patients), irinotecan (six patients), and fluorouracil (four patients). Only 11 of the 37 patients (30%) responded to previous chemotherapy (as measured by RECIST criteria). The 14 patients who received bevacizumab and erlotinib as first-line treatment were felt to have a poor chance of responding to combination chemotherapy for the following reasons: multiple liver metastases, nine patients; more than two visceral metastatic sites, four patients; multiple bone metastases, one patient.

The median duration of treatment was 4 months (range, 2 to 15+ months); one patient continues treatment after a duration of 15 months.

Efficacy
Forty-seven (92%) of 51 patients were evaluated for response, and one patient who progressed before 8 weeks is also included as a nonresponder. Five of 48 assessable patients (10%; 95% CI, 3% to 23%) had partial responses to treatment. Four of these responses were evident at the time of first re-evaluation (ie, 8 weeks), whereas one response was not documented until the re-evaluation at 16 weeks. An additional 29 patients (61%) had stable disease as their best response to treatment. Eleven of these 29 patients (23% of all assessable patients) had measurable reductions in tumor size between 10% and 29%, as measured by RECIST criteria. Fourteen patients (29%) had progressive disease at time of first re-evaluation.

After a median follow-up of 20 months, the median progression-free survival was 3.9 months, with a 1-year progression-free survival of 16% (Fig 1). The remission durations in the five partial responders were 4, 5, 7, 15, and 24+ months. Five of the 29 patients with stable disease had continued disease stability for more than 6 months, and two of these patients were stable for more than 12 months. Two of these patients remain progression free 22 and 24 months after beginning treatment. The clinical features of patients with objective response or prolonged disease stability were diverse, and benefit was seen in patients with various visceral sites of tumor involvement. Three of five partial responders and four of five patients with stable disease lasting more than 6 months had received previous chemotherapy.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Progression-free survival (PFS; N = 51).

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival (N = 51).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Treatment for most patients with carcinoma of unknown primary site remains difficult. Although the development of taxane/platinum and gemcitabine/platinum first-line regimens has resulted in modestly improved response rates and survival, adequate second-line therapy is available for very few patients. During the last several years, we have evaluated single-agent gemcitabine, and the gemcitabine/irinotecan combination in the second-line treatment of patients with carcinoma of unknown primary site.^10,11 Although both treatments had modest activity, the response rates were quite low (8% and 10%, respectively), and median survival was short (3 and 4.5 months, respectively).

This phase II trial evaluated the efficacy of combined inhibition of VEGF and EGFR with bevacizumab and erlotinib, in a group of predominantly pretreated patients with carcinoma of unknown primary site. At the time this study was initiated, there was no clinical experience with either drug as a single agent, or in combination with chemotherapy, in the treatment of patients with carcinoma of unknown primary site. However, the respective targets of these two agents are known to play integral roles in the biology of many solid tumors, a fact that has been substantiated by a broad range of clinical experience. In addition, the combination of bevacizumab and erlotinib has been well tolerated and active in patients with refractory non–small-cell lung cancer, and is currently being evaluated in a variety of malignancies.

The results of this phase II study document the activity of bevacizumab/erlotinib in patients with carcinoma of unknown primary site. In this group of patients, the partial response rate was 10%; however, an additional 61% had stable disease when re-evaluated after 8 weeks of therapy, and 11 of these patients had measurable decrease in tumor size. Survival results with bevacizumab/erlotinib (median survival, 7.4 months; 1-year survival, 33%) also appear substantially improved when compared retrospectively to our previous experiences with gemcitabine and the gemcitabine/irinotecan combination (median survival, 3 and 4.5 months, respectively).

The toxicity of bevacizumab/erlotinib has been well described previously, and the combination was also well tolerated in most patients in this clinical trial. One elderly patient developed fatal sepsis as a result of severe exfoliative dermatitis and cellulitis (presumably related to erlotinib). One patient developed substantial proteinuria that resolved after treatment was discontinued. Other grade 3/4 toxicity was uncommon and easily managed.

In summary, the combination of bevacizumab and erlotinib has activity in the treatment of patients with carcinoma of unknown primary site, even when used in the second- or third-line setting. Survival in this patient group was better than has been previously published with other second-line regimens. In fact, the survival of patients in this group was similar to that of many first-line chemotherapy regimens, which typically produce median survivals of 8 to 10 months. The combination of bevacizumab and erlotinib deserves further evaluation in patients with this syndrome. We have currently initiated a first-line trial using paclitaxel and carboplatin in combination with bevacizumab and erlotinib, with the aim of further improving the efficacy of first-line treatment.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: John D. Hainsworth, Genentech; David R. Spigel, Genentech; F. Anthony Greco, Genentech Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: John D. Hainsworth, F. Anthony Greco

Administrative support: Cindy Farley

Provision of study materials or patients: John D. Hainsworth, David R. Spigel, Dana S. Thompson, Dianna L. Shipley, F. Anthony Greco

Collection and assembly of data: John D. Hainsworth, Cindy Farley

Data analysis and interpretation: John D. Hainsworth

Manuscript writing: John D. Hainsworth

Final approval of manuscript: John D. Hainsworth, David R. Spigel, Cindy Farley, Dana S. Thompson, Dianna L. Shipley, F. Anthony Greco

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Minnie Pearl Cancer Research Network Participating Sites: Tennessee Oncology, PLLC, Nashville, TN; Oncology Hematology Associates of SW Indiana, Evansville, IN; Medical Oncology, LLC, Baton Rouge, LA.

	NOTES

 
Supported by grants from Genentech Inc and the Minnie Pearl Foundation.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted October 2, 2006; accepted January 29, 2007.

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