Gefitinib is often referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5-1 M or more, well within the IC 50 values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with <4% of the dose in the urine. After daily oral administration, steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses. Gefitinib effectiveness was demonstrated in a randomized, double-blind, Phase II, multicenter trial comparing two oral doses of gefitinib (250 versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0 -16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6 -18.6؉ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n ‫؍‬ 1093) or carboplatin plus paclitaxel (n ‫؍‬ 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese postmarketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in diseaserelated symptoms or incr...

Purpose: To describe the Food and Drug Administration (FDA) review and approval of sunitinib malate (Sutent). Sunitinib received regular approval for the treatment of gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate (Gleevec). Additionally, sunitinib received accelerated approval for the treatment of advanced renal cell carcinoma. Experimental Design: For the GIST indication, FDA reviewed data from a randomized, placebo-controlled trial with supportive evidence from a single-arm study. For the advanced renal cell carcinoma indication, FDA reviewed data from two single-arm studies of patients with cytokinerefractory metastatic renal cell carcinoma. Results: In patients with imatinib refractory or intolerant GIST, time-to-tumor progression of sunitinib-treated patients was superior to that of placebo-treated patients. Median time-to-tumor progression of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebotreated patients (P < 0.0001). Partial responses were observed in 6.8% of sunitinib-treated patients. In patients with metastatic renal cell carcinoma, partial responses were observed in 25.5% (95% confidence interval, 17.5, 34.9) and 36.5% (95% confidence interval, 24.7, 49.6) of patients treated with sunitinib. Median response durations were 27.1and 54 weeks. The most common adverse events attributed to sunitinib included diarrhea, mucositis, skin abnormalities, and altered taste. Reductions in left ventricular ejection fraction and severe hypertension were also more common in sunitinib-treated patients. Conclusions: On January 26, 2006, the FDA approved sunitinib for the treatment of patients with imatinib refractory or intolerant GIST. Accelerated approval was granted 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,, 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 handfoot 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.

The dose finding study of 54 patients showed a higher response rate for patients given 1.3 mg/m 2 compared with 1.0 mg/m 2 twice weekly for two of the 3-week schedule, but the study was too small for statistical dose-response comparisons. The most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness) in 65%, nausea (64%), diarrhea (51%), appetite decreased (including anorexia; 43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%, including peripheral sensory neuropathy and peripheral neuropathy aggravated), pyrexia (36%), vomiting (36%), and anemia (32%).Conclusions: The FDA granted marketing approval to Millennium Pharmaceuticals on May 13, 2003 for bortezomib for use as a single agent for the treatment of multiple myeloma in patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. Accelerated approval was based on a surrogate end point of response rate rather than clinical benefit, such as an improvement in survival. The recommended dose of bortezomib is 1.3 mg/m 2 administered twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). Accelerated approval was based on the results of two Phase II studies in a total of 256 patients and additional Phase I safety information. Mandated Phase IV study commitments to characterize clinical efficacy and safety more precisely are discussed.

LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Discuss the mechanism of action of the newly approved targeted cancer drug sunitinib.2. List the current approved oncology indications for this agent.3. Describe the pharmacology, metabolism, and side effect profile of sunitinib.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACT

Purpose: OnJune 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome^positive acute lymphoblastic leukemia (Ph + ALL) with resistance or intolerance to prior therapy including imatinib.This summary reviews the database supporting this approval. Experimental Design: Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph + ALL was major hematologic response. Results: The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph + ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached.The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph + ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention. Conclusions: This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph + ALL based on the rates and durability of cytogenetic and hematologic responses.

Purpose: To discuss vorinostat approval for treatment of cutaneous manifestations of advanced cutaneousT-cell lymphoma (CTCL). Experimental Design: Data from 1single-arm, open-label, multicenter pivotal trial and 11other 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 pruritis 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 61patients (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 SWATscore 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 pruritis 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 pruritis relief.

Chronic nicotine administration has been reported to increase acoustic startle response (ASR) amplitude in rats, which has been offered as evidence that some dosages of nicotine can enhance attention. The present experiments examined effects of acutely administered nicotine on amplitude and pre-pulse inhibition (PPI) of acoustic startle in rats. PPI, the decrease in ASR amplitude by a stimulus preceding the startle-eliciting event, reflects pre-attentive neural processes underlying sensory gating. Nicotine had a biphasic dose effect on startle amplitude, with increases at lower dosages (0.01 mg/kg) and decreases at higher dosages (0.5-5.0 mg/kg SC). Lower dosages of nicotine (0.001-0.01 mg/kg) increased PPI and the increase at 0.001 mg/kg occurred independently of changes in ASR amplitude. These results confirm that increases in PPI are not dependent upon changes in ASR amplitude. Results are consistent with nicotine's enhancements of performance on cognitive tasks in humans and are the first reported use of the PPI paradigm to model such effects. These findings indicate that ASR paradigms are useful to study effects of nicotine.