ESMO: Regorafenib Improved PFS for GIST in Post-Imatinib/Sunitinib Setting

October 22, 2012

Treatment of gastrointestinal stromal tumor (GIST) with regorafenib after prior treatment failure with both imatinib and sunitinib resulted in a PFS survival benefit for patients across all prespecified subgroups.

Treatment of gastrointestinal stromal tumor (GIST) with regorafenib after prior treatment failure with both imatinib and sunitinib resulted in a progression-free survival (PFS) benefit for patients across all prespecified subgroups, according to a study presented recently at the European Society for Medical Oncology 2012 Congress. The results also showed that patients who were continued on the drug, even after disease progression, had an additional PFS benefit.

“In the post-progression phase, continued regorafenib gives an additional nearly 5-month progression-free survival, which clearly supports the notion that continuing tyrosine kinase inhibition is an important treatment modality in gastrointestinal stromal tumor,” said Peter Reichardt, MD, PhD, of HELIOS Klinikum in Bad Saarow, Germany, who presented the results of the phase III GRID trial.

Although imatinib revolutionized the initial management of advanced GIST, resistance to tyrosine-kinase inhibitors will ultimately occur in 85% or more of patients, leading to disease progression, according to Reichardt. Sunitinib is often of benefit to patients with GIST after imatinib failure; however, there is currently no approved therapy after failure of both imatinib and sunitinib.

Regorafenib is a structurally distinct oral agent with a unique profile of inhibiting multiple kinases relevant to GIST. Reichardt and colleagues had previously published results from the GRID trial that showed that regorafenib improved PFS in patients with GIST who had failed on imatinib and sunitinib.

This presentation included results on the subgroup analyses and post-progression analyses of GRID.

GRID was a multicenter, randomized, double-blind study that included patients from 17 countries. The study included 199 patients with metastatic unresectable GIST who were progressing despite prior treatment with at least imatinib and sunitinib.

Patients were randomly assigned two to one to treatment with best supportive care plus either 160 mg regorafenib (n=133) or placebo (n=66). Upon disease progression the study was unblinded and patients assigned placebo could cross over to regorafenib; patients assigned regorafenib could continue treatment with the drug.

Previously presented data on PFS indicated that patients assigned to the study drug had a median PFS of 4.8 months (95% CI, 4.1-5.8) compared with 0.9 months for patients assigned to placebo (95% CI, 0.9-1.1). Overall, regorafenib significantly improved PFS compared with placebo (HR=0.27; 95% CI, 0.19-0.39).

When looking at PFS per investigator assessment, the median PFS for patients assigned regorafenib was 7.4 months (95% CI, 6.5–A) compared with 1.7 months for placebo (95% CI, 1–1.9), indicating a HR of 0.22 (95% CI, 0.14–0.35) for patients assigned the study drug.

After the exploratory sensitivity analyses, the researchers found that PFS was similarly affected across a wide variety of prespecified subgroups including number of prior therapies, geographical region, age, baseline ECOG score, duration of prior treatment with imatinib, or KIT/PDGFRA mutation.

“The prespecified subgroup analysis shows an overall benefit for regorafenib,” said Reichardt. “There is no single factor that would prevent patients from benefiting from this drug.”

The data were then analyzed for the post-progression period. Taking both the blinded and unblinded periods together 188 patients received regorafenib on study. The 56 patients in the placebo arm who crossed over had a median PFS of 5 months. Those patients in the regorafenib arm who elected to stay on drug after progression had a median PFS of 4.5 months.

“Patients who were defined as having progressive disease by central review, but stable by investigators assessment had an additional 4.5 months survival from the time point of unblinding,” said Reichardt. “This clearly shows that patients benefit from continued drug exposure even after progression as defined by central review.”

Overall survival rates were not significantly different because of the cross-over structure of the trial.

“However, with this statistical method we can support that there would be an overall survival benefit with regorafenib without crossing over,” Reichardt said.