Regorafenib Approved for Gastrointestinal Stromal Tumors

Zosia Chustecka

February 25, 2013

The indication for the oral targeted agent regorafenib (Stivarga, Bayer) has been expanded by the US Food and Drug Administration (FDA); it is now approved for the treatment of gastrointestinal stromal tumors (GIST). Specifically, it is indicated for use in patients with tumors that cannot be surgically removed and no longer respond to imatinib (Gleevec) and sunitinib (Sutent), the 2 other FDA-approved treatments for this disease.

Regorafenib is already marketed for use in metastatic colorectal cancer; it was approved for that indication in September 2012.

This is "the third drug approved by the FDA to treat gastrointestinal stromal tumors," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research, in a statement. "It provides an important new treatment option for patients with GIST in whom other approved drugs are no longer effective," he explained.

Under the FDA's priority review program, regorafenib was granted orphan product designation because it is intended to treat a rare disease.

"Strong Case" for Use in GIST

The GIST indication was approved on the basis of data from the GRID (GIST– Regorafenib in Progressive Disease) trial (Lancet. 2013;381:295-302). This study, headed by George Demetri, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, involved 199 patients with metastatic or unresectable GIST who had progressed after treatment with imatinib and sunitinib. Patients were treated with best supportive care and randomized in a 2:1 ratio to either regorafenib (160 mg daily for 3 weeks followed by a 1-week break) or placebo.

There was a statistically significant improvement in progression-free survival with regorafenib, compared with placebo (4.8 vs 0.9 months; hazard ratio, 0.27; P < .0001).

For the indication metastatic colorectal cancer, regorafenib was approved on the basis of the pivotal CORRECT trial (Lancet. 2013;381:303-312), which was published in the same issue as the GRID trial.

In a comment that accompanied the 2 studies (Lancet. 2013;381:273-275), Tom Waddell, MD, and David Cunningham, MD, FRCP, both from the Royal Marsden Hospital, Sutton, Surrey, United Kingdom, write that there was a "much earlier separation of curves" in the GRID trial than in the CORRECT trial.

However, there was no significant difference in overall survival in the GRID trial, as there was in the CORRECT trial. Drs. Waddell and Cunningham explain that this was "probably attributable to planned extensive crossover to regorafenib" (85% of patients in the placebo group went on to take regorafenib when their disease progressed).

Nevertheless, the editorialists conclude that there is a "strong" case for the routine use of regorafenib in patients who have failed imatinib and sunitinib, whereas the case for using regorafenib in metastatic colorectal cancer is "less compelling."

The most common adverse effects reported with regorafenib are weakness and fatigue, hand-foot syndrome, diarrhea, loss of appetite, high blood pressure, mouth sores, infection, changes in voice volume or quality, pain, weight loss, stomach pain, rash, fever, and nausea.

Serious adverse events are rare and reported in less than 1% of patients. These include liver damage, severe bleeding, blistering and peeling of skin, very high blood pressure requiring emergency treatment, heart attacks, and intestinal perforations.

The GRID and CORRECT trials were sponsored by Bayer, the manufacturer of regorafenib. Several coauthors of the 2 papers report being employed by Bayer or report relationships with pharmaceutical companies, as detailed in the papers. Dr. Demetri reports serving as a consultant to Novartis, Pfizer, Lilly, Infinity, GlaxoSmithKline, Plexxikon, Koltan, and Blueprint Medicines. 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.