San Francisco, CA—The novel tyrosine kinase inhibitor (TKI) regorafenib, used as a single agent to treat treatment-refractory metastatic colorectal cancer (CRC), significantly improved survival and delayed disease progression in an international phase 3 trial presented at the 2012 Gastrointestinal Cancers Symposium.
Regorafenib is an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases. “Regorafenib will likely join the list of useful therapeutics for metastatic colorectal cancer,” commented Herbert I. Hurwitz, MD, Duke Cancer Institute, Durham, NC, who was asked to discuss the findings at the meeting, “although efforts to improve its efficacy, ie, biomarkers, are still needed.”
Axel Grothey, MD, Mayo Clinic, Rochester, MN, presented the results of the CORRECT trial, which randomized 760 patients with advanced (ie, treatment-refractory) disease from 105 centers at a 2:1 ratio to best supportive care plus either regorafenib (160 mg/day every 3 weeks) or to placebo. The primary end point was overall survival (OS).
“This drug was tested in a setting in which many companies shy away from drug development. These patients are more difficult to treat. But this is a patient population that is truly in need,” Dr Grothey said.
At the second interim data analysis, the median OS was 6.4 months with regorafenib and 5.0 months with placebo, a 29% increase in OS (P = .005). “Regorafenib is the first small molecular kinase inhibitor showing proof of efficacy in colorectal cancer, and it thereby identifies itself as a potential new standard of care in metastatic patients who have progressed on other treatments,” Dr Grothey said. “For patients who are running out of treatment options, who have a very poor prognosis, regorafenib added 1.4 months of benefit, a 29% improvement in survival, that I think is statistically and clinically significant.”
The median progression-free survival was 1.9 months for regorafenib and 1.7 months for placebo (P <.001), which translated to a 51% reduction in progression risk. “The median difference of only 0.2 months demonstrates that medians are not the best way to show efficacy,” Dr Grothey said. “The main emphasis,” he added, “is that the drug delayed disease progression. Although response rates were low in both arms [1.6% with regorafenib, 0.4% with placebo], regorafenib produced a much higher rate of disease control [44% vs 15%, respectively],” he said.
“This drove the efficacy of the drug,” he observed. “I personally have treated 35 of the 78 patients who received regorafenib. I have had one patient on the drug for 12 months, with excellent performance status, and virtually no side effects.”
Other Small Molecules Have Not Worked in CRC
Dr Grothey acknowledged that up to now, small-molecule TKIs have not yet made an impact in CRC. “So far, in drug development, sorafenib, gefitinib, and PTK/ZK [vatalanib], which were all added to first-line or second-line chemotherapy, have not produced the desired result,” he said in a press briefing.
By contrast, regorafenib was evaluated as a single agent in a treatment-refractory population, which Dr Grothey credits with providing the treatment effect.
“We know that tumors change over time and activate multiple pathways and resistance mechanisms. It could be that we need more promiscuous multikinase inhibitors in later lines of therapy,” he suggested.