Pharmacy & Therapeutics- July 2008 - (Page 403) Meeting Highlights: ASCO months for chemotherapy alone (HR = 0.860, P = 0.015). Although median overall survival was longer for 121 Asians (19.5 months) than for 946 Caucasians (9.6 months) and for the chemotherapy-alone group than for the chemotherapy/ cetuximab group, the small sample size in this trial did not allow for a definitive conclusion. The overall survival benefit for chemotherapy/cetuximab among Caucasians, when considered alone, was greater than in the overall group; median overall survival was 10.5 months vs. 9.1 months for chemotherapy alone (HR = 0.803, P = 0.003). The benefit was also noted for patients with adenocarcinoma, squamous cell carcinoma, and other histological diseases. Side effects, Dr. Pirker said, were as expected and were manageable, with acne-like rash as the main cetuximab-related adverse event. He concluded that the cetuximab/chemotherapy regimen demonstrated better overall survival than chemotherapy alone in patients with advanced EGF-R–expressing NSCLC. He added, “Cetuximab added to a platinum-based chemotherapy sets a new standard for the first-line treatment of patients with advanced NSCLC.” Dr. Lynch, an ASCO discussant, called the FLEX benefit “clinically meaningful,” but raised concerns about the 22% fever/neutropenia rate. He also commented that patient selection through biomarker analysis “may improve the cost effectiveness of this agent.” • viable osteoclasts (tartrate-resistant acid phosphatase isoform 5b [TRAP 5b]) • bone-specific alkaline phosphatase (BSAP) After 25 weeks of treatment, sCTx levels were reduced by about 80% with both IV bisphosphonates and denosumab in treatment-naive patients and by about 50% and 80%, respectively, with IV bisphosphonates and denosumab in patients with previous exposure to IV bisphosphonates. TRAP 5b levels were reduced by 40% and by 60% in treatment-naive patients who received IV bisphosphonates and denosumab and by about 10% and 70% with IV bisphosphonates and denosumab in patients who had previously been treated with IV bisphosphonates. “The marked difference in TRAP 5b levels suggests the persistence of functioning osteoclasts despite treatment with IV bisphosphonates,” Dr. Gralow commented. BSAP reductions were similar (40%) for both treatment groups and with both agents. Rates of adverse events were similar between the groups. For these two studies, Dr. Gralow concluded that denosumab’s inhibition of the RANKL pathway suppressed bone resorption regardless of patients’ previous exposure to IV bisphosphonates. She said, “In patients still having active turnover despite being on IV bisphosphonates, being switched to denosumab gives a really dramatic and rapid decrease in markers of bone turnover. Ultimately, the combination of the two agents might prove to be more useful—hitting the osteoclasts in a couple of ways.” IV Bisphosphonates versus Denosumab (AMG-162) In Preventing Bone Turnover • Julie Gralow, PharmD, University of Washington Cancer Care Alliance, Seattle, Wash. Regardless of prior intravenous (IV) use of bisphosphonates, cancer patients with various tumor types who received denosumab, an investigational agent, had decreased markers of bone turnover, according to Dr. Gralow. She noted that although IV bisphosphonates are the current standard of care, “they have limitations in both efficacy and safety.” Specifically, regarding safety, IV bisphosphonates are associated with renal toxicity; first-infusion effects, including fever, and chills; and osteonecrosis of the jaw (ONJ). Denosumab is a fully human monoclonal antibody that binds and neutralizes receptor activator for nuclear factor-kappa B ligand (RANKL). RANKL accelerates bone turnover and has been found to have harmful effects on bone volume and strength. Denosumab has demonstrated no renal toxicity, no first-infusion effects, and no ONJ to date, Dr. Gralow said. Her study was designed to test whether earlier exposure to IV bisphosphonates affected denosumab’s ability to induce bone turnover suppression. Dr. Gralow compared results from studies of denosumab versus IV bisphosphonates in 255 bisphosphonates-naive patients (with breast cancer and bone metastases) and results in men or women (n = 111) with solid tumors and bone metastases or multiple myeloma, with high levels of bone resorption despite previous IV bisphosphonate therapy. The key endpoints were three markers of bone turnover: • serum C-telopeptide (sCTx) Ipilimumab for Melanoma • Steven O’Day, MD, Angeles Clinic and Research Institute, Santa Monica, CA • Omid Hamid, MD, Angeles Clinic and Research Institute, Santa Monica, Calif. • Jeffrey Weber, MD, PhD, Director, Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center, Tampa, Fla. Among nearly 500 patients with advanced melanoma who were treated with the investigational agent ipilimumab (MDX010, Bristol-Myers Squibb) in pivotal trials, tumor growth was stopped within the first 12 weeks in about 30% of patients, followed by tumor shrinkage. After that, 10% to 20% of patients who had continued at first to progress then developed later responses, according to Dr. O’Day. Ipilimumab is a fully human, monoclonal antibody directed against CTLA-4, a key negative regulator of T-cell response to tumor-associated antigens. Phase 3 trials of first-line ipilimumab with or without chemotherapy in melanoma are now under way. The objective of Dr. O’Day’s open-label, multicenter study, which included 155 patients (median age 59 years, 52% male) with unresectable stage III or IV malignant melanoma, was to estimate the best overall response rate, as assessed by World Health Organization criteria. Patients received ipilimumab induction dosing of 10 mg/kg every three weeks for four cycles, with maintenance dosing every 12 weeks starting at week 24. Overall sur vival and sur vival at one year were continued on page 425 Vol. 33 No. 7 • July 2008 • P&T® 403
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