ANTITUMOR ACTIVITY OF IMATINIB IN PROGRESSIVE, HIGHLY EXPRESSING KIT ADENOID CYSTIC CARCINOMA OF THE SALIVARY GLANDS: A PHASE II STUDY. J. Guigay 1 , F. Bidault 2 , S. Temam 3 , F. Janot 3 , E. Raymond 4 , S. Faivre 4 . 1 Medicine, 2 Radiology, 3 Head and Neck Surgery, Institut Gustave Roussy, Villejuif, and 4 Medical Oncology, Beaujon University Hospital, Clichy, FRANCE OBJECTIVE The purpose of this phase II study was to explore the antitumor effects of imatinib given at 800 mg daily in a phase II study for patients with recurrent or metastatic ACC failing locoregional treatments. 2 Results have been updated since abstract submission and summarized in table 1 and 2. Population Patient characteristics are summarized in table 1 Since 2004 to date, 21 pts (M/F: 6/15, median age 49, range 33- 71) have entered the study. Target lesions were pulmonary metastasis (13 pts), pulmonary + renal metastasis (1 pt), pulmonary + hepatic metastasis (1pt), pulmonary + renal + hepatic metastasis (2pts), pulmonary + hepatic + bone metastasis (1pt), locoregional (2 pts) and pulmonary + locoregional (1 pt) recurrences. Previous treatment with chemotherapy was reported in 9 pts. Clinical toxicity Toxicity was mild to moderate in all but 3 patients : - One pt presented grade 3 neutropenia and anemia requiring transfusion and dose reduction - Two pts experienced severe fatigue requiring treatment discontinuation and were withdrawn early on for toxicity. One pt was not assessable for efficacy and the other displayed clinical and radiological progression after 2 months. Other mild to moderate toxicities included edema, rash, fatigue, nausea, requiring dose reductions in 9 pts and G1 or 2 anemia (4 pts), hypokaliema (1pt), hypocalcemia (2 pts). Mean imatinib dose received by patient was 600mg. Median duration of treatment was 6 months (range, 1-16 months). Response To date, 17 pts were assessable (1 early withdrawn for toxicity, 1 excluded as KIT expression < 1% after control, 2 follow-up < 3 months). Among these 17 evaluable pts with tumor progression at study entry : - 2 pts displayed partial responses (PR) of 42% and 35% (RECIST) after 3 months of treatment. These objective responses were associated with early symptomatic improvement (dyspnea/pain) and occurred in platinum-resistant pulmonary metastasis and a locoregional recurrence treated with neutrontherapy 6 years before, lasting 14 months and 15+ months, respectively (figure 2 and 3). The later patient, a 33 old woman who experienced hypokaliema requiring early dose reduction, is still stable under treatment at 400 mg/d and has stopped all analgesics. - 6 pts were stable (SD) after 3+, 6+, 12+ (Imatinib stopped after 6 months), 15+, 16+ and 30+ (Imatinib stopped after 1 y) months of follow-up (figure 4). Among them, 2 had received previous chemotherapy. - 9 pts continued progression (P) despite imatinib treatment which was stopped after 3 months in 6 patients ; others pts include a patient who was withdrawn for toxicity and progressed before 3 months, and two pts evaluated SD according to RECIST criteria but with 8% and 16% increase of target lesions who stopped imatinib after 3 months. Clinical benefit (PR + SD) is 47 %. CONCLUSION o o Although sporadic, objective responses can be observed in patients with progressive ACC treated with imatinib as well as long-lasting tumor stabilisations. o o Final accrual and time to progression determinations are ongoing. o o Translational research that could help to identify patients who would respond to imatinib mesylate is warranted. 6 RESULTS MATERIAL & METHODS Patients Patients (pts) eligible for the study had : - Histologically proven recurrent or metastatic ACC - Highly (50-100% of tumor cells) expressing KIT tumor - Failed locoregional treatments, without possibility of curative therapy - CT or MRI scan documented progressive disease. Patients were required to display documented tumor progression on two consecutive CT and/or MRI scans performed 3 to 4 months apart before study entry and to have at least one measurable target lesion > 2 cm. Inclusion criteria included the ability to take the oral medication, performance status 0-1, normal bone marrow and normal renal and hepatic function, life expectancy of more than three months. Prior chemotherapy or radiotherapy must have been completed at least four weeks before beginning therapy. Medications which could interact with imatinib were not allowed. Treatment Imatinib mesylate was administered at 400 mg orally bid (800 mg/d) until progression or toxicity. This dose was chosen following reports of a prolonged effect of imatinib in patients with GIST receiving a higher dose of imatinib. Imatinib (Glivec) was provided by Novartis, France. Monitoring Patients were monitored every two weeks during the first 3 months and every month after, with history and physical examination, toxicity checklist with special care to fatigue, nausea and edema, and CBC and liver and renal function tests. In case of toxicity, doses were reduced by step of 200 mg to a minimum of 400 mg/day. End points and antitumor activity assessment Imaging of the measurable lesion (CT or MRI) was carried out every three months on study in the absence of clinical progression (in which cases imaging was carried out after a shorter interval) and were classified according to RECIST criteria. The primary end point of our study was the assessment of time to tumor progression (TTP) given the low proliferative fraction characterizing this disease. Secondary endpoints were safety and clinical benefit including partial response and stable disease in this population of patients displaying tumor progression, as objective tumor shrinkage with any previously used anticancer agent was unusual. 4 3 DISCUSSION Encouraging results in our phase II trial suggest that imatinib mesylate may have, at least in a limited subset of patients, antitumor activity in ACC. 2 partial responses are reported here, both in irradiated area and in patient failing prior therapy with platinum. Antitumor activity was preceded by early evidence of clinical benefit : disappearance of pain for locoregional relapse, complete resolution of dyspnea for pulmonary metastasis in our experience after a few weeks of treatment. In this study, conducted in a poor prognostic population essentially metastatic, with 40% of patients already treated with chemotherapy, long-lasting stabilizations have been obtained in 1/3 pts. Final accrual and time to progression determinations are ongoing. However, two phase II studies recently published, testing imatinib efficacy in ACC, have appeared disappointing, with no evidence of objective response. Based on their results, the authors concluded that imatinib has no major effect on advanced ACC of the head and neck (1,2). Therefore, discrepancies in results might be, at least in part, explained by different reasons : - The level of KIT overexpression might play a role in imatinib mesylate sensitivity. A strong overexpression of KIT by tumor cells was a prerequisite to enter our study. The 2 patients who responded exhibited strong CD117 immunostaining. Conversely, only four of 16 patients were reported to display strong KIT expression in one published study (1), and in the other (2) tumors were considered positive if more than 10% of tumour cells showed a strong immuno-reaction. In the absence of overexpression and/or KIT mutations, response to imatinib mesylate is likely to be low and might account for the absence of drug activity in this 2 studies. We are currently investigating the type of KIT mutation harbored by our responding patients (4,5). - In our study, the first tumor evaluation was performed only after 3 months of treatment that was further maintained in the absence of tumor progression. Thus, the median duration of treatment in the first published study might be regarded as insufficient to draw definitive conclusions on imatinib mesylate efficacy in ACC (1). Response to imatinib mesylate is known to sometimes occur only after several months of treatment and be preceded by sustained tumor stabilization. - Finally, in our trial patients had clear documented tumor progression at study entry. The nonrequirement for documented tumor progression at baseline in the 2 studies (1,2), suggesting that most of their patients might have been treated in the absence of cellular proliferation, might have limited the potential of imatinib mesylate to induce tumor regression. BACKGROUND ❏ Adenoid cystic carcinoma (ACC) of the salivary glands is a rare orphan disease of the head and neck usually resistant to conventional chemotherapy, that was found to express KIT in 87% (39/45) of cases in our institutions (figure 1). ❏ Imatinib mesylate (Glivec or Gleevec) is a tyrosine kinases inhibitor, including those associated with Bcr-Abl, the PDGF-R and c-kit, which play a role in tumour cell proliferation and are preferentially expressed in tumour cells. Patients with gastrointestinal stromal sarcoma (GIST), which is also characterized by high level of c-kit expression, have shown important clinical responses to Imatinib. 1 Dir Com IGR, MMB, 06 _ 2007 REFERENCES 1. Hotte SJ, Winquist EW, Lamont E, et al: Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands expressing c-kit: A Princess Margaret Hospital phase II consortium Study. J Clin Oncol 23:585-590, 2005. 2. Pfeffer MR, Talmi Y, Catane R, et al. A phase II study of Imatinib for advanced adenoid cystic carcinoma of head and neck salivary glands. Oral Oncol. 2007 Jan;43(1):33-6. 3. Alcedo JC, Fabrega JM, Arosemena JR, et al: Imatinib mesylate as treatment for adenoid cystic carcinoma of the salivary glands: Report of two successfully treated cases. Head Neck 26:829-831, 2004 4. 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. 5. 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. 6. Faivre S, Raymond E, Casiraghi O, et al. Imatinib mesylate can induce objective response in progressing, highly expressing KIT adenoid cystic carcinoma of the salivary glands. J Clin Oncol 2005;23:6271-3. Figure 1 : Highly (50-100% of tumor cells) expressing KIT tumor. Table 1 : Patient characteristics Table 2 : Summary of results for 17 evaluable pts . CT : chemotherapy ; LR : locoregional ; M : metastases ; PR :partial response ; SD : stable disease ; P : progression. Figure 2 : Computed tomography. Baseline (A)-(C) and evidence of objective response (B)-(D) in patient 14 with multiple pulmonary metastasis of an adenoid cystic carcinoma after 3 months of daily oral 800 mg imatinib mesylate. Figure 3 : Axial contrast enhanced T1 weighted MRI. Baseline and evidence of objective response in patient 1 with loco- regional recurrence of an adenoid cystic carcinoma after 3 and 6 months of daily oral 600 mg imatinib mesylate. Figure 4 : Computed tomography. Baseline and evidence of stable disease in patient 4 with multiple pulmonary metastasis of an adenoid cystic carcinoma after 12 months of daily oral 800 mg imatinib mesylate. 5 View publication stats View publication stats