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Imatinib Mesylate in Patients With Adenoid Cystic Cancers of the Salivary Glands Expressing c-kit: A Princess Margaret Hospital Phase II Consortium Study

From the Princess Margaret Hospital Phase II Consortium; The University of Chicago Phase II Consortium; and Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD

Address reprint requests to Sebastien J. Hotte, MD, Juravinski Cancer Centre at Hamilton Health Sciences, 699 Concession St, Hamilton, Ontario, Canada, L8V 5C2; e-mail: sebastien.hotte{at}hrcc.on.ca

	ABSTRACT

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PURPOSE: This study aimed to assess the antitumor activity of imatinib in adenoid cystic carcinoma (ACC) of the salivary gland expressing c-kit. A high level of c-kit expression has been identified in more than 90% of ACCs. Imatinib specifically inhibits autophosphorylation of the bcr-abl, platelet-derived growth factor receptor beta, and c-kit tyrosine kinases.

PATIENTS AND METHODS: In a single-arm, two-stage, phase II clinical trial, adult patients with unresectable or metastatic ACC measurable by Response Evaluation Criteria in Solid Tumors Group criteria and expressing c-kit by immunohistochemistry were treated with imatinib 400 mg orally bid. Response was assessed every 8 weeks.

RESULTS: Sixteen patients have been enrolled onto the study; 10 were female. Median age was 47 years (range, 31 to 69 years). Median Eastern Cooperative Oncology Group performance status was 1 (range, 0 to 2). Fourteen patients had lung metastases, 14 had prior radiotherapy, and six had prior chemotherapy. Toxicities occurring in at least 50% of patients included fatigue, nausea, vomiting, diarrhea, anorexia, edema, dyspnea, and/or headache, usually of mild to moderate severity. In 15 patients assessable for response, no objective responses have been observed. Nine patients had stable disease as best response. Six patients had progressive disease after two cycles.

CONCLUSION: Because of the lack of activity, the study has been stopped after the first stage and additional evaluation of imatinib in this population is not warranted. Overexpression of wild-type c-kit was not sufficient for clinical benefit from imatinib in ACC. Accrual to this study was rapid for a relatively rare cancer, encouraging additional efforts to identify more effective systemic therapy for these patients.

	INTRODUCTION

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Salivary gland cancers are uncommon malignancies, with an incidence of 10 occurrences per million in the United States, and account for 7% of head and neck tumors. Among the many different histologic subtypes of salivary gland cancers with heterogeneous clinical behaviors, adenoid cystic carcinoma (ACC), lymphoepithelioma-like salivary gland carcinoma, and myoepithelial salivary gland carcinoma share the common feature of c-kit overexpression, rendering these subtypes attractive for molecular targeted therapeutics. Approximately 22% of malignant salivary tumors are ACC, with a greater occurrence in minor than major salivary glands. The natural history of ACC is often protracted, with patients occasionally living for 10 to 20 years after confirmation of metastatic disease.¹ Typical survival figures are 50% to 90% at 5 years, 30% to 67% at 10 years, and 25% at 15 years, respectively.¹

Initial definitive therapy for these malignancies usually consists of surgical resection followed by radiotherapy for tumors deemed to have a high risk of local recurrence. The role of systemic therapy in ACC is in the management of local recurrence no longer amenable to additional surgery or radiotherapy, and in the palliation of symptoms from distant metastases. The response rates of ACC to conventional cytotoxic chemotherapy have been generally modest, and were primarily derived from small institutional series and clinical trials. For example, the objective response rates of ACC to cytotoxic agents such as fluorouracil, anthracyclines, platinum compounds, paclitaxel, and vinorelbine are in the range of 15% to 30%.^2-7 Duration of responses to chemotherapy typically was in the range of 6 to 9 months, with some responses lasting in excess of a year.

The c-kit proto-oncogene encodes a 145- to 165-kd transmembrane cell surface receptor (Kit) in the same subclass as the receptors for platelet-derived growth factor and colony-stimulating factor.⁸ Various mutations in c-kit may result in aberrant signaling pathways.^9-11 For instance, gain of function mutations in exon 11 (juxtamembrane domain) and exon 17 (tyrosine kinase domain) are involved in c-kit activation in gastrointestinal stroma tumors (GISTs) and mast cell tumors, respectively.⁸ In one series,⁹ c-kit expression was identified in ACC (20 of 25), and lymphoepithelium-like (six of six) and myoepithelial (two of two) carcinomas of the salivary gland. Expression of c-kit was not identified in other types of salivary gland tumors (zero of 46). Among the salivary tumors with c-kit protein expression, genetic alterations in exon 11 or 17 were not detected by DNA sequencing. Hence, c-kit overexpression is likely implicated in the pathogenesis of these salivary gland tumors, but genetic mutation is not the mechanism of c-kit activation. Similarly, in another series of 30 ACC patients, c-kit protein expression was demonstrated in 90% of the archival tumor specimens, but again no mutations in exons 11 or 17 were identified.¹² Kit-positivity was associated with histologic grade 3 tumors and solid growth patterns.

Imatinib (formerly known as STI 571) is a derivative of the 2-phenylaminopyrimidine series of protein tyrosine kinase inhibitors. It has been shown to inhibit potently the tyrosine kinases of ABL, the platelet-derived growth factor receptor (PDGFR), and the receptor for c-kit. In a randomized study of 1,105 patients with newly diagnosed, chronic-phase, chronic myelogenous leukemia (CML), imatinib was far superior to interferon and cytarabine in inducing hematologic and cytogenetic responses and in decreasing the likelihood of progression to accelerated-phase or blast-crisis CML due to constitutive activation of the BCR-ABL tyrosine kinase.¹³ Imatinib has now been approved for use in patients with CML. Imatinib has also been evaluated in a number of other tumors expressing c-kit or PDGFR, such as GISTs,¹⁴ small-cell lung cancer,¹⁵ and systemic mast cell disease¹⁶ with varying levels of efficacy. Significant disease regression has been demonstrated with imatinib in more than 50% of patients with unresectable and/or metastatic GISTs, resulting in its approval by the US Food and Drug Administration for GIST patients in advanced stage.¹⁷ In contrast, a phase II study of imatinib in 19 patients with small-cell lung cancer reported no objective response. However, only 20% of the patients on that study had tumor specimens stained positive for c-kit by immunohistochemistry.

On the basis of the lack of standard approach in the treatment of ACC of the salivary glands, the Princess Margaret Hospital Phase II Consortium, in collaboration with the University of Chicago Phase II Consortium, initiated a multi-institutional phase II study to evaluate the safety and efficacy of single-agent imatinib in this tumor type. Because reports in the literature have suggested that the vast majority of ACC overexpress the c-kit tyrosine kinase receptors, and that imatinib has demonstrated anticancer activity in some c-kit–positive tumors such as GISTs, c-kit positivity by immunohistochemistry was a requirement for entry onto the present study.

	PATIENTS AND METHODS

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Patient Eligibility
Patients 18 years of age or older with histologically documented or cytologically confirmed ACC were eligible if they had c-kit–positive tumors. C-kit positivity was determined using archival paraffin samples if possible; patients for whom archival samples were unavailable were required to undergo a biopsy to determine the c-kit status of their tumor. C-kit positivity was measured using immunohistochemistry performed locally at each participating institution and determined by primary mouse monoclonal antibody to CD117/c-kit. Immunostaining was done using the peroxidase-antiperoxidase technique after microwave treatment. The antibody dilution was 1:100 (catalog number A4502; DAKO, Carpinteria, CA). The sections were scored for c-kit positivity and classified as being absent, weak, moderate, or strong. For each case, at least one examiner scanned the entire slide at x40 to x100 magnification. Patients must have had at least weak c-kit staining to be eligible for this study.

Patients were required to have disease that was deemed unresectable and/or metastatic, radiologically documented, and measurable with at least one site of disease that could be measured unidimensionally as 20 mm with conventional techniques or as 10 mm with spiral computed tomography (CT) scan. Patients may have had unlimited prior therapy but must have had at least a 4-week interval between any chemotherapy, radiotherapy, or surgery and study enrollment; adequate performance status of Eastern Cooperative Oncology Group status 0, 1, or 2; life expectancy of at least 12 weeks; normal bone marrow and organ function defined as absolute neutrophil count more than 1,500/µL, platelets more than 100,000/µL, total bilirubin less than 1.25x upper limit of normal (ULN), AST and/or ALT less than 2.5x ULN, creatinine less than 1.25x ULN or creatinine clearance more than 50 mL/min/1.73 m². Patients were excluded if they had known brain metastases; a history of other active malignancy in the last 5 years, with the exception of adequately treated cervical carcinoma-in-situ and nonmelanomatous skin cancers; a serious medical condition; or were receiving therapeutic doses of warfarin. Pregnant or breastfeeding women were also excluded. Participants gave informed consent before they entered onto the study, and the study was approved by the local research ethics committees of all participating centers.

Therapy
Study treatment was administered on an outpatient basis, and consisted of imatinib at a starting dose of 400 mg orally bid (ie, total dose of 800 mg/d) taken immediately before or during meals, by a continuous schedule. Imatinib was supplied by the National Cancer Institute, Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program. Cycle length was defined as 4 weeks or 28 days and treatment was continued until disease progression, unacceptable toxicity, patient's refusal, or physician's decision.

Toxicity Assessment and Dose Reductions
Toxicity was graded according to National Cancer Institute Common Toxicity Criteria, version 3. No dose interruption or modification was made for grade 1 nonhematologic toxicity. For intolerable grade 2 or for grade 3 or 4 nonhematologic toxicity, imatinib was withheld until the toxicity returned to grade 1 or baseline, and the dose was reduced by 25% to 600 mg daily. If the toxicity recurred, imatinib was withheld until the toxicity returned to grade 1 or baseline, and the dose was again reduced to 400 mg daily. If the toxicity recurred again at this point, the drug was discontinued permanently. Patients were taken off study if the interruption lasted longer than 3 weeks without recovery to grade 1 or baseline level. Patients were removed from the study if they develop a grade 4 nonhematologic toxicity that was judged to be life threatening. The days during which the study drug was withheld or interrupted were not counted as part of the current treatment cycle. For example, if a drug was withheld for 1 week during a cycle, then the total length of that cycle was 5 instead of 4 weeks. For grade 3 or 4 hematologic toxicity, the drug was withheld until the toxicity had resolved to grade 1, and then resumed at the same dose. If the grade 3 or 4 toxicity recurred, imatinib was withheld until recovery to grade 1, and the dose was reduced to 600 mg daily. This procedure could be repeated one more time and the imatinib dose reduced to 400 mg daily before permanent discontinuation.

Assessment of Response
Patients were evaluated for response every 8 weeks and responses were classified according to criteria proposed by the Response Evaluation Criteria in Solid Tumors Committee.¹⁸

Statistical Considerations
The primary objective of this study was to determine the objective response rate (complete and partial responses) of single-agent imatinib in ACC. Because ACC can often be a slow-growing disease, prolonged stable disease was not believed to be an appropriate outcome measure. Secondary objectives were to evaluate the duration of response, and safety and tolerability of imatinib in this population. To minimize the number of patients treated in the event that the regimen proved ineffective, a two-stage design was used, according to Simon.¹⁹ The null hypothesis assumed that the response rate was less than 5% and the alternative hypothesis assumed that the response rate was at least 20%. The design allowed the study to be terminated after enrollment of 12 patients in the first stage if at least one response was not noted. If at least one response was observed, the study was to continue enrollment with an additional 25 patients to a total of 37.

	RESULTS

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Patients and Treatment
Between July 2002 and May 2003, 16 patients were enrolled onto this study at four centers in Canada and the United States (16 patients were enrolled to ensure that at least 12 would be assessable at the first stage). All patients enrolled onto study had positive immunohistochemical staining for c-kit and all patients had a diagnosis of ACC. Twenty-one (88%) of the 24 patients screened for c-kit stained positive. Five patients who were screened positive for c-kit did not subsequently enroll onto the study because they failed to meet other eligibility criteria. Fifteen of 16 enrolled patients were assessable for efficacy assessment. All patients were assessable for toxicity. Patient characteristics are listed in Table 1. All patients had measurable disease. C-kit immunohistochemical staining scores and best clinical responses for each patient are listed in Table 2. Two patients completed more than six cycles of treatment: one patient had stable disease and progressed after cycle 13, and a second patient had unconfirmed partial response after cycle 8, but returned to stable disease status again in cycle 10 and experienced disease progression after cycle 12.

Median survival for the patients entered onto this study was 30 weeks, and the 6-month survival rate was 61.4% (95% CI, 41.3% to 91.3%). Median progression-free survival was 10 weeks, and 6-month progression-free survival was 12.5% (95% CI, 3.4% to 45.7%). To date, eight patients have died and eight patients remain alive.

Toxicity
Imatinib was modestly tolerated by most patients, and a number of patients experienced significant toxicity. Grade 1 and 2 nonhematologic toxicities included fatigue, nausea, vomiting, diarrhea, and/or anorexia, which occurred in more than 50% of patients. A smaller proportion of patients experienced edema, dyspnea, and/or headache, usually of mild to moderate severity (Table 3). Table 4 describes all grade 3 or higher hematologic, nonhematologic, and biochemical toxicities experienced by patients at any point during the study that were believed to be possibly, probably, or definitely related to imatinib. Seventeen (28%) of 60 cycles had grade 3 or 4 adverse events that were at least possibly drug related. The most common grade 3 or higher toxicities included lymphopenia (four cycles); dyspnea and hypophosphatemia (three cycles each); and pleural effusion, hyponatremia, hemoglobin, and abdominal pain (two cycles each). Six patients required dose reductions during their course on the study.

	DISCUSSION

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Although patients with ACC tend to experience disease progression relatively slowly, a large number of patients with locoregional or distant metastatic recurrence will eventually die as a result of their disease. To date, no treatment has been able to improve the natural history of ACC, and there continues to be no accepted standard therapy other than surgery. The large proportion of tumors expressing c-kit in pathologic studies raised the possibility that agents targeting c-kit, such as imatinib, could play a role in the treatment of this disease and warranted clinical evaluation. Our study seems to refute this hypothesis because no objective response was observed in 16 enrolled patients. Although two patients have had prolonged stable disease of at least 6 months, the slow natural history of these tumors precludes any suggestion that imatinib played a role in arresting or slowing down tumor growth. One positive aspect of this study is that, despite the fact that ACC is a rare tumor, enrollment has been rapid, and 16 patients were enrolled within 9 months. Enthusiasm on the part of investigators and patients alike was excellent and should provide the foundation for conducting other studies evaluating novel therapeutic modalities in patients with ACC and in other uncommon malignancies.

It has been hypothesized recently that patients with GISTs who responded to imatinib were those who had specific activating mutations of c-kit.²⁰ Heinrich et al²⁰ examined 127 patients with GISTs enrolled onto a phase II clinical study of imatinib for mutations of c-kit or PDGFR- and correlated mutation types with clinical outcomes. In patients harboring exon 11 c-kit mutations (n = 85), the partial response rate was 83.5%, whereas patients with tumors containing an exon 9 c-kit mutation had a partial response rate of 47.8%. In contrast, patients with no detectable mutation of c-kit or PDGFR- had no objective responses at all. Unfortunately, in series of patients with ACC, DNA sequencing determined that genetic alterations of the c-kit juxtamembrane domain (exon 11) and tyrosine kinase domain (exon 17) were not present, and that in most cases, wild-type c-kit was observed.^9,12 In light of these findings, it is perhaps not surprising that imatinib was inactive in our study.

In conclusion, although imatinib was generally well tolerated, it was found to have no clinical activity in patients with advanced ACC. On a positive note, accrual to this study was rapid, despite the fact that ACC is a rare tumor, which should encourage additional efforts to identify more effective systemic therapy for these patients.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Cynthia Bajda, Peggy Francis, and Trish Haines for their assistance as research coordinators on this study.

	NOTES

 
Supported by clinical trial contracts from the US National Cancer Institute, N01-CM-17107-01 and N01-CM-17102-01.

Presented in part at the European Conference on Clinical Oncology (ECCO) meeting, Copenhagen, Denmark, September 21-25, 2003.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Sessions RB, Harrison LB, Forastiere A: Tumors of the salivary glands and paragangliomas, in Devita VT, Hellman S, Rosenberg SA (eds): Principles and Practice of Oncology. Philadelphia, PA, Lippincott-Raven Publishers, 2000

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4. Verweij J, de Mulder PH, de Graeff A, et al: Phase II study on mitoxantrone in adenoid cystic carcinoma of the head and neck. Ann Oncol 7:867-869, 1996[Abstract/Free Full Text]

5. Hill ME, Constenla DO, A'Hern RP, et al: Cisplatin and 5-fluorouracil for symptom control in advanced salivary adenoid cystic carcinoma. Oral Oncol 33:275-278, 1997[Medline]

6. Airoldi M, Fornari G, Pedani F, et al: Paclitaxel and carboplatin for recurrent salivary gland malignancies. Anticancer Res 20:3781-3784, 2000[Medline]

7. Airoldi M, Pedani F, Succo G, et al: Phase II randomized trial comparing vinorelbine versus vinorelbine plus cisplatin in patients with recurrent salivary gland malignancies. Cancer 91:541-547, 2001[CrossRef][Medline]

8. Longley BJ, Reguera MJ, Ma Y: Classes of c-KIT activating mutations: Proposed mechanisms of action and implications for disease classification and therapy. Leuk Res 25:571-576, 2001[CrossRef][Medline]

9. Jeng YM, Lin CY, Hsu HC: Expression of the c-kit protein is associated with certain subtypes of salivary gland carcinoma. Cancer Lett 154:107-111, 2000[CrossRef][Medline]

10. Krystal GW, Honsawek S, Kiewlich D, et al: Indolamine tyrosine kinase inhibitors block Kit activation and growth of small cell lung cancer cells. Cancer Res 61:3660-3668, 2001[Abstract/Free Full Text]

11. Lev S, Blechman JM, Givol D, et al: Steel factor and c-kit proto-oncogene: Genetic lesson in signal transduction. Crit Rev Oncog 5:141-168, 1994[Medline]

12. Holst VA, Marshall CE, Moskaluk CA, et al: KIT protein expression and analysis of c-kit gene mutation in adenoid cystic carcinoma. Mod Pathol 12:956-960, 1999[Medline]

13. O'Brien SG, Guilhot F, Larson RA, et al: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994-1004, 2003[Abstract/Free Full Text]

14. Demetri GD, von Mehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480, 2002[Abstract/Free Full Text]

15. Sonia JC, Johnson BE, Chevalier TL: Imatinib in small cell lung cancer. Lung Cancer 41(suppl 1):S49-S53, 2003

16. Pardanani A, Elliott M, Reeder T, et al: Imatinib for systemic mast-cell disease. Lancet 362:535-536, 2003[CrossRef][Medline]

17. Dagher R, Cohen M, Williams G, et al: Approval summary: Imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 8:3034-3038, 2002[Abstract/Free Full Text]

18. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

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20. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349, 2003[Abstract/Free Full Text]

Submitted June 16, 2004; accepted October 6, 2004.

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