New targeted therapy effective in patients with drug-resistant metastatic gastrointestinal stromal tumor

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A new molecularly targeted drug, regorafenib, can significantly control life-threatening metastatic disease in patients with gastrointestinal stromal tumors (GIST) that have developed resistance to the only two FDA-approved drugs available, Dana-Farber Cancer Institute investigators will report at the annual meeting of the American Society of Clinical Oncology (ASCO) June 1-5 in Chicago.

Dana-Farber's George Demetri, MD, who designed and led an international clinical trial of the treatment, will discuss his findings (abstract LBA 10008) during a press briefing on Sunday, June 3, 9 a.m. CT and present them in an oral session on Monday June 4, 3 p.m., CT, S406, McCormick Place. Demetri is the director of the Ludwig Center and Sarcoma Center at Dana-Farber in Boston, and he led the studies which resulted in the FDA approvals of both imatinib Gleevec and sunitinib (Sutent) for patients with metastatic GIST.

The phase III trial determined that in patients whose tumors developed resistance to both of the approved targeted therapies, Gleevec and Sutent, treatment with regorafenib induced prolonged disease control (progression-free survival of 4.8 months) in contrast to the disease worsening in less than one month in patients who received a matched placebo. This was highly statistically significant, with regorafenib reducing the risk of disease progression or death by more than 70 percent.

"If approved, regorafenib will fulfill an urgent unmet need for patients with GIST who have exhausted all other treatment options," said Demetri.

"Targeted therapy has revolutionized treatment for this rare cancer, but we've been on the hunt for additional effective treatments for nearly 90 percent of patients whose cancer eventually develops resistance to the only two available therapies. Regorafenib appears to target GIST tumors in a different and possibly more powerful way than the current FDA-approved therapies, making it a potentially significant new option to help patients."

Regorafenib works by the same principle as the molecular "smart drugs" Gleevec and Sutent: by targeting abnormalities in cancer cell signaling pathways driven by a mutated, uncontrolled enzyme called KIT, these drugs shut off the switch that keeps the cancer cells alive and growing, resulting in disease control.

Gleevec and Sutent produce sustained periods of tumor remission in the vast majority of patients with GIST. Over time, however, new mutations often arise that render the mutant KIT even more mutated, and completely resistant to the standard drugs, allowing tumor growth to resume.

Regorafenib appears to interfere with the KIT circuitry in a different way, providing therapeutic benefit to those patients even after the development of resistance to the standard treatments. In addition, regorafenib appeared to work equally well across various molecular subtypes of GIST, characterized by different mutations in the key cell signaling enzyme, KIT.

The new study, a unique collaboration between academic and industrial research teams in 15 countries, involved 199 patients whose GIST had progressed despite prior treatment with Gleevec or Sutent. Patients were randomly assigned, in a 2-to-1 ratio, to receive either regorafenib (160 mg once daily, on a three weeks on/one week off schedule) or a matching placebo; all patients were followed closely and received best measures of supportive care.

A key design of the study stipulated that if the disease progressed in patients receiving a placebo, they could switch — or crossover — to regorafenib. By the time the study was completed, 85 percent of the participants had received regorafenib. Because of this provision, there was no statistical difference in the survival rates between patients enrolled in either of the two study groups, since virtually all patients were able to access the active drug.

The overall safety profile of regorafenib was consistent with results from previous clinical studies. The most common drug-related side effects included hand-foot skin reaction (56.1 percent of the treatment group, compared to 15.2 percent of the placebo group); hypertension (48.5 percent, compared to 16.7 percent); and diarrhea (40.9 percent, compared to 7.6 percent).

The study was funded by Bayer Pharmaceuticals in Germany.

In addition to Demetri, the study represented a global collaboration among researchers from HELIOS Klinikum Bad Saarow, Bad Saarow, Germany; Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; University Claude Bernard Lyon I, Centre Léon Bérard, Lyon, France; Helsinki University Central Hospital, Helsinki, Finland; Mount Sinai School of Medicine, New York; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Mannheim University Medical Center, Mannheim, Germany; Leiden University Medical Center, Leiden, Netherlands; The Christie NHS Foundation Trust, Manchester, United Kingdom; Fox Chase Cancer Center, Philadelphia; Universitaire Ziekenhuis Gasthuisberg, Leuven, Belgium; Mount Sinai Hospital, Toronto; Institut Gustave Roussy, Villejuif, France; University of Palermo, Palermo, Italy; Affiliated Hospital of Academy Military Medical Sciences, Beijing; Osaka Police Hospital, Osaka, Japan; Bayer HealthCare Pharmaceuticals, Berlin; and Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

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Gastrointestinal Stromal Tumor (GIST)
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