Striking Activity Shown for Regorafenib in Advanced GIST


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Regorafenib, an orally administered investigational tyrosine kinase inhibitor that has shown activity in chemorefractory metastatic colorectal cancer, markedly delayed disease progression in patients with treatment-refractory metastatic gastrointestinal stromal tumor (GIST) in the phase III GRID trial, presented at the ASCO Annual Meeting in Chicago.1

“Although imatinib [Gleevec] and sunitinb [Sutent] have revolutionized the management of GIST, drug resistance remains a challenge. GIST that is refractory to tyrosine kinase inhibitors is a life-threatening unmet medical need,” said George D. Demetri, MD, of the Dana-Farber Cancer Institute, Boston, who presented the results.

The Gist of GRID

“This randomized international phase III trial showed that regorafenib significantly increases progression-free survival vs placebo in patients with metastatic GIST that is progressing despite prior therapy with at least the only two standard drugs available,” he said. “We feel that regorafenib has the potential to fulfill an unmet need for advanced GIST patients and potentially represents a new standard of care for this patient population.”

The GRID trial (GIST–Regorafenib in Progressive Disease) rapidly accrued 236 patients with metastatic or unresectable GIST whose disease progressed after treatment with both imatinib and sunitinib, as well as in nearly half the patients following treatment with other unapproved agents such as other kinase inhibitors. Patients were randomized 2:1 to oral regorafenib at 160 mg/d plus best supportive care for repeating 4-week cycles, given 3 weeks on, 1 week off, or to best supportive care and matching placebo. The placebo group was allowed to cross over to open-label regorafenib upon disease progression, which 85% did.

Regorafenib was associated with a median progression-free survival of 4.8 months, compared with 0.9 months with placebo—a 73% reduction in risk (P < .0001). Disease control (response or stable disease ≥ 12 weeks) was achieved by 52.6% vs 9.1%, respectively, Dr. Demetri reported.

Benefit was observed across all the prespecified subgroups. “It was immaterial whether patients were on third-line treatment, or fourth, or greater,” he said, “the hazard ratios were quite similar: 0.23 and 0.31, respectively.”

Median overall survival has not been reached in either arm. “Because of the crossover design, the lack of statistical significance between study arms in terms of overall survival was not unexpected, since the vast majority of placebo patients rapidly crossed over to receive unblinded regorafenib. Nevertheless, there is a trend for [an overall survival benefit with] regorafenib, with a hazard ratio of 0.77 (P = .199),” he noted.

Further Analysis

Interestingly, an exploratory analysis after crossover showed that placebo patients who later received regorafenib had a median progression-free survival of 5 months (by investigator assessment), not much different from those originally randomized to regorafenib (7.4 months, as assessed by investigators), he pointed out.

As expected with this class of drugs in disease already resistant to other kinase inhibiors, the objective response rate was low at 4.5%, vs 1.5% with placebo.

Adverse events have occurred in 21.8% of the regorafenib arm and 25.6% of those on placebo. Regorafenib was well tolerated. The most significant toxicities of at least grade 3, for regorafenib vs placebo, were hand-foot skin reactions (19.7% vs 1.5%), hypertension (22.7% vs 3.0%), and diarrhea (5.3% vs 0%), but these did not lead to excess study discontinuations (6.1% vs 7.6%). “Patients were able to stay on study with appropriate dose modifications,” he said.

Data on genotype were available for approximately half the patients. Analyses showedyvirtually identical benefits with regorafenib in patients with the KIT exon 11 mutation (HR = 0.21) and exon 9 mutation (HR = 0.239), in terms of progression-free survival. ■

Disclosure: Dr. Demetri reported no potential conflicts of interest.

Reference

1. Demetri GD, Reichardt P, Kang Y, et al: Randomized phase III trial of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumor progressing despite prior treatment with at least imatinib and sunitinib: GRID trial. 2012 ASCO Annual Meeting. Abstract LBA10008. Presented June 4, 2012.


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