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The oral multikinase inhibitor regorafenib extended OS in patients with metastatic colorectal cancer and improved PFS in patients with gastrointestinal stromal tumors.
Photo by © ASCO/Todd Buchanan 2009
Eric Van Cutsem, MD, PhD
The oral multikinase inhibitor regorafenib extended overall survival (OS) in patients with metastatic colorectal cancer (mCRC) and improved progression-free survival (PFS) in patients with gastrointestinal stromal tumors (GISTs), according to separate phase III trials presented at ASCO 2012. Regorafenib obstructs multiple tumor pathways, inhibiting targets and receptors including VEGFR1-3, TIE2, PDGFR, FGFR, KIT and RET.
Based on the mCRC data, Bayer has submitted a New Drug Application to the FDA for the treatment of patients whose disease has progressed following standard treatment. On September 27, the FDA approved the drug under its expedited priority review process for mCRC. At the time of publication, an application for a GIST indication had not yet been submitted to the FDA.
In the pivotal phase III CORRECT trial, 760 patients with mCRC were randomized 2:1 to regorafenib (160 mg orally once daily on a 3-weeks-on/1-weekoff cycle; n = 505) or placebo (n = 255), plus best supportive care.1 All patients had progressed in ≤3 months with standard treatments, including chemotherapy, bevacizumab (Avastin), cetuximab (Erbitux), and panitumumab (Vectibix).
At an interim analysis, the trial met its primary endpoint with a 1.4-month improvement in median OS versus placebo (6.4 months vs 5.0 months; hazard ratio [HR] = 0.77; P = .0052). Regorafenib also produced a statistically significant improvement in PFS, as compared with placebo (HR = 0.49; P <.000001). The benefits with regorafenib were maintained across all prespecified subroups, including KRAS mutational status.
The survival results met a predetermined stopping criteria and the study was unblinded per the recommendation of the independent Data Monitoring Committee. Patients in the placebo arm were thus allowed to cross over and receive regorafenib.
The most common grade 3/4 adverse events in the regorafenib arm were hand-foot skin reaction (16.6%), fatigue (9.6%), hypertension (7.2%), diarrhea, (7.2%), and rash (5.8%). There were five patients in the regorafenib arm with grade 5 adverse events, compared with zero patients in the placebo arm.
In a presentation of the CORRECT data at ASCO, co-author Eric Van Cutsem, MD, PhD, University Hospitals Gasthuisberg/Leuven, Belgium, said, “It’s fair to conclude that regorafenib is a new potential standard of care for patients with chemorefractory metastatic colorectal cancer.
George Demetri, MD
In the phase III GRID trial, regorafenib reduced the risk of disease progression by 73% in patients with GISTs who had exhausted all other treatment options.2
Imatinib (Gleevec) and sunitinib (Sutent) are the only FDA-approved therapies for GIST; however, 90% of patients eventually become resistant to these treatments. Regorafenib’s unique shape allows the drug to inhibit the KIT and PDGFRA mutations that drive GISTs in a different way than imatinib and sunitinib. Thus the drug has the potential to benefit patients after the failure of those treatments.
The GRID trial involved 199 patients with metastatic and/or unresectable GIST that had become resistant to imatinib and sunitinib. Patients were randomized 2:1 to regorafenib (160 mg orally once daily on a 3-weeks-on/1-weekoff cycle) or placebo, plus best supportive care.
The results showed that treatment with regorafenib led to a statistically significant 3.9-month improvement in PFS, as compared with placebo (4.8 months vs 0.9 months; HR = 0.27; P <.0001).
In a press briefing at ASCO, lead study author George Demetri, MD, director of the Ludwig Center at Dana-Farber Cancer Institute and Sarcoma Center at Harvard Medical School in Boston, Massachusetts, said it was important to note that the PFS benefit was sustained across the different molecular subtypes of GIST.
With the secondary endpoint of OS, there was not a statistically significant difference between the two study arms (HR = 0.77; P = .199). Demetri said this result was expected because as part of the trial design, patients receiving placebo whose disease progressed were allowed to cross over unblinded to the regorafenib arm.
“It’s completely expected and explicable why there was not a survival benefit, because 85% of the patients on placebo crossed over to the active drug,” Demetri said.
The safety profile of regorafenib was commensurate with previous studies. The most common grade ≥3 adverse events associated with regorafenib were hand-foot skin reaction (56.1%), hypertension (48.5%), and diarrhea (40.9%). According to Demetri, these adverse events were “all manageable with the appropriate dose modifications built into the study.”
When asked about a timeframe for regulatory submission, Demetri did not offer specifics but noted, “We’ve been pushing our industrial collaborators, Bayer, about as hard as we can, and I must say they’ve responded nicely—they see the urgency of getting this drug to patients in need.”