Clinical Spotlight from ASH 2009: mTOR Inhibitors

Congress Alert - Clinical Spotlight from ASH

	mTOR Inhibition: A Novel Therapeutic Strategy in Hematologic Malignancies December 7, 2009—During the 51^st ASH Annual Meeting and Exposition in New Orleans, data were presented demonstrating the efficacy and safety of mammalian target of rapamycin (mTOR) inhibition as a therapeutic strategy in Waldenström macroglobulinemia, multiple myeloma, and leukemia. Mammalian target of rapamycin is a key regulator of cell proliferation, cell differentiation, and angiogenesis. Dysregulation of the mTOR signal transduction pathway has been implicated in a variety of solid tumors and hematologic malignancies. Two mTOR inhibitors, everolimus (RAD001) and temsirolimus, are currently available for the treatment of advanced renal cell carcinoma. Evidence of antitumor activity in preclinical and early clinical studies supports further examination of mTOR inhibition in several hematologic malignancies. Everolimus in relapsed/refractory Waldenström macroglobulinemia Irene Ghobrial, MD (Dana-Farber Cancer Institute, Boston, Massachusetts, United States), presented data from a phase II trial evaluating the safety and efficacy of monotherapy with everolimus in patients with relapsed or refractory Waldenström macroglobulinemia. A total of 50 patients with measurable disease (IgM monoclonal protein >1000 mg/dL with >10% marrow involvement or nodal masses >2 cm) received oral everolimus 10 mg daily. The following results were obtained from this trial: Overall clinical benefit rate (CBR) was 70% Partial response (PR) was 42% Minor response (MR) was 28% Median time to response for patients achieving PR was 2 months Median duration of response (DR), progression-free survival (PFS), and overall survival (OS) for the entire study population were not reached Estimated PFS at 6 months and 12 months was 75% and 62%, respectively No association between response status and age, hemoglobin level at baseline, IgM level at baseline, or β2 microglobulin level at baseline Dose reductions due to toxicity occurred in 52% of patients, and the most common grade 3/4 toxicities included cytopenias, diarrhea, fatigue, and stomatitis. These data demonstrated that everolimus had high single-agent activity with manageable toxicity in patients with relapsed or refractory Waldenström macroglobulinemia, and may offer an additional therapeutic strategy for this patient population. Blood. 2009;114(22): Abstract 587. Everolimus in relapsed/refractory multiple myeloma Andreas Günther, MD (University of Kiel, Germany), presented data from a phase I/II study evaluating the use of single-agent everolimus in patients ≥18 years of age with relapsed or refractory multiple myeloma. The primary objectives in phase I of the trial were to determine the safety and optimal dose of everolimus, while the primary objective of phase II was to evaluate response rate after 6 months. The phase I portion of the trial followed a classic dose-escalation design with 3 planned dose levels (5 mg, 7.5 mg, and 10 mg), and patients demonstrating benefit from everolimus were allowed to continue with treatment. Results from the first 15 patients enrolled in this study demonstrated that single-agent everolimus had an acceptable safety profile in heavily pretreated patients with multiple myeloma. Grade 3/4 toxicities included leukopenia, thrombocytopenia, infection, and an increase in creatine phosphokinase. Two out of 7 serious adverse events were assessed to be possibly related to everolimus. Preliminary efficacy data demonstrated response or disease stabilization in ~50% of patients. The authors conclude that these data warrant additional phase II studies of everolimus, alone and in combination with other agents, for the treatment of patients with relapsed or refractory multiple myeloma. Blood. 2009;114(22): Abstract 3850. A preclinical study presented by Yosuke Minami, MD, PhD (Nagoya University Graduate School of Medicine, Japan), suggests that everolimus may also be important in overcoming imatinib resistance in chronic myeloid leukemia. In this study, everolimus potently induced cell death in imatinib-resistant Philadelphia chromosome–positive leukemia cell lines harboring the T315I mutation, implying that mTOR inhibition may be able to overcome the clinical challenge of imatinib resistance in chronic myeloid leukemia. Clinical studies will be will be critical in verifying these results and evaluating the potential of mTOR inhibition in this setting. Blood. 2009;114(22): Abstract 3277. Taken together, data from these studies demonstrate a potential role for the use of mTOR inhibitors in a wide range of malignancies. Several clinical trials, including a phase III trial of everolimus in diffuse large B-cell lymphoma, are underway to further evaluate the clinical use of mTOR inhibitors in hematologic malignancies.