Regorafenib Lengthens Survival in Colorectal Cancer With KRAS Mutations

CHICAGO – The investigational multikinase inhibitor regorafenib continues to produce small but significant improvements in progression-free survival along with a trend toward better overall survival of metastatic colorectal cancer bearing KRAS mutations.

Among patients with wild-type KRAS in the phase III, randomized CORRECT trial, progression-free survival was 2.0 months with regorafenib and best supportive care, compared with 1.8 months with placebo (hazard ratio, 0.475; 95% confidence interval, 0.362-0.623), Dr. Eric Van Cutsem reported at the annual meeting of the American Society of Clinical Oncology.

The respective medians were 1.9 and 1.7 months (HR, 0.525; 95% CI, 0.425-0.649) among patients with KRAS mutations conferring resistance to EGFR (epidermal growth factor receptor) inhibitors, said Dr. Van Cutsem, a professor of gastrointestinal oncology at University Hospital Leuven (Belgium) in Gasthuisberg.

Likewise, the median overall survival favored regorafenib in patients with wild-type KRAS, reaching 7.3 months in the experimental arm vs. 5.0 months among similar patients assigned to placebo (HR, 0.653; 95% CI 0.476-0.895). Among patients with KRAS mutations, the respective medians were 6.2 and 5.1 months (HR, 0.867; 95% CI, 0.670-1.123).

"Regorafenib increases overall survival and progression-free survival in patients with metastatic colorectal cancer who have failed current standard therapies. The benefit is shown across prespecified subgroups.

"Side effects are manageable in this patient population, and therefore it’s fair to conclude that regorafenib is a new potential standard of care for patients with chemorefractory metastatic colorectal cancer," Dr. Van Cutsem said.

Bayer Healthcare announced that it has applied in Europe and the United States for approval of regorafenib for patients with metastatic colorectal cancer based on these results. The company said at the end of June that the Food and Drug Administration granted priority review, which would require a decision in 6 months.

The CORRECT (Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy) trial randomized 760 patients: 505 to regorafenib plus best supportive care, and 255 to placebo plus best supportive care. More than half had KRAS mutations; nearly half had metastatic disease.

Investigators reported the primary and secondary end points of the study at a symposium on gastrointestinal cancers sponsored by ASCO in January 2012.

Regorafenib added a median benefit of just 1.4 months, compared with placebo plus best supportive care (6.4 months vs. 5.0 months; hazard ratio, 0.77; P = .0052), lead investigator Dr. Axel Grothey, professor of oncology at the Mayo Clinic in Rochester, Minn., said at that meeting. Although the added time was short, he noted, all participants were running out of options after the failure of standard therapies, including bevacizumab (Avastin) and EGFR inhibitors.

In the new presentation at the ASCO annual meeting, Dr. Van Cutsem reiterated those data and gave updated information on response rates and prespecified subgroup analyses.

There were no complete responses for patients on either the active drug or placebo, and only 1% of the 505 patients on regorafenib had a partial response, compared with 0.4% of 255 patients on placebo.

More patients on regorafenib had stable disease (42.8% vs. 14.5%), and fewer progressed while on the drug (49.5% vs. 80.0%). The disease control rate (defined as partial responses and stable disease combined at least 6 weeks after randomization) was significantly better for regorafenib (P less than .000001), Dr. Van Cutsem noted.

Regorafenib was superior to placebo in overall survival among men and women, patients younger than 65 years, those with baseline ECOG (Eastern Cooperative Oncology Group) performance status scores of 0 or 1, and patients with the primary disease site in the colon.

The most frequent grade 3 adverse events with regorafenib were hand-foot skin reactions, fatigue, diarrhea, hypertension, and rash. Drug-related deaths occurred in 1% of patients on regorafenib, compared with none in patients on placebo.

Speaking about the overall trial results, the invited discussant Dr. Chris Garrett of the University of Texas M.D. Anderson Cancer Center in Houston said, "I think [regorafenib] should be an option for patients with chemotherapy-refractory metastatic colorectal cancer who have a good performance status. However, patients should be made aware of the toxicities that may come with it. In the future, hopefully, biomarker studies will help us optimize which patients get the most benefit from this therapy."

The CORRECT trial was sponsored by Bayer HealthCare AG in Leverkusen, Germany. Dr. Van Cutsem has received research funding from the company. Dr. Garrett reported having no relevant financial disclosures.