STIVAGRA APPROVED IN EUROPE

The targeted agent regorafenib (Stivarga, Bayer/Onyx) has been approved by the European Commission for use in adult patients with metastatic colorectal cancer.

Regorafenib is already approved for this indication in the United States, and recently also obtained approval in the US for the additional indication of gastrointestinal stromal tumors(GIST).

The product label carries a warning about hepatotoxicity, and a recommendation to monitor hepatic function prior to and during treatment. "Severe and sometimes fatal hepatotoxicty has been observed in clinical trials," it notes.

The metastatic colorectal cancer indication is based on results from the phase 3 trial known as CORRECT (colorectal cancer treated with regorafenib or placebo after failure of standard therapy), which were published in The Lancet in November 2012 (CORRECT abstract).

As previously reported onMedscape Medical News, the CORRECT study involved 760 patients who had progressed on all approved standard therapies. These included chemotherapy (fluoropyrimidine, oxaliplatin, and irinotecan), the vascular endothelial growth-factor monoclonal antibody bevacizumab (Avastin, Genentech), and, for patients who have wild-type KRAStumors, the epidermal growth-factor receptor monoclonal antibodies cetuximab (Erbitux, Eli Lilly) and panitumumab (Vectibix, Amgen).

Participants had progressed during or within 3 months of the last standard therapy, or had stopped taking standard therapy because of unacceptable adverse effects. They all received best supportive care and were randomized in a 2:1 ratio to receive regorafenib or placebo. The treatment regimen consisted of oral regorafenib 160 mg daily for 3 weeks, followed by a 1-week break; this was repeated as necessary.

There was a significant improvement in overall survival with regorafenib, compared with placebo (6.4 vs 5.0 months; hazard ratio [HR], 0.77; P = .0052). There was also a significant improvement in progression-free survival (1.9 vs 1.7 months; HR, 0.49; P < .0001) and disease control (41% vs 15%; P< .0001) with regorafenib.

This is the first time a significant benefit in overall survival has been seen in patients with treatment-refractory metastatic colorectal cancer treated with a small-molecule kinase inhibitor, noted the study authors, headed by Axel Grothey, MD, from the Mayo Clinic, in Rochester, Minnesota. (Such an effect has been seen with bevacizumab, but it is administered by intravenous infusion.)

"In view of these findings, regorafenib could be a new standard of care in late-stage metastatic colorectal cancer," the authors concluded.

However, in an accompanying editorial (comment), Tom Waddell, MD, and David Cunningham, MD, FRCP, both from the Royal Marsden Hospital, Sutton, Surrey, United Kingdom, wrote: "We find it difficult to agree with the authors' conclusion."

They pointed out that the median improvement in overall survival was only 1.4 months and in progression-free survival only 0.2 months. "The clinical benefits are modest," they wrote.

There is also a price to pay for this small benefit — literally; the initial cost of the drug is $9350 per 28-day cycle. In addition, more patients in the regorafenib group experienced grade 3 or 4 toxic effects than in the placebo group (54% vs 14%), Drs. Waddell and Cunningham note. These include hand-foot skin reaction, fatigue, diarrhea, hypertension, rash, or desquamation.

The curves for progression-free survival show that more than half of the patients had progressed by the computed tomography assessment at 8 weeks, they report. "Therefore, despite receiving treatment that would now cost almost $20,000 each, many patients did not seem to derive benefit from therapy but were exposed to potentially substantial toxic effects," they add.

The case for using this drug in metastatic colorectal cancer would be "greatly enhanced by the identification of a biomarker that allows selection of the subset of patients who really benefit from regorafenib," the editorialists commented. The study authors said that an analysis of biomarkers is under way.

The CORRECT study was sponsored by Bayer, the manufacturer of regorafenib. Dr. Grothey reports acting as a consultant for Genentech, Roche, Onyx, Bayer, ImClone, Bristol-Myers Squibb, and Sanofi, with honoraria from these, as well as research funding for clinical studies, all going to the Mayo Clinic. Dr. Waddell has disclosed no relevant financial relationships. Dr. Cunningham's research unit has received funding from Amgen, Roche, Celgene, AstraZeneca, Merck-Serono, and sanofi-aventis.

Lancet. Published online November 22, 2012. CORRECT abstract, comment