Regorafenib Potential Treatment for Metastatic Colorectal Cancer Failing Standard Treatment Options

Axel Grothey, MD

For patients with metastatic colorectal cancer (mCRC) that has progressed on multiple lines of standard therapy, regorafenib may be a new treatment option that achieves disease control, according to results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) presented at the ASCO 2012 Gastrointestinal Cancers Symposium.

“Regorafenib increased overall survival versus placebo in patients with mCRC who have run out of other treatment options. This is the first small-molecule kinase inhibitor with proof of efficacy in colorectal cancer and is a potential new standard of care in this patient population,” stated lead author Axel Grothey, MD, Mayo Clinic, Rochester, Minnesota.

Regorafenib is an experimental oral multikinase inhibitor that blocks kinases involved in tumor cell proliferation, new blood vessel formation, and the interaction between tumor cells and the micro-environment. Preliminary evidence suggested that the drug has acceptable side effects and antitumor effects in mCRC.

CORRECT randomized 760 patients with mCRC progressing after previous standard therapies in a 2:1 ratio to regorafenib 160 mg/ day for 3 weeks with 1 week off (1 cycle) (n=505) plus best supportive care (BSC) or placebo plus BSC (n=255). Overall survival (OS) from time to enrollment in the trial was the primary endpoint of the trial.

The primary endpoint was met at a preplanned interim analysis; the estimated hazard ratio for OS was 0.773 and was statistically significant (P = .0051). Median OS was 6.4 months versus 5 months, respectively, an improvement of 29% for regorafenib. The trial was stopped to allow placebo patients to cross over to active treatment.

“The main emphasis of these findings is that this drug delays disease progression, achieving a much higher disease control rate than placebo,” Grothey stated. For disease control, the estimated hazard ratio was 0.49 (P < .000001).

Grade 3 side effects associated with regorafenib included fatigue (15%), anorexia (4.4%), diarrhea (8.2%), handfoot skin reaction (16.6%), hypertension (7.4%), weight loss (0.4%), and voice changes (0.2%).

“These side effects were consistent with observations from previous clinical trials. Dose adjustments were helpful in managing side effects,” Grothey commented.

During the question-and-answer session at a press conference, Grothey explained that patients in the trial failed on therapies that included 5-FU, oxaliplatin, irinotecan, bevacizumab, and cetuximab. No difference in response was seen in patients treated with two versus three or four lines of prior therapy.

“It would be more meaningful to know how rapidly patients moved through these lines of therapy,” he commented.

Grothey also noted that previous studies of other small-molecule mutikinase inhibitors looked at these agents in combination with chemotherapy and failed to show a benefit. “I think regorafenib could produce these results in this study because it was used as a single agent. Tumors change over time and activate resistance, and this study was done in a lastline setting. In that setting, a ‘promiscuous’ multitargeted therapy may be needed. It remains to be seen whether regorafenib will work when added to chemotherapy. A lot of pharmaceutical companies shy away from this very sick patient population, but this is a population at need, and we can do drug development here,” he said.

“CORRECT demonstrates that accrual to placebo-controlled trials is feasible in a population with unmet needs, and that refractory colorectal cancer is a realistic avenue for drug development,” Grothey stated.