NEW ORLEANS—Everolimus (RAD001), an oral agent targeting the mTOR (mammalian target of rapamycin) signal transduction pathway, has shown high single-agent activity with a combined partial and measurable response rate of 70% and manageable toxicity in patients with relapsed Waldenstrom's macroglobulinemia. Now, according to Phase II data reported here at the ASH Annual Meeting, everolimus also offers a potential new therapeutic strategy for this patient group.
First author Irene M. Ghobrial, MD, Assistant Professor in Medicine at Dana-Farber Cancer Institute, along with colleagues from the Mayo Clinic in both Rochester, MN, and Scottsdale, AZ, explained that the phosphatidylinositol 3-kinase mTOR signal transduction pathway controls cell proliferation and survival.
The 50 patients treated (median age of 63) had measurable disease (IgM monoclonal protein greater than 1,000 mg/dL with more than 10% marrow involvement or nodal masses larger than 2 cm); a platelet count 75,000 × 106/L or greater, a neutrophil count of 1,000 × 106/L or greater; and creatinine and bilirubin levels two times or higher than the laboratory upper limit of normal.
Patients received oral everolimus at 10 mg daily and were evaluated monthly. Tumor response was assessed after the second and sixth cycles and then every three cycles until disease progression.
The overall response rate of 70% included a partial response rate of 42% and a rate of measurable response of 28%, Dr. Ghobrial reported, adding that the median duration of response and median progression-free survival have not been reached.
The estimated progression-free survival rates are 75% at six months and 62% at 12 months.
Grade 3 or higher toxicities were observed in 56% of patients, the most common of which were hematological toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients, and dose reductions due to toxicity occurred in 52% of patients.
Asked for her opinion about the study, Julie Vose, MD, Professor of Internal Medicine in the Section of Hematology & Oncology at the University of Nebraska Medical Center, said that everolimus as an oral medication appears to be relatively well tolerated, and to have a modest response rate. “Perhaps one could use it either as a maintenance-type drug in the future, or perhaps combined with other agents that may be helpful [in Waldenstrom's macroglobulinemia],” she said.
Dr. Ghobrial's coauthors were Morie A. Gertz, MD; Betsy LaPlant; John Camoriano, MD; Suzanne R. Hayman, MD; Martha Q. Lacy, MD; Stacey Chuma; Patricia Sheehy, NP; Brianna Harris; Renee Leduc; Meghan Rourke; Stephen M Ansell; Daniel J. DeAngelo, MD, PhD; Angela Dispenzieri; Leif Bergsagel; Craig B. Reeder, MD; Kenneth C. Anderson, MD; Paul Richardson, MD, PhD; Steven Treon, MD, PhD; and Thomas E. Witzig, MD.
Also in Myeloma
Another study at the meeting from researchers in Germany found that single-agent everolimus was also helpful in patients with relapsed or refractory multiple myeloma. In that Phase I/II poster study, everolimus given orally at doses of 5 to 10 mg daily showed an acceptable safety profile in heavily pretreated myeloma patients—“and the observed responses even at suboptimal dose levels are promising,” the researchers, from the University of Kiel and the University of Munich, concluded. “Further evaluation of everolimus, alone and in combination with other drugs, is warranted.”