(ChemotherapyAdvisor) – Oral regorafenib prolongs progression-free survival (PFS) by nearly 4 months among patients with imatinib- and sunitinib-resistant metastatic or unresectable gastrointestinal stromal tumor (GIST), according to a randomized, placebo-controlled multinational phase 3 clinical trial published in The Lancet.

Imatinib and sunitinib are FDA-approved treatments for GIST, and prolong survival – but in most patients, GIST eventually develops resistance to both drugs, noted lead author George D. Demetri, MD, of the Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA, and his coauthors.

“Until now, only imatinib and sunitinib have proven clinical benefits in patients with gastrointestinal stromal tumors,” Dr. Demetri and his coauthors explained. But “almost all metastatic GIST eventually develops resistance to these agents, resulting in fatal disease progression.”

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Regorafenib is an oral multi-kinase inhibitor that blocks molecular mechanisms involved in tumor growth and progression, including angiogenesis, oncogenesis, and the tumor microenvironment. Trial participants were 199 patients with metastatic or unresectable GIST with failure of imatinib and sunitinib. Patients were randomized 2:1 to receive either oral regorafenib (160 mg daily; n=133) or placebo (n=66) for the first 3 weeks of each 4-week cycle, the authors noted.

Median PFS for regorafenib-arm patients was 4.8 months, compared to 0.9 months (range 0.9-1.8 months) among patients receiving placebo (hazard ratio [HR] 0.27; 95% CI, 0.19-0.39; P<0.0001).

After progression, 56 placebo-arm patients (85%) crossed over to receive regorafenib.

Regorafenib-related toxicities were nearly universal (n=130 patients; 98%), with the most common grade 3+ drug-related adverse events being hypertension (23%), hand-foot skin reaction (20%), and diarrhea (5%), the authors reported.

The case for routine use of regorafenib against GIST following imatinib and sunitinib is “strong,” wrote Tom Waddell, MD and David Cunningham, MD, both of the Royal Marsden Hospital in Surrey, England, in an accompanying commentary.

“As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients,” the authors noted.

The FDA approved regorafenib’s use for metastatic colorectal cancer (mCRC) in September 2012, based on early results from the phase 3 CORRECT (Colorectal cancer treated with regorafenib or placebo after failure of standard therapy) trial, which has now also been published in The Lancet.

“The publication of the CORRECT and GRID trials in The Lancet signifies the potential of regorafenib as a new and effective treatment  option for both mCRC and GIST, where there is a high unmet need,” said Shurjeel Choudhri, MD, Bayer HealthCare Pharmaceuticals’ vice president for medical and scientific affairs.

The GRID study was funded by Bayer HealthCare Pharmaceuticals.

ClinicalTrials.gov GRID Abstract (NCT 01271712)
CORRECT Trial Abstract