George Demetri, MD
The oral multikinase inhibitor regorafenib reduced the risk of disease progression by 73% in patients with gastrointestinal stromal tumors (GISTs) who had exhausted all other treatment options, according to a phase III trial presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO).
Imatinib (Gleevec, Novartis) and sunitinib (Sutent, Pfizer) 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
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 efficacy and safety of regorafenib were examined in the phase III GRID trial, which was a collaborative effort among academic and industrial research teams in 15 countries that was funded by Bayer HealthCare Pharmaceuticals.
The study 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 week off cycle) or placebo, plus best supportive care.
The results showed that treatment with regorafenib led to a statistically significant 3.9-month improvement in progression-free survival (PFS), as compared with placebo (4.8 months vs 0.9 months; hazard ratio [HR] = 0.27; 95% CI, 0.19-0.39; P
In a press briefing at ASCO, lead study author George Demetri, MD, director of the Ludwig Center and Sarcoma Center at Dana-Farber Cancer Institute and 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 overall survival (OS), there was not a statistically significant difference between the two study arms (HR = 0.77; 95% CI, 0.42-1.41; 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.”
Demetri added that he is not concerned that the lack of a clinically proven OS benefit will hinder regorafenib’s regulatory approval outlook. He explained that in previous discussions with US and European regulatory agencies, the researchers had received support for the crossover aspect of the trial design because “the regulatory authorities have looked at progression-free survival as a highly validated endpoint for patients with metastatic GIST.”
Data were also presented at ASCO demonstrating regorafenib’s positive activity in metastatic colorectal cancer, and Bayer has already submitted a New Drug Application to the FDA for this indication.
Demetri GD, Reichardt P, Kang YK, et al. Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial. J Clin Oncol. 2012;30(suppl; abstr LBA10008).
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