GRID Trial: Regorafenib Shows Promise for Patients with GIST

The novel oral multikinase inhibitor regorafenib appears to provide a significant improvement in progression- free survival (PFS) over placebo in patients with metastatic and/ or unresectable gastrointestinal stromal tumor (GIST) progressing after failure ofimatinib and sunitinib.

Outcomes from the randomized, phase III GIST-Regorafenib in Progressive Disease (GRID) trial were presented by George D. Demetri, MD, of the Dana-Farber Cancer Institute and Harvard Medical School, at the Sarcoma Oral Abstract Session (Abstract LBA10008). “Regorafenib has the potential to fulfi ll an unmet need for patients with advanced GIST progressing after imatinib and sunitinib,” said Dr. Demetri. “It potentially represents a new standard of care for this patient population.”

Dr. Demetri noted that the two available tyrosine kinase inhibitors (TKIs)—imatinib and sunitinib—are the mainstay of therapy for patients with metastatic GIST. However, no effective therapies are available for patients with TKI-resistant GIST.

Regorafenib is a novel oral kinase inhibitor that has been shown to block VEGFR2-3, c-KIT, TIE2, PDGFR beta, FGFR1, RET, RAF, and p38 MAPK. After preclinical and phase I studies showed substantial activity of the compound, a phase II study was undertaken. In that study of patients with disease progression after receiving both imatinib and sunitinib, regorafenib was associated with a 79% disease control rate.

Based on these results, a global group of investigators undertook the doubleblind, placebo-controlled GRID trial, which was open to patients with metastatic and/or unresectable GIST who had previously received both imatinib and sunitinib. Eligible patients could have discontinued imatinib because of intolerance or disease progression but were required to stop sunitinib because of disease progression. The trial was conducted in 17 countries across Europe, North America, and Asia. Accrual began in January 2011 and was completed 7 months later.

A total of 199 patients were randomly assigned 2:1 to 160 mg of oral regorafenib once daily in a 3-weekson, 1-week-off schedule (133 patients) or to placebo (66 patients), each with best supportive care. Crossover to openlabel regorafenib was allowed upon disease progression for patients assigned to placebo; 85% of patients in the placebo arm went on to cross over to regorafenib.

In his discussion of the results, Grant McArthur, MBBS, PhD, of the Peter Mac- Callum Cancer Centre, Australia, congratulated the investigators on the rapid recruitment to their trial and on their ability to successfully cross over 85% of patients from the placebo arm to active treatment.

The trial met its primary endpoint, with regorafenib demonstrating a significant improvement over placebo—with a median PFS of 4.8 months compared with 0.9 months—in a blinded central review (hazard ratio: 0.27; 95% CI: 0.19- 0.39; p < 0.0001).

An exploratory analysis showed a significant PFS benefit with regorafenib in almost all subgroups, including in patients who had received four or more prior lines of therapy. The only subset in which there was no significant PFS benefit with regorafenib consisted of patients who had received imatinib for fewer than 6 months, although this was the smallest group of patients.

Disease control rates were 53% and 9% with regorafenib and placebo, respectively. The median overall survival was not reached at the time of analysis. There were no survival differences between arms, given the high rate of crossovers.

Notably, the investigators reported a similar PFS rate in patients initially assigned to placebo who crossed over to regorafenib as for those who were initially assigned to the regorafenib arm.

Treatment-related adverse events of at least grade 3 in severity reported during the study included hypertension (23%), hand-foot skin reaction (20%), and diarrhea (5%). These were managed with dose modifications and did not result in higher rates of discontinuations.