On August 31, 2012, the U. S. Food and Drug Administration approved enzalutamide (XTANDI® Capsules, Medivation, Inc. and Astellas Pharma US, Inc.), for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.
The approval was based on a single randomized, placebo-controlled, multicenter trial enrolling 1199 patients with metastatic castration-resistant prostate cancer who had received prior docetaxel. Patients were randomly allocated to receive enzalutamide 160 mg orally once daily (N = 800) or placebo (N = 399). Study treatment continued until disease progression, initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients were required to continue androgen deprivation therapy and were allowed, but not required, to continue or initiate glucocorticoids during the study period. Forty-eight percent (48%) of patients on enzalutamide and 46% on placebo received glucocorticoids.
The primary efficacy endpoint was overall survival (OS). At the pre-specified interim analysis after 520 events, a statistically significant improvement in OS [HR 0.63 (95% CI: 0.53, 0.75), p < 0.0001, log rank test] was observed. The median OS was 18.4 and 13.6 months in the enzalutamide and placebo arms, respectively.
The most common (≥5%) grade 1-4 adverse reactions included asthenia or fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3-4 adverse reactions were reported in 47% of patients treated with enzalutamide and in 53% of those on placebo.
Seizures occurred in 0.9% of patients on enzalutamide. No patients on the placebo arm experienced seizures. In the clinical trial, patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizures were excluded from the clinical trial. The safety of enzalutamide in patients with predisposing factors for seizures is unknown.
The recommended dose and schedule for enzalutamide is 160 mg orally once daily.
Friday, August 31, 2012
Monday, August 6, 2012
On August 3, 2012, the U. S. Food and Drug Administration approved ziv-aflibercept injection (ZALTRAP®, Sanofi U.S., Inc.) for use in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin containing regimen. Ziv-aflibercept (previously known as aflibercept) is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2 that are fused to the Fc portion of the human IgG1 immunoglobulin.
This approval is based on the results of a randomized, double-blind, placebo-controlled, global, multicenter trial enrolling patients with mCRC that progressed during or within 6 months of receiving oxaliplatin-based combination chemotherapy, with or without prior bevacizumab.
The Phase 3 trial accrued 1226 patients who were randomly allocated (1:1) to receive FOLFIRI (irinotecan 180 mg/m2 IV infusion over 90 minutes, leucovorin 400 mg/m² IV infusion over 2 hours, followed by 5-FU 400 mg/m² IV bolus, followed by 5-FU 2400 mg/m² continuous IV infusion over 46-hours) with either ziv-aflibercept (N=612) or placebo (N=614). Ziv-aflibercept was administered at a dose of 4 mg/kg IV infusion over 1 hour prior to FOLFIRI. The treatment cycles on both arms were repeated every 2 weeks. Patients were treated until disease progression or unacceptable toxicity. The primary efficacy endpoint was overall survival (OS). Treatment assignment was stratified by the ECOG performance status and prior exposure to bevacizumab.
Median age of randomized patients was 61 years, 59% were men, and 98% had an ECOG performance status of 0 or 1. All patients had received prior oxaliplatin treatment. A statistically significant improvement in OS was observed in patients receiving FOLFIRI plus ziv-aflibercept compared to those receiving FOLFIRI plus placebo [HR 0.82 (95% CI: 0.71, 0.94), p=0.0032, stratified log-rank test]. The median OS was 13.5 and 12.06 months for patients on the ziv-aflibercept and placebo arms, respectively. Median progression-free survival in the ziv-aflibercept arm was 6.9 compared to 4.7 months in the placebo arm [HR 0.76 (95% CI: 0.66, 0.87), p=0.00007].
The most common adverse reactions, (all grades), occurring in greater than or equal to 20% of patients in the ziv-aflibercept plus FOLFIRI arm (with greater than or equal to 2% difference between arms) were leukopenia, diarrhea, neutropenia, proteinuria, increased AST and ALT, stomatitis, fatigue, thrombocytopenia, hypertension, decreased weight, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine, and headache. The most common grade 3-4 adverse reactions (greater than or equal to 5%) reported at a higher incidence in the ziv-aflibercept plus FOLFIRI arm (greater than or equal to 2% difference between arms) were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.
Severe and sometimes fatal hemorrhages, including gastrointestinal hemorrhages, have been reported in patients receiving ziv-aflibercept. Grade 3-4 hemorrhagic events occurred in 2.9% of patients receiving FOLFIRI plus ziv-aflibercept compared with 1.7% of those receiving FOLFIRI plus placebo. In addition to hemorrhage, the ziv-aflibercept label contains a Boxed Warning for the serious adverse reactions gastrointestinal perforation and compromised wound healing.
Arterial thromboembolic events were observed in 1.7% and 2.6% of patients in the placebo and ziv-aflibercept containing arms, respectively. Venous thromboembolic events were also observed more frequently with ziv-aflibercept: 9% patients in the ziv-aflibercept-containing arm compared to 7% in the placebo-containing arm. Fistula formation and reversible posterior leukoencephalopathy syndrome have also been reported in patients who received ziv-aflibercept.
The recommended ziv-aflibercept dose and schedule is 4 mg/kg administered as a 60-minute IV infusion every 2 weeks in combination with the FOLFIRI regimen.