Pharmacy & Therapeutics- July 2008 - (Page 400) Meeting Highlights: ASCO and at 24 months were the same (27%), and neutropenia rates (49% and 50%) and thrombocytopenia rates (48% and 49%) were similar. In addition, grade 3 and 4 nonhematological side effects did not increase substantially, and among patients who had been intolerant of imatinib, cross-intolerance to dasatinib was not observed. “Dasatinib efficacy was demonstrated,” Dr. Stone concluded, “across subgroups, including all but one of 43 different baseline mutations.” He noted also that based on similar efficacy but a more favorable risk–benefit ratio, dasatinib 100 mg daily is the currently approved dose for patients with CP–CML. in 7%. Rates for grade 3 and 4 anemia were 10%; for neutropenia, 30%; and for thrombocytopenia, 28%. The median duration of anemia was nine days, of neutropenia, 15 days; and of thrombocytopenia, 23 days. Grade 1 and 2 peripheral edema was reported in 6% of patients, and pericardial and pleural effusion were seen in 2% and 4% (all grades). Results of this phase 2 trial, Dr. Kantarjian concluded, showed significant activity for nilotinib in CML–CP after unsuccessful imatinib therapy, with excellent tolerability and minimal occurrence of grade 3 and 4 adverse events. Nilotinib (Tasigna) for Chronic Myelogenous Leukemia • Hagop M. Kantarjian, MD, MD Anderson Cancer Center, Houston, Tex. Nilotinib (Tasigna, Novartis) had significant activity in chronic phase–chronic myelogenous leukemia (CML–CP), with a 91% survival rate at 18 months among 321 patients for whom imatinib therapy had failed, according to Dr. Kantarjian. The highly selective Bcr–Abl inhibitor, he said, binds to Abl with higher affinity and greater selectivity than imatinib mesylate (Gleevec) and inhibits most imatinib-resistant Bcr– Abl mutations (except the T3151 mutation). Nilotinib was approved in the U.S. in October 2007 for patients with refractory CML–CP or those who did not tolerate previous therapy. The primary endpoint of this clinical trial was the MCyR rate. Patients received nilotinib 400 mg orally twice daily two hours before or after meals. Their median age was 58 years, and the median duration of CML was 58 months. Prior imatinib therapy had ranged from 400 mg to more than 800 mg; 72% of patients had received 600 mg/day or more. The median duration of prior imatinib therapy was 33 months. The ratio of imatinib-resistant to imatinib-intolerant patients was 71% to 29%. Patients received nilotinib at a median dose of 788 mg/day for a median of 465 days. Dose reductions were required in 25% of patients, and dose interruptions were needed for 55% for a median of 19 days. The median time to achieve complete hematological responses was one month, and the median time to achieve MCyRs was 2.8 months. Complete hematological responses were reported in 77% of the patients, with MCyR and CCyR rates at 58% and 42%, respectively. MCyRs were 56% for the imatinib-resistant patients and 63% for the imatinib-intolerant patients, and CCyRs were 39% and 50%, respectively. At 18 months, MCyRs were sustained in 84% of patients, and the progression-free survival rate was 67%; 95% of patients were alive at 12 months, and 91% were alive at 18 months. These durations exceeded those reported for other therapies and for allogeneic stem-cell transplantation.1 Therapy was discontinued in 53% of patients (23% because of disease progression and 17% because of adverse events). Rash (in 30%), pruritus (in 25%), and nausea (in 24%) were the most common nonhematological adverse events, but grade 3 and 4 rates were 2% or lower. Biochemical abnormalities were noted in many patients, but grade 3 and 4 events were uncommon, consisting of lipase elevation (in 16%), hypophosphatemia (in 15%), hyperglycemia (in 12%), and total bilirubin, Cetuximab (Erbitux) and Chemotherapy For Non–Small-Cell Lung Cancer • Robert Pirker, MD, Medical University of Vienna, Vienna, Austria • Thomas J. Lynch, Jr., MD, Harvard Medical School, Boston, Mass. Results from the First-line in Lung cancer with Erbitux (FLEX) trial of cetuximab (Erbitux, Bristol-Myers Squibb/ ImClone), added to first-line chemotherapy with cisplatin/ vinorelbine (Platinol, Bristol-Myers Squibb)/Navelbine, GlaxoSmithKline), suggest the regimen as a new standard for the first-line treatment of advanced non–small-cell lung cancer (NSCLC). Dr. Pirker, lead investigator, noted that about 40% of NSCLC patients present with advanced disease and that epidermal growth factor receptor (EGF-R) expression is associated with tumor growth, metastasis, and a poor prognosis. Cetuximab is a monoclonal antibody that binds to EGF-R, blocking signal transduction and promoting receptor internalization (a process by which receptor signalizing is downregulated) and degradation. The goal of FLEX was to demonstrate superior overall survival with cetuximab plus chemotherapy (arm A) versus chemotherapy alone (arm B). The investigators randomly assigned 1,125 patients with EGF-R–detectable advanced NSCLC, in a ratio of 1:1, to receive cetuximab 400 mg/m2 as an initial dose, then 250 mg/m2 per week plus cisplatin 80 mg/m2 on day 1, as well as vinorelbine 25 mg/m2 on days one and eight ever y three weeks (arm A). Patients in arm B received cisplatin/vinorelbine alone. The primary endpoint was overall survival. Patients (median age, 59 years; 70% men) were naive to both chemotherapy and anti–EGF-R therapy; 94% had stage IV NSCLC, 47% had adenocarcinoma, and 34% had squamous cell carcinoma. Eighty-three percent of the patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1. The median duration of treatment was 14 weeks. Median overall survival was 11.3 months (a one-year survival rate of 47%) with chemotherapy/cetuximab and 10.1 months (one-year survival of 42%) with chemotherapy alone (HR = 0.871, P = 0.044). Dr. Pirker noted that the survival benefit was observed in the subgroups for ECOG status, smoking, histology, sex, age, and tumor stage. Median response rates were 36% with chemotherapy/cetuximab versus 29% for chemotherapy alone (P = 0.012); the median progression-free survival rate was 4.8 months in both groups. The time-to-treatment failure was 4.2 months for chemotherapy/cetuximab and 3.7 400 P&T® • July 2008 • Vol. 33 No. 7
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