Regorafenib Increases Progression-Free Survival in Patients with GIST

Chicago—Patients with gastrointestinal stromal tumors (GIST) whose disease progressed after taking 2 FDA-approved therapies (imatinib and sunitinib) had a significant increase in progression-free survival when taking regorafenib compared with placebo, according to a phase 3, multicenter, randomized, double-blind, placebo-controlled study.

Median progression-free survival, the primary end point, was 4.8 months in the regorafenib group compared with 0.9 months in the placebo group (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.19-0.39; P<.0001). Pre-specified subgroup analyses such as the line of cancer treatment, sex, and age all favored regorafenib. In addition, 52.6% of patients who took regorafenib had durable stable disease for ≥12 weeks compared with 9.1% who received placebo.

In late June, the FDA granted a priority review for regorafenib, an oral drug. The agency will make a decision on the drug’s approval within 6 months. Imatinib and sunitinib are the only FDA-approved drugs to treat patients with GIST.

George D. Demetri, MD, director, Ludwig Center at Dana-Farber/Harvard Cancer Center and Sarcoma Center, presented the results in a late-breaking oral abstract session at the American Society of Clinical Oncology 2012 Annual Meeting in June. Bayer Pharma AG, the manufacturer of the drug, funded the study.

“We feel that regorafenib has the potential now to fulfill an unmet medical need,” Dr. Demetri said. “It potentially represents a new standard of care in this patient population.”

Dr. Demetri said in the past decade scientists have gained a better understanding of the disease that has “truly translated into revolutionary improvements in patient care.” Before 2000, patients with metastatic disease survived 3 to 6 months, according to Dr. Demetri. Now, patients typically live >5 years.

The study included 199 patients ≥18 years of age with metastatic or unresectable GIST who failed treatment with imatinib and sunitinib. Exclusion criteria included prior treatment with any vascular endothelial growth factor receptor inhibitor other than sunitinib, another cancer 5 years prior to randomization, and cardiovascular dysfunction.

Patients were enrolled between January 2011 and June 2011 and randomized in a 2:1 ratio to receive 160 mg of regorafenib once daily plus best supportive care (n=133) or placebo plus best supportive care (n=66). During each cycle, they took the drug for 3 weeks and then were off the drug for a week. The groups were well balanced. The median age was 58 years, 64% of patients were male, and 68% were white.

The median overall survival was not reached in either group, with 29 deaths in the regorafenib group and 17 deaths in the placebo group (HR, 0.77; 95% CI, 0.42-1.41; P=.199). Dr. Demetri said the difference was not statistically significant because if a patient had disease progression, they could switch from placebo to regorafenib. Approximately 85% of patients crossed over.

“We did not seek statistical significance in the overall survival,” Dr. Demetri said. “This cross-over design gives us the ability to expect a lack of statistical significance.”

Based on investigator assessment, there was a significant progression-free survival benefit in patients who crossed over to regorafenib. This benefit was similar to patients who remained on regorafenib throughout the study.

The most common adverse events (AEs) in the regorafenib group were hand-foot skin reaction (occurring in 56.1% of patients), hypertension (48.5%), diarrhea (40.9%), and fatigue (38.6%). There were no significant grade 4 or grade 5 AEs. In addition, 6.1% of patients in the regorafenib group and 7.6% of patients in the placebo group discontinued the study because of treatment-emergent AEs.