Novel Agent Improves Survival in Metastatic Colorectal Cancer

Roxanne Nelson

January 18, 2012

January 18, 2012 (San Francisco, California) — The experimental agent regorafenib appears to significantly improve survival and delay disease progression in patients with metastatic colorectal cancer, according to data that will be presented at the 2012 Gastrointestinal Cancers Symposium.

In a phase 3 randomized trial, patients treated with regorafenib had a median overall survival of 6.4 months, compared with 5.0 months for placebo — a 29% increase in survival.

Regorafenib is under development by Bayer, and the company says it intends to file for approval for metastatic colorectal cancer sometime this year.

The drug is a novel oral multkinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases, explained lead author Axel Grothey, MD, professor of oncology at the Mayo Clinic in Rochester, Minnesota. "It can inhibit a variety of different kinases; this is really the main characteristic of the drug."

"In early clinical testing, regorafenib has shown an acceptable side-effects profile and preliminary antitumor effects," he said during a presscast that was held ahead of the meeting.

The CORRECT trial was conducted to evaluate the efficacy and safety of regorafenib in patients with metastatic disease who had progressed after receiving all approved standard therapies. "This highlights a patient population that has an unmet need and for which placebo randomization is ethically sound," said Dr. Grothey.

Superior Overall and Progression-Free Survival

The study cohort consisted of 760 patients with documented metastatic colorectal cancer who had progressed during standard therapy or within 3 months of receiving it. In the cohort, 505 patients were randomly assigned to oral regorafenib 160 mg (3 weeks on and 1 week off) plus best standard care, and 255 were assigned to placebo plus best standard care.

Patients were to continue with the treatment until disease progression, death, or unacceptable toxicity. The primary end point was overall survival. Secondary end points included progression-free survival, overall response rate, disease control rate, safety, and quality of life.

At a preplanned second interim analysis, there was a statistically significant survival benefit for regorafenib. The estimated hazard ratio for overall survival was 0.773 (95% confidence interval [CI], 0.635 to 0.941; 1-sided P = .0051).

In addition to improved overall survival, progression-free survival was superior; median progression-free survival was 1.9 months (95% CI, 1.88 to 2.17) for regorafenib and 1.7 months (95% CI, 1.68 to 1.74) for placebo. The estimated hazard ratio for progression-free survival was 0.493 (95% CI, 0.418 to 0.581; 1-sided P < .000001).

The authors found a substantial difference in disease control rate in the regorafenib and placebo groups (44% vs 15%; P <.000001). Because the prespecified overall survival efficacy boundary was crossed (1-sided nominal α = 0.0093), the Data Monitoring Committee recommended that the study be unblinded to allow patients in the placebo group to cross over.

Adverse events were consistent with observations from previous clinical trials, said Dr. Grothey. Dose adjustment was helpful in managing adverse effects; "most patients could continue on the drug in a dose-reduced manner," he explained.

The most frequent grade 3+ adverse events in the regorafenib group were hand–foot skin reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension (7%).

Dr. Grothey noted that regorafenib appears to be more effective in stabilizing disease and delaying progression than in shrinking tumors. He added that a subset of patients has responded particularly well to regorafenib and continue to have stable disease. He said that he is personally treating a patient who has been on the drug for 12 months whose disease has stabilized and who has not experienced any adverse effects.

"This is the first small-molecule kinase inhibitor with proof of efficacy in metastatic colorectal cancer," he said, adding that this is a potential new standard of care in this patient population.

There are plans to study regorafenib in patients with earlier-stage disease.

This is a very noteworthy study, said Morton Kahlenberg, MD, from the University of Texas Health Science Center at San Antonio, who moderated the presscast. He added that these are positive findings in people with disease that has already progressed and who have failed other therapies.

"This really lays the groundwork for further work," he added.

Dr. Grothey and several coauthors report multiple relationships, including relationships with Bayer.

2012 Gastrointestinal Cancers Symposium (GICS): Abstract LBA385. To be presented January 21, 2012.

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