Pharmacy & Therapeutics- July 2008 - (Page 399) MEETING HIGHLIGHTS: ASCO reported in only 4% of patients. Dr. Motzer concluded, “Everolimus is the first and only agent with established benefit for the treatment of patients with renal cell carcinoma after VEGF-R/TKI therapy. It should be the standard of care in this setting, pending approval.” Dr. Rini, an ASCO discussant, noted that given the absence of a real standard of care in this setting, the findings are of particular importance. “Everolimus significantly prolongs progression-free survival versus placebo across risk groups in TKI-refractory renal cell carcinoma,” he said, adding that prospective translational and clinical investigation is needed to define the most appropriate sequence of therapies. parable patients receiving ixabepilone. He said that his team had developed an equation to estimate tumor regression and growth rates that correlated with overall survival. Applying this analysis to findings from this trial, compared with mRCC patients previously treated with placebo at the National Cancer Institute, the team noted that ixabepilone reduced the growth rate constant of mRCC by two-fold. Dr. Huang concluded, “Ixabepilone is a potent microtubulestabilizing agent active in metastatic renal cell cancer. It induces tumor regression and retards tumor growth while prolonging overall survival.” Ixabepilone should be considered in combination with novel targeted therapies in future studies, he added. Ixabepilone (Ixempra) and Renal Cell Cancer • Hui Huang, MD, National Cancer Institute, Bethesda, Md. In a further clinical trial of therapy for RCC, ixabepilone (Ixempra, Bristol-Myers Squibb) demonstrated a two-fold reduction in the growth rate constant and a correlation of that rate with overall survival in patients with metastatic RCC (mRCC). Approved in 2007 for the treatment-resistant metastatic breast cancer, this epothilone B analogue, explained Dr. Huang, is a potent microtubule-stabilizing agent that is active in mRCC. “It induces both tumor regression, retards tumor growth, and prolongs overall survival,” he stated. The phase 2 trial included 87 patients with mRCC (65 men, 22 women; mean age, 56.1 years); 83% were Caucasian. Patients received ixabepilone 6 mg/m2 per day intravenously for five days every two weeks. Most of these patients (76.7%) had clear-cell histology, most (91%) had undergone nephrectomy, and 51.7% had received no previous systemic or medical therapy. These patients had extensive disease at the time of enrollment, with a median total of 20.1 cm of measurable disease, as assessed in the RECIST trial (Response Evaluation Criteria in Solid Tumors), and a mean total tumor size larger than 24.3 cm. Most subjects had none (43%) or only one (43%) of the following risk factors: poor performance status, high corrected calcium, or anemia. Metastatic disease sites were most commonly in the lung (in 71 of 87 patients) and lymph nodes (in 68 of 87 patients). The trial’s primary endpoint was efficacy. Patients received an average of 6.78 cycles (median, five cycles), with most patients (506 of 590) receiving a dose of 6 mg/m2 per day; 14 patients received some cycles at lower doses, and 20 patients received some cycles at higher doses. Dr. Huang noted that tissue was obtained before and after treatment in the first cycle to evaluate target engagement. The overall response rate was 12.6% (one complete response and 10 partial responses) with a median tumor shrinkage of 12% in the 37% of patients with measurable shrinkage. The median response duration was 5.5 months. Treatment-related adverse events were primarily grades 1 and 2. Grade 4 neutropenia was reported in 13 patients during 15 cycles. Treatment-related neuropathy was predominantly sensory and mild to moderate. Tissue analysis showed microtubule stabilization in 84% to 92% of serial biopsies. Dr. Huang also mentioned that in the registration trial for sorafenib (Nexavar), overall survival was 19.3 months—15.9 months for placebo and 19.25 months for com- Dasatinib (Sprycel) in Chronic Myelogenous Leukemia • Richard M. Stone, MD, Clinical Director, Adult Leukemia Program, Dana-Farber Cancer Institute, Boston, Mass. Long-term follow-up of the Src/Abl Tyrosine Kinase Inhibition Activity Research Trial (START-C) of dasatinib 70 mg (Sprycel, Bristol-Myers Squibb) revealed continuing efficacy for the tyrosine kinase inhibitor (TKI) among patients with chronic-phase chronic myelogenous leukemia (CP–CML), according to Dr. Stone. The phase 2 START-C trial included 387 patients with CP–CML who received dasatinib 70 mg twice daily, all of whom were resistant to or intolerant of therapy with imatinib (Gleevec, Novartis). Eighty-two percent had a prior complete hematological response to imatinib, 37% had a major cytogenetic response (MCyR), and 19% had a complete cytogenetic response (CCyR) before imatinib failed. Ten percent of the patients had undergone stem cell transplantation. Bcr–Abl mutations were present in 40%. Reporting two-year results, Dr. Stone said that CCyRs were achieved by 53% of patients; among these patients, 79% had a major molecular response (MMR), defined as more than a 3log reduction in Bcr–Abl burden. Overall, 62% had MCyRs, and 91% had complete hematological responses. Among those who entered the trial without a response at baseline (excluding imatinib-intolerant patients), rates were similar: complete hematological response, 87%; MCyR, 59%; and CCyR, 52%. The 91% progression-free survival rate at 12 months declined to 80% at 24 months, and the 97% overall survival rate at 12 months declined only slightly to 94% at 24 months. Isolating the imatinib-resistant patients, whom Dr. Stone called “the worst of the worst,” he found that they did almost as well as patients who had prior responses. Their CCyR rate was 45% (among these, 70% had MMRs), and their MCyR rate was 55%. Progression-free survival (88% at 12 months) declined only to 75% at two years, and overall survival declined from 96% to only 92% over the same period. “This is a drug that can deal with resistance,” Dr. Stone said. The likelihood of response was similar regardless of mutation status, except for the T3151 mutation. At 24 months, progression-free survival rates were 75% with any mutation and 83% without any mutations. Concerns that longer-term treatment would exacerbate cytopenias were not borne out. Rates of leukopenia at 12 months Vol. 33 No. 7 • July 2008 • P&T® 399
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