Regorafenib Anticipated to Show Survival Advantage in Colorectal Cancer


Phase III data on regorafenib, the first small-molecule kinase inhibitor to demonstrate a significant survival advantage in colorectal cancer, will be presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium opening Jan. 19.

Other noteworthy studies include a reanalysis of the phase III RADIANT-2 trial suggesting that everolimus (Afinitor) may be of greater benefit in neuroendocrine tumors than previously shown, and research that could improve the early detection of esophageal and pancreatic cancer.

CORRECT Trial in Colorectal Cancer

Investigators will present results on Jan. 21 from the phase III CORRECT trial showing that the oral, investigational multikinase inhibitor, regorafenib, plus best supportive care, significantly increased median overall survival by 29% in 760 patients whose metastatic colorectal cancer progressed after standard therapies (hazard ratio 0.773; P value = .0051).

This added a median benefit of just 1.4 months compared with placebo and best supportive care (6.4 months vs. 5.0 months), but lead investigator Dr. Axel Grothey pointed out during a press briefing that the patients were running out of options after failing all standard therapies including bevacizumab and epidermal growth factor receptor inhibitors if they had KRAS-wild type tumors.

The response rate was similar between regorafenib and placebo (1.6% vs. 0.4%), but where regorafenib distinguished itself was in a much higher disease-control rate than placebo (44% vs. 15%).

The median difference in progression-free survival was again small, at just 1.2 months, but this corresponded to a 51% reduction in the risk of progression (HR 0.493; P less than .000001), said Dr. Grothey, professor of oncology at Mayo Clinic in Rochester, Minn. "There is clearly a benefit for about 50% of patients compared to the placebo-control," he said.

The side effect profile was similar to that observed in the phase I trial and included grade 3 hand-foot skin reactions, fatigue, anorexia, and a class effect of hypertension that was controlled with dose reductions.

The trial was stopped based on the preliminary results from the preplanned interim analysis to allow patients on placebo to cross over to treatment with regorafenib.

Dr. Grothey said regorafenib "identifies itself as a potential new standard of care in this patient population," and that it will move into earlier lines of therapy. Phase II studies are underway to evaluate the agent in combination with standard chemotherapy backbones such as 5FU and irinotecan.

Presscast moderator Dr. Morten S. Kahlenberg, medical director of Surgical Oncology Associates of South Texas in San Antonio, called results from the late-breaking abstract exciting and very noteworthy, particularly in such a heavily pretreated population, and agreed that the research lays the groundwork for further study to evaluate whether regorafenib could "possibly become a component of standard therapies for colorectal cancer."

Dr. Grothey suggested that regorafenib may have achieved the results it did in part because it was used as a single agent, whereas trials of other small-molecule kinase inhibitors such as gefitinib (Iressa), sorafenib (Nexavar), and PTK/ZK involved adding the agents to first- or second-line chemotherapy.

"This is not unheard of that adding a kinase inhibitor to chemotherapy does not produce the desired result," he said, noting that the addition of sorafenib to FOLFOX chemotherapy actually appeared detrimental in patients with metastatic colorectal cancer.

RADIANT-2 Reanalysis

On Jan. 20, Dr. James C. Yao, deputy chair of gastrointestinal medical oncology at M.D. Anderson Cancer Center in Houston, will present a reanalysis of the phase III RADIANT-2 trial in patients with advanced nonpancreatic neuroendocrine tumors.

The analysis identified several prognostic factors that could help physicians better identify which patients should be treated. It could also explain why the addition of everolimus to standard therapy with octreotide LAR (Sandostatin LAR Depot) delayed progression by a median of 5.1 months, but just missed statistical significance.

In multivariate analysis, significant prognostic factors included WHO performance status, bone involvement, lung as primary site, and, most notably, baseline levels of chromogranin A, a secretory protein present in neuroendocrine tissue.

Patients with elevated chromogranin A (CgA) had a significantly shorter progression-free survival of 11.3 months vs. 26.8 for those with nonelevated chromogranin A.

At baseline, there was a significant imbalance in mean and median CgA levels between patients receiving everolimus plus octreotide and those given octreotide alone, he said.

An exploratory analysis that adjusted for these prognostic indicators indicated that everolimus had a significant benefit, changing the reduction in risk of neuroendocrine progression from 23% as originally reported to 38% (HR 0.62). A larger trial, RADIANT-4, is planned to confirm these results, Dr. Yao said.

Dr. Kahlenberg said the results provide clinicians with additional insights on how to determine which patients would benefit from everolimus therapy. "In that providers are really limited by the small number of successful therapies for neuroendocrine tumors, your study is that much more meaningful," he added.


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