SAN FRANCISCO — A new, multitargeted biologic therapy halted gastrointestinal tumor progression so dramatically, a phase III study was unblinded early so that patients assigned to placebo could immediately receive the drug, researchers reported at a symposium sponsored by the American Society of Clinical Oncology.
The drug, sunitinib, underwent expedited review at the Food and Drug Administration and received approval during the meeting for the treatment of gastrointestinal stromal tumors (GIST) resistant to the first-line drug imatinib, and for treatment of advanced kidney cancer.
Dr. George D. Demetri used a Certs analogy of “two mints in one” to describe the multipronged way in which sunitinib targets tumors: blocking mutated signaling enzymes that permit uncontrolled cell growth, while cutting off growth factors to blood vessels that feed tumors.
An interim analysis of an international study found that sunitinib made a “truly dramatic difference” in the time it took tumors to progress in patients with GIST. Among 207 patients randomly assigned to receive sunitinib, time to progression was 27.3 weeks, compared with 6.4 weeks in 105 patients receiving placebo.
The difference equated to a 70% reduction in the risk of progression in the study patients, all of whom had developed either intolerance or resistance to imatinib (Gleevec), which Dr. Demetri called the “poster child drug for selectively inhibiting … kinase signaling enzymes.”
The study also found a 51% reduction in the relative risk of death among patients taking sunitinib, reported Dr. Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute, Boston.
The trial was unblinded after patients had been on the drug for 6–8 months, when an interim analysis demonstrated “strongly positive” efficacy. At the time of the American Society of Clinical Oncology's gastrointestinal symposium, median survival had not been reached in either treatment group.
Beyond offering hope for patients with imatinib-resistant GIST tumors, sunitinib's success may offer a blueprint for how to develop drugs quickly based on customized genetic tumor profiles.
Dr. Demetri described an analysis of how well compounds selectively bind to signaling enzymes—kinases—that are known to spur the growth of cancer cells. In this case, sunitinib was shown to potently bind not only to KIT—a tyrosine kinase and an imatinib target—but also to many other signaling enzymes.
“We can [now] look for mutations that cause resistance, much as you would analyze bacteria for resistance to antibiotics,” he explained. “This gives us a tool to move very quickly from laboratory compounds to new effective things that can be tested for helping patients in the clinic.
Sunitinib was generally well tolerated, even among patients who could not tolerate imatinib due to that agent's side effects, which can include a life-threatening rash.
The most common side effects associated with sunitinib were fatigue, diarrhea, nausea, mouth sores, and skin discoloration.
Dr. Demetri said the new agent will provide oncologists with a therapeutic option for patients whose tumors become resistant to imatinib, a problem that generally develops after 18 months to 2 years of therapy.
The symposium was also sponsored by the American Gastroenterological Association, the American Society for Therapeutic Radiology and Oncology, and the Society of Surgical Oncology.
PET images of gastrointestinal stromal tumors in the liver show how multitargeted biologic therapy can halt growth. Photos courtesy Dr. Annick D. Van den Abbeele and Dr. George D. Demetri/Dana-Farber Cancer Institute
