Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma.

PURPOSE: To discuss vorinostat approval for treatment of cutaneous manifestations of advanced cutaneous T-cell lymphoma (CTCL). EXPERIMENTAL DESIGN: Data from 1 single-arm, open-label, multicenter pivotal trial and 11 other trials submitted to support the new drug application for vorinostat in the treatment of advanced primary CTCL were reviewed. The pivotal trial assessed responses by changes in overall skin disease score using a severity-weighted assessment tool (SWAT). Vorinostat could be considered active in CTCL if observed response rate was at least 20% and the lower bound of the corresponding 95% confidence interval (95% CI) excluded 5%. Patients reported pruritus relief using a questionnaire and a visual analogue scale. RESULTS: The pivotal trial enrolled 74 patients with stage IB or higher CTCL. Median number of prior treatments was 3, and 61 patients (82%) had stage IIB or higher disease. The objective response rate in the skin disease assessed by change in the overall SWAT score from the baseline was 30% (95% CI, 18.5 to 42.6) in patients with stage IIB or higher disease. Median response duration (end of response defined by 50% increase in SWAT score from the nadir) was 168 days. Median time to tumor progression was 148 days for overall population and 169 days for patients with stage IIB or higher disease. Assessment of pruritus relief was considered unreliable. CONCLUSIONS: Vorinostat showed activity in CTCL, and skin responses were a clinical benefit. Vorinostat was approved for treatment of cutaneous manifestations of CTCL. A nonblinded, single-arm trial did not allow a reliable assessment of pruritus relief.

Sorafenib for the treatment of advanced renal cell carcinoma.

PURPOSE: This report describes the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar, BAY43-9006), a new small-molecule, oral, multi-kinase inhibitor for the treatment of patients with advanced renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: After meeting with sponsors during development studies of sorafenib, the FDA reviewed the phase 3 protocol under the Special Protocol Assessment mechanism. Following new drug application submission, FDA independently analyzed the results of two studies in advanced RCC: a large, randomized, double-blinded, phase 3 international trial of single-agent sorafenib and a supportive phase 2 study. RESULTS: In the phase 3 trial, 902 patients with advanced progressive RCC after one prior systemic therapy were randomized to 400 mg sorafenib twice daily plus best supportive care or to a matching placebo plus best supportive care. Primary study end points included overall survival and progression-free survival (PFS). A PFS analysis, pre-specified and conducted after a total of 342 events, showed statistically significant superiority for the sorafenib group (median = 167 days) compared with that for the controls (median = 84 days, log-rank P < 0.000001); the sorafenib/placebo hazard ratio was 0.44 (95% confidence interval, 0.35-0.55). Results were similar regardless of patient risk score, performance status, age, or prior therapy. The (partial) response rate to sorafenib was 2.1%. Overall survival results are preliminary. The principal toxicities in the sorafenib patients included reversible skin rashes in 40% and hand-foot skin reaction in 30%; diarrhea was reported in 43%, treatment-emergent hypertension was reported in 17%, and sensory neuropathic changes were reported in 13%. Grade 4 adverse events were uncommon. Grade 3 adverse events were hand-foot skin reaction (6%), fatigue (5%), and hypertension (3%). Laboratory findings included asymptomatic hypophosphatemia in 45% of sorafenib patients versus 11% in the placebo arm and elevation of serum lipase in 41% of sorafenib patients versus 30% in the placebo arm. Grade 4 pancreatitis was reported in two sorafenib patients, although both patients subsequently resumed sorafenib, with one at full dose. CONCLUSIONS: Sorafenib received FDA regular approval on December 20, 2005 for the treatment of advanced RCC based on the persuasive magnitude of improvement in PFS with acceptable safety. The recommended dose is 400 mg (two 200-mg tablets) twice daily taken either 1 h before or 2 h after meals. Adverse events were accommodated by temporary dose interruptions or reductions.

Fulvestrant in postmenopausal women with advanced breast cancer.

PURPOSE: Patients with hormone-sensitive breast cancer who have responded to tamoxifen (TAM) may receive additional benefit from a second endocrine agent after progression or relapse after TAM therapy. Fulvestrant (FVT; Faslodex; i.m. injection, ICI 182,780; AstraZeneca Pharmaceuticals, Wilmington, DE) was developed as a selective antagonist of estrogen. In postmenopausal women, FVT is reported to inhibit the proliferative effects of estrogen on sensitive tissues and has no apparent measurable estrogenic activity. In this report, we describe the data and analyses supporting marketing approval for FVT by the United States Food and Drug Administration (FDA). EXPERIMENTAL DESIGN: The FDA review of 16 clinical trials and 6 pharmacokinetic trials, as well as preclinical pharmacology and chemistry data, are described. The bases for marketing approval are summarized. RESULTS: Toxicology studies in the mouse, rat, and dog showed minimal toxicity except for antiestrogenic effects. Because of FVT aqueous insolubility, an i.m. formulation, given at monthly intervals, was selected for clinical studies. Pharmacokinetic studies demonstrated sustained concentrations with monthly injection. In in vitro studies FVT was extensively metabolized, primarily by hepatic cytochrome P450 3A4. Phase I studies showed minimal toxicity, and the maximal dose (250 mg) was limited by FVT solubility. In two Phase III trials, 851 patients were randomized to either 250 mg FVT i.m. monthly or to anastrozole (ANZ) 1 mg p.o. daily. Ninety-six percent of patients had received TAM previously for early (adjuvant treatment) or advanced breast cancer. Response rates (RR) were 17% for both FVT and ANZ study arms in the North American trial, and were 20% versus 15% for FVT versus ANZ, respectively, in the European trial. There were no observed differences between study arms with respect to time to progression or survival. The most common FVT adverse events reported as potentially treatment-related were injection site reactions and hot flashes. CONCLUSIONS: FVT was approved on April 25, 2002 by the FDA for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy. The recommended dose is 250 mg i.m. monthly as a single 5 ml injection or as two concurrent 2.5 ml injections into the buttocks. Approval was based on results of two randomized trials comparing response rates and time to progression of FVT- and ANZ-treated patients. Complete prescribing information is available on the FDA website.