Regorafenib Approved to Treat Metastatic Colorectal Cancer

The US Food and Drug Administration (FDA) approved regorafenib (Stivarga, Bayer HealthCare Pharmaceuticals, Inc.) for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemo­therapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. Regorafenib approval was granted on September 27, 2012.

The FDA approval was based on the results of Study 14387, an international, randomized, double-blind, placebo-controlled trial that enrolled 760 patients who had been previously treated for mCRC. All the patients in the trial had received treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and with bevacizumab. Of the patients with KRAS wild-type tumors, all but 1 received panitumumab or cetuximab.

Patients randomized to the regorafenib arm received regorafenib 160 mg orally once daily for the first 21 days of each 28-day cycle plus best supportive care. Patients in the control group received matching placebo with best supportive care.

Patients in the regorafenib arm had a statistically significant prolongation in overall survival (hazard ratio [HR] 0.77; 95% confidence interval [CI]: 0.64, 0.94; P= .0102). The median survival time was 6.4 months (95% CI: 5.8, 7.3) in the regorafenib arm and 5.0 months (95% CI: 4.4, 5.8) in the placebo arm.

There was also a statistically significant improvement in progression-free survival (HR 0.49; 95% CI: 0.42, 0.58; P <.0001). In the regorafenib arm, the median progression-free survival was 2.0 months (95% CI: 1.9, 2.3). Median progression-free survival was 1.7 months (95% CI: 1.7, 1.8) in the placebo arm. No difference in overall response rate was observed. Partial responses were experienced by 5 patients (1%) in the regorafenib arm and by 1 patient (0.4%) in the placebo arm.

Asthenia/fatigue, decreased appetite and food intake, hand-foot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension, and dysphonia were the most frequently observed adverse drug reactions (≥30%) in patients receiving regorafenib. The most serious adverse drug reactions in patients receiving regorafenib were hepatotoxicity, hemorrhage, and gastrointestinal perforation. Regorafenib was approved with a boxed warning describing the risk of hepatotoxicity.

Regorafenib was reviewed under the FDA’s priority review program that provides an expedited 6-month review for drugs that offer major advances in treatment or that provide treatment when no adequate therapy exists. Regorafenib was approved 1 month ahead of the product’s prescription drug user fee goal date of October 27, 2012, the date the FDA was scheduled to complete review of the drug application.

Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evalua­tion and Research, noted that regorafenib “is the latest colorectal cancer treatment to demonstrate an ability to extend patients’ lives and is the second drug approved for patients with colorectal cancer in the past two months.”

Potentially Contaminated Medication From NECC
On October 4, 2012, the FDA and the US Centers for Disease Control and Prevention (CDC) recommended that all healthcare professionals cease use and remove from pharmaceutical inventory any product produced by the New England Com­pounding Center (NECC). The FDA and CDC issued the health advisory after a multistate outbreak of Aspergillus meningitis among patients who received an epidural steroid injection of preservative-free methylprednisolone acetate suspension prepared by NECC.

On October 6, NECC announced a voluntary recall of all products currently in circulation that were compounded at and distributed from its facility in Framingham, Massachusetts, stating that it was taking this action “out of an abundance of caution due to the potential risk of contamination, and in cooperation with an investigation being conducted by the U.S. Food and Drug Administration, the Centers for Disease Control and Prevention and the Massachusetts Board of Registration in Pharmacy.”

The situation with NECC has focused attention on the regulation of pharmaceutical compounding companies. Currently, the FDA has limited authority over the operations of compounding pharmacies, which are mainly regulated at the state level. According to the International Academy of Compounding Pharmacists, there are approximately 7500 pharmacies in the United States that specialize in advanced compounding services, with approximately 3000 providing sterile compounding.