Pharmacy & Therapeutics - February 2009 - (Page 102)

MEETING HIGHLIGHTS: San Antonio Breast Cancer Symposium In the highest-dose everolimus arm, at 5 mg daily, dose reductions were frequent because of dose-limiting toxicities, including grade 3 and 4 neutropenia, grade 3 stomatitis, grade 3 fatigue, grade 2 dermatitis acneiform, and grade 3 anorexia. The most feasible dose was determined to be 30 mg weekly. For 34 evaluable patients, Dr. Fasolo reported one complete response (3%), five partial responses (15%), stable disease in 21 patients (62%), and disease control in 27 (79%). Dr. O’Regan concluded, “Data presented at this meeting affirm the potential of RAD001 to reverse Herceptin resistance and to restore patient response to treatment.” aging adverse effects. Only nine patients had to discontinue treatment. “The combination of letrozole and lapatinib offers a first-line orally active treatment approach for postmenopausal women with hormone receptor–positive, HER-2–positive metastatic breast cancer,” Dr. Johnston said. He qualified his conclusion, noting that suitability for endocrine therapy is determined by the distribution of metastatic sites, performance status, and the absence of symptomatic or rapidly progressive visceral disease. Lapatinib (Tykerb) plus Letrozole (Femara) or Letrozole Alone for Postmenopausal Hormone Receptor–Positive Metastatic Breast Cancer • Stephen Johnston, PhD, Royal Marsden NHS Foundation Trust, U.K. • Carlos Arteaga, MD, Vanderbilt–Ingram Cancer Center, Nashville, Tennessee First results from the EGF 2008 clinical trial evaluating letrozole (Femara, Novartis) plus lapatinib (Tykerb, GlaxoSmith Kline) in postmenopausal women with hormone receptor– positive (HR+) and HER-2+ metastatic breast cancer indicated that the combination was active as a first-line therapy. Dr. Atreaga, moderator of the meeting’s press conference, commented that the study was likely to have an impact on the standard of care for this population. Endocrine resistance is associated with activation of the growth factor receptors epidermal growth factor receptor (EGF-R) and HER-2. Resistance to tamoxifen (Nolvadex, AstraZeneca) occurs in the presence of positive estrogen receptor (ER+) and HER-2+ status, and acquired expression of EGF-R/HER-2 may account for relapses. Complex crosstalk between EGF-R/HER-2 and ER pathways suggests that dual targeting may overcome endocrine resistance. Lapatinib, a small-molecule tyrosine kinase inhibitor (TKI) that blocks both EGF-R and HER-2, has demonstrated synergy with tamoxifen in models of endocrine resistance. A randomized phase 3, double-blind, controlled trial enrolling 1,286 postmenopausal women with previously untreated ER+ and/or progesterone receptor–positive (PgR+) metastatic breast cancer (stage IIIb/IIIc/IV) included a subgroup of 219 women with HER-2+ status. They were randomly assigned to receive letrozole 2.5 mg daily plus placebo or lapatinib 1,500 mg daily. Median progression-free survival was three months for the women receiving letrozole/placebo and 8.2 months for those receiving letrozole/lapatinib. At 42 months, 82% of the patients had disease progression or had died in the letrozole-alone group, compared with 79% receiving the combination (hazard ratio [HR], 0.71, P = 0.019). The clinical benefit rate—complete responses plus partial responses plus stable disease at six months or more—in this population was 29% for letrozole/placebo and 48% for letrozole/lapatinib (P = 0.003). The overall response rates (complete and partial responses) were 15% and 28%, respectively (P = 0.021). Typical low-grade diarrhea and rash with the letrozole/lapatinib combination were treated by interrupting or reducing the dose or by man- Sequential Letrozole (Femara) and Tamoxifen (Nolvadex) for Postmenopausal, EndocrineResponsive Breast Cancer • Henning Mouridsen, MD, PhD, Professor, Department of Oncology, Copenhagen University Hospital, Denmark Updated results of the Breast International Group trial (BIG 1-98) suggest that for postmenopausal women with endocrineresponsive breast cancer, overall survival might be better with letrozole (Femara) than with tamoxifen (Nolvadex) and that women at high risk for early recurrence should receive firstline letrozole therapy. Preliminary results of BIG 1-98, published in 2005, demonstrated that five years of first-line therapy with letrozole significantly prolonged disease-free survival (i.e., the time from randomization to the first occurrence of relapsing invasive breast cancer, invasive contralateral breast cancer, a second non-breast malignancy, or death from any cause) and reduced the risk of relapse in distant sites, compared with five years of initial tamoxifen therapy. BIG 1-98, a multinational trial conducted in 27 countries, enrolled 8,028 women. These patients were randomly assigned to one of four treatment arms: • tamoxifen for five years • letrozole for five years • tamoxifen for two years, followed by letrozole for three years • letrozole for two years, followed by tamoxifen for three years Other patients received monotherapy with tamoxifen or letrozole. The primary endpoint was disease-free survival. Dr. Mouridsen’s presentation focused on letrozole and tamoxifen given in sequence, compared with letrozole alone (median follow-up, 71 months), and updated the comparison of letrozole alone with tamoxifen alone (median follow-up, 76 months). That latter comparison was complicated by the fact that after unblinding of the tamoxifen-alone arm, 619 patients (25.2%) selectively crossed over to letrozole monotherapy, mostly in the third to fifth years. In the update of the monotherapy arms (N = 4,922), diseasefree survival significantly favored letrozole (HR = 0.88, P = 0.03). A favorable trend was noted also in overall survival (HR = 0.87, P = 0.08). The time to distant recurrence significantly favored letrozole at the 0.05 level (HR = 0.85). Analyses censoring crossovers produced stronger letrozole-favoring hazard ratios (disease-free survival, 0.84; overall survival, 0.81; and 102 P&T® • February 2009 • Vol. 34 No. 2

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - February 2009

Pharmacy & Therapeutics - February 2009 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Pushing an Expanded Role for Pharmacists Better Asthma Management with Advanced Technology Pharmaceutical Approval Update 58th Annual Meeting, American Society of Human Genetics, 2008 American Society of Hematology, 50th Annual Meeting and Exposition 2008 San Antonio Breast Cancer Symposium Stahl’s Essential Psychopharmacology, 3rd Edition Author Guidelines

Pharmacy & Therapeutics - February 2009

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