CHICAGO — The targeted multikinase inhibitor regorafenib quadrupled PFS compared with placebo among patients with gastrointestinal stromal tumors that progressed due to resistance to other available treatments, according to results of an international Phase 3, double-blind randomized controlled trial.
The findings suggest regorafenib (Bayer HealthCare), if approved, could fill an unmet need for patients with gastrointestinal stromal tumors (GIST) who have exhausted other treatment options, said researcher George Demetri, MD, director of the Ludwig Center and Sarcoma Center at Dana-Farber Cancer Institute and Harvard Medical School in Boston.
Imatinib (Gleevec, Novartis) and sunitinib (Sutent, Pfizer) are the only two drugs approved by the FDA to treat GIST. The oral pills inhibit the abnormalities in cancer cell signaling pathways driven by the KIT enzyme that cause the disease, but new mutations eventually evolve and lead to the creation of new drug-resistant forms of the KIT enzyme. Resistance occurs in nine out of 10 patients, Demetri said during a press conference.
Regorafenib has shown an ability to inhibit the cancer-promoting signals, even demonstrating efficacy in patients whose cancers have become resistant to initial treatments, the researchers said.
Demetri and colleagues randomized 199 patients with metastatic and/or inoperable GIST to either regorafenib 160 mg orally once daily (n=133) or placebo (n=66). The patients assigned to regorafenib underwent treatment on a 3-weeks-on, 1-week-off schedule.
All patients had undergone prior therapy with other standard treatment options, including imatinib and sunitinib. During this study, they all received best supportive care to alleviate disease symptoms.
Patients were stratified according to geographical region and the number of prior systemic therapies.
The primary endpoint was PFS.
Patients assigned to regorafenib experienced significantly longer PFS than those assigned to placebo [4.8 months vs. 0.9 months (HR=0.27; 95% CI, 0.18-0.39; P<.0001)].
Patients assigned to regorafenib demonstrated longer PFS at 3 months (60% vs. 11%) and 6 months (38% vs. 0).
At the time of disease progression, patients assigned to placebo were eligible to cross over to regorafenib treatment. Eighty-five percent of patients initially assigned to placebo eventually switched to regorafenib treatment. Consequently, there was no statistical difference in OS between the two patient cohorts.
The durable stable disease rate, which represents disease control for more than 3 months, was 52.6% among patients in the regorafenib arm, compared with 9.1% among patients in the placebo arm.
Regorafenib was well tolerated, and adverse events were manageable with dose modifications, the researchers said. The most common grade-3 or higher adverse events were hypertension (28%); hand-foot skin reaction (21%); and diarrhea (8%).
“Targeted therapy has revolutionized treatment for this rare cancer, but we’ve been on the hunt for additional effective treatments for the 85% of patients whose cancer eventually develops resistance to the only two available therapies,” Demetri said in a press release. “Regorafenib appears to target GIST in a different and possibly more powerful way than the current FDA-approved therapies, making it a potentially significant new option to help patients.”
For more information:
Demetri GD. Abstract #LBA10008. Presented at: the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago.
Disclosure: The researchers report serving in consultant or advisory roles with, receiving research funding or honoraria from, and holding employment or leadership positions with Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Pfizer, Sanofi and other pharmaceutical companies.