Axel Grothey, MD
Results from two phase III trials in metastatic colorectal cancer (mCRC) and unresectable gastrointestinal stromal tumors (GIST) that have progressed despite prior treatment indicate that the multi-tyrosine kinase inhibitor regorafenib may offer some benefit.
The phase III international CORRECT trial showed that regorafenib may be a new treatment option that achieves disease control in mCRC that has progressed on multiple lines of standard therapy including 5-fluorouracil (FU), oxaliplatin, irinotecan, bevacizumab, and cetuximab. The trial achieved a statistically significant improvement in overall survival (OS). The trial was unblinded in October 2011 after an interim analysis of patients in the placebo arm were offered regorafenib therapy. The full results of the trial were presented at the American Society of Clinical Oncology (ASCO) 2012 Gastrointestinal Cancers Symposium in January 2012. The trial has since been expanded to a phase IIIb open-label protocol for mCRC patients who have progressed following standard of care. Follow-up results will be presented at the upcoming ASCO Annual Meeting in June 2012.
A total of 760 patients with mCRC who had progressed despite therapy were randomized 2:1 to receive either regorafenib or placebo. Both study arms also received best supportive care. Patients received regorafenib 160 mg (n=505) or placebo (n=255) once daily for three weeks, followed by one week with no treatment.
Median OS was 6.4 months for regorafenib and 5.0 months for the placebo arm, an improvement of 29%. The estimated hazard ratio for OS was 0.773 (one-sided P
= .0051). Median progression- free survival was 1.9 months and 1.7 months for the regorafenib and placebo arms, respectively. The most frequent grade 3 or higher adverse events included hand-foot skin reaction in 17%, fatigue in 15%, and diarrhea in 8% of patients. Some patients had their dosages reduced to manage side effects.
“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,” said lead author Axel Grothey, MD, Mayo Clinic, Rochester, Minnesota. “The main emphasis of these findings is that this drug delays disease progression, achieving a much higher disease control rate than placebo,” Grothey added. The disease control rate was 44% for regorafenib and 15% for placebo (P
Regorafenib is a multikinase inhibitor that shows antiangiogenic activity against vascular endothelial growth factor receptor 2 (VEGFR2) and TIE2. The inhibitor blocks various kinases involved in tumor cell proliferation, new blood vessel formation, and the interaction between tumor cells and the microenvironment.
Study findings showed no difference in response in patients treated with two versus three or four lines of prior therapy, according to Grothey. Previous smallmolecule multikinase inhibitors were investigated in conjunction with chemotherapy but showed no benefit in mCRC.
Grothey believes that regorafenib worked because it was used as a single agent. He speculated that because tumors evolve due to therapy exposure, a “promiscuous” multitargeted therapy may be needed in a last-line setting. The drug is under investigation in combination with FOLFIRI chemotherapy as a second-line treatment for mCRC in a phase II trial.
“A lot of pharmaceutical companies shy away from this very sick patient population, but this is a population in need, and we can do drug development here,” Grothey said. He added that the CORRECT trial shows that placebo-controlled trials are feasible in a population with unmet needs, particularly refractory colorectal cancer.
Regorafenib also holds promise for patients with GIST. In April 2012 it was announced that the phase III GRID trial met its primary endpoint of a statistically significant improvment in progression- free survival in patients with metastatic and/or unresectable GIST whose disease had progressed despite prior therapy. Full trial results will be presented at the upcoming ASCO annual meeting in June 2012.
Finally, regorafenib is being investigated in phase II trials for treatment-naïve patients with metastatic renal cell carcinoma and liver cancer.
Grothey A, Sobrero AF, Siena S, et al. Results of a phase III randomized, double-blind, placebocontrolled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. Presented at the ASCO Gastrointestinal Cancers Symposium; January 19-21, 2012; San Francisco, CA. J Clin Oncol. 2012;(suppl 4; abstr LBA385).