In September 2012, the FDA approved regorafenib for treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, with an anti-EGFR therapy.
The approval was based on the multinational phase III CORRECT trial2(regorafenib monotherapy for previously treated mCRC), which demonstrated that the multikinase inhibitor prolonged survival in treated patients.
With this action, regorafenib became the first small-molecule multikinase inhibitor conferring survival benefits in mCRC that had progressed after treatment with all standard therapies. According to clinicians such as Richard Kim, MD, a medical oncologist at the Gastrointestinal Oncology Department at H. Lee Moffitt Cancer Center, Tampa, Florida, a next step might be to investigate use of the drug in the second-line setting in combination with the chemotherapy regimen FOLFIRI.
Subsequently, Italian researchers focused attention on radiological tumor changes that were documented as part of the clinical data from their institution’s enrollees in the CORRECT study.3Computed tomography (CT)-based radiological changes had previously been reported in association with bevacizumab treatment,4and the investigators reasoned that similar data from regorafenib-treated patients might help to identify individuals who would receive particular benefit from this new targeted agent, whose cost effectiveness, especially in advanced patients, was in question.3
Accordingly, in a retrospective analysis of radiological data from 37 patients with mCRC from their institution who were enrolled in either the treatment or placebo arms of the CORRECT study, regorafenib (but not placebo) was found to have induced changes in tumor density and cavitation of lung metastases.3
These changes possibly represented a biological effect, and the investigators hypothesized that the changes would likely be evident by contrast CT imaging at the earliest postbaseline evaluation at week 8, and that they would be an indicator of clinical outcome.
Indeed, researchers did find that early radiological tumor changes tended to be associated with better progression-free survival and overall survival, and included any tumor shrinkage without the appearance of new lesions, onset of cavitation in lung metastases, and low tumor density at baseline.
“I agree with the authors that the available measures to capture the benefit of targeted agents such as bevacizumab or regorafenib are insufficient and not well developed,” said Heinz-Josef Lenz, MD, in an interview. Lenz is associate director for Clinical Research and coleader of the Gastrointestinal Cancers Program at the University of Southern California (USC) Norris Comprehensive Cancer Center, and professor of Medicine and Preventive Medicine at the USC Keck School of Medicine.
“To monitor the effect of anti-angiogenic drugs [on] cavitation and central necrosis may be critical to identify the patients who benefit the most from these agents. Only, measurement of tumor size is not enough to fully characterize the biological effect of anti-angiogenic therapies. We need to develop better clinical outcome tools and replace the RECIST criteria for being able to test and evaluate novel drugs in our clinical trials and practices,” Lenz said.