CHICAGO – Regorafenib, an investigational tyrosine kinase inhibitor, dramatically delayed disease progression among patients with treatment-refractory metastatic gastrointestinal stromal tumor in a phase III trial.
Median progression-free survival reached 4.8 months with regorafenib vs. 0.9 months for placebo in the GRID (GIST–Regorafenib in Disease) study (hazard ratio, 0.27; P less than .0001).
"Regorafenib has the potential to fulfill an unmet need for GIST patients progressing after imatinib and sunitinib, and potentially represents a new standard of care," said Dr. George D. Demetri, who presented the results at the annual meeting of the American Society of Clinical Oncology.
"It is immaterial whether patients in this study were on third line, fourth line, or greater line, the hazard ratios were quite similar – [showing] a significant robust effect regardless of the number of prior inhibitors that these patients had been exposed to," added Dr. Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.
GIST, the most common sarcoma subtype, until fairly recently had no known treatment. The advent of imatinib (Gleevec) and later sunitinib (Sutent) changed the disease from one that was essentially untreatable into one that has two Food & Drug Administration–approved treatment options; with median survival increasing from 3-6 months to 5 years or more. Within just a few years of therapy, however, 90% of tumors can become resistant to the anticancer effects of both approved agents.
Regorafenib is a multitarget tyrosine kinase inhibitor (TKI), which has a high affinity for two mutated, activated kinases – KIT and platelet-derived growth factor receptor – that act as the main biological drivers of GIST, Dr. Demetri explained.
"GIST is truly addicted to KIT," he said during a press briefing. Regorafenib also targets vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, RET, BRAF, and the fibroblast growth factor receptor 1.
Preclinical and early-phase clinical trials have shown regorafenib has a range of anticancer activity, including a recently published phase II trial in which it was given to patients with advanced GIST after imatinib or sunitinib failure (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9394]). These promising results, released at last year’s ASCO annual meeting, prompted the phase III, double-blind, placebo-controlled GRID trial.
GRID was a "unique academic/industrial collaboration" undertaken in 17 countries across North America, Europe, and Asia-Pacific that took just 7 months from initiation to complete patient accrual. A total of 236 patients with metastatic, unresectable GIST intolerant to or progressing despite treatment with imatinib and sunitinib were screened, with 199 randomized (2:1) to regorafenib (160 mg/day) or placebo plus best supportive care.
The median age of patients was 58 years, with 75% of regorafenib-treated patients receiving two prior lines of therapy (imatinib and sunitinib only), and 59% receiving more than two prior treatments (imatinib, sunitinib, and others). Regorafenib-treated patients also had been exposed to were nilotinib (Tasigna, 21.8%), other TKIs (1.5%), mTOR inhibitors (2.3%), and cytotoxic chemotherapy (9.8%).
Active treatment or placebo was given in 4-week cycles, with 3 weeks on, and 1 week off treatment until disease progression. After disease progression, treatment was unblinded and placebo-treated patients could cross over to active treatment and receive open-label regorafenib until the next disease progression. Patients could also continue regorafenib if the clinician felt that this was of benefit. At the next progression, however, treatment was stopped.
The primary end point was progression-free survival, which clearly favored regorafenib over placebo. Exploratory analysis suggested regorafenib is effective in all molecular subtypes of GIST, including those with exon 9 and exon 11 mutations in KIT.
Important secondary end points were disease control and overall response rates. The disease control at 12 weeks or more was 52.6% for regorafenib and 9.1% for placebo, while overall response rates were 4.5% vs. 1.5%.
Dr. Demetri noted that another important secondary end point, overall survival would be confounded if the drug worked – and indeed 85% of placebo-patients crossed over to receive regorafenib. This was an intentional part of the study design, he said.
"The hazard ratio [0.77] for overall survival trended in favor of the patients who got started on regorafenib, there was a 23% decrease in the risk of death, but that was not statistically significant," Dr. Demetri said. Median overall survival has not currently been reached for either study arm.
Grade 3 drug-related side effects included those commonly associated with multitargeting TKIs or other cancer therapies, with hypertension (22.7%), hand-foot syndrome (19.7%), diarrhea (5.3%), fatigue (2.3%), mucositis (1.5%), and alopecia (1.5%) reported, as well as a few others including nausea, constipation, and myalgia.