Roxanne Nelson

June 05, 2012

June 5, 2012 (Chicago, Illinois) — A new targeted agent might fulfill an unmet need for patients with gastrointestinal stromal tumors (GIST) that become resistant to current treatment.

According to the results of an international phase 3 trial, presented here at the 2012 Annual Meeting of the American Society of Clinical Oncology, the investigational agent regorafenib (Bayer) improved outcomes for patients who had developed resistance to imatinib (Gleevec) and sunitinib (Sutent).

In patients with metastatic and/or inoperable tumors, progression-free survival was significantly longer with regorafenib than with placebo (4.8 vs 0.9 months; hazard ratio, 0.27; P < .0001).

The treatment landscape for metastatic GIST changed dramatically after the approval of imatinib, and later sunitinib, for this indication. "We are now measuring survival in terms of years instead of months," said Christopher Ryan, MD, from the Oregon Health & Science University Knight Cancer Institute in Portland. However, for patients who progress after these therapies, there is currently no standard treatment, he said during a review presentation.

The dramatic improvement in outcomes was also noted by lead author George Demetri, MD, director of the Ludwig Center at the Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.

Before 2000, survival was 3 to 6 months, Dr. Demetri explained during a press briefing held in advance of the presentation. Now, survival in this population is 5 years and counting. "I'm still taking care of patients who have been on imatinib for 12 years," he said.

"However, only 1 in 10 is that lucky," he continued. "For the other 9, resistance occurs, and with the emergence of drug resistance comes a fatal outcome, eventually."

Met Primary End Points

Regorafenib is an orally bioavailable small molecule with potential antiangiogenic and antineoplastic activities being developed by Bayer. It binds to and inhibits vascular endothelial growth-factor receptors (VEGFRs) 2 and 3, and Ret, Kit, PDGFR, and Raf kinases. In an earlier phase 2 trial of patients with GIST who failed both imatinib and sunitinib therapy, regorafenib demonstrated substantial activity, according to Dr. Demetri and colleagues.

In the current study, they evaluated the efficacy and safety of regorafenib in 199 patients with metastatic and/or unresectable GIST who had failed previous treatment with imatinib and sunitinib.

The cohort was randomly assigned, in a 2:1 ratio, to receive best supportive care plus either regorafenib 160 mg once daily (3 weeks on, 1 week off) or placebo. The primary end point was progression-free survival (measured using modified Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), and secondary end points included overall survival, disease control rate (defined as the rate of partial response plus stable disease lasting at least 12 weeks), response rate, duration, safety, and correlative genotype.

At the advent of disease progression, patients were eligible for unblinding and could cross over to open-label regorafenib.

At the time of randomization, all patients were stratified according to previous systemic therapies and geographic region. The baseline characteristics were balanced in the 2 study groups.

Dr. Demetri noted that the primary end point of progression-free survival was met. At 3 months, the progression-free survival rate was 60% in the regorafenib group and 11% in the placebo group; at 6 months, it was 38% and 0%, respectively. The disease control rate was 53% and 9%, respectively.

"Progression-free survival was highly statistically significant," Dr. Demetri reported. "Regorafenib induced almost 5 months of disease control, compared with less than 1 month in the group that got the placebo."

Trend for Overall Survival

The hazard ratio for overall survival was 0.77 (P = .20), with 85% of the patients on placebo crossing over to the active drug.

Dr. Demetri noted that it was not surprising that objective tumor shrinkage was small. Survival was also confounded because of the high crossover rate. "Overall survival trended in favor of patients who started on regorafenib, with a 23% decrease in the risk of death," he said, "but that was not statistically significant, as expected."

"The crossover design allowed patients to participate in the trial while minimizing the risks of being assigned to placebo," he explained.

Adverse events were also as expected. The most common grade 3 treatment-emergent adverse events in the regorafenib group were hypertension (28%), hand–foot skin reaction (21%), and diarrhea (8%).

"This phase 3 study clearly shows that there are effective therapies for patients with rare tumors, and the crossover design is very important for patients to be able to access the drug," said Sylvia Adams, MD, assistant professor in the Department of Medicine at New York University Langone Medical Center in New York City, who served as briefing moderator.

At a Highlights of the Day session, Dr. Ryan noted that regorafenib produced a significant improvement in progression-free survival after treatment failure on standard therapy, which is an unmet clinical need. However, he added that there is no information on how this result compares with the strategies that are currently used in such patients, such as the off-label use of other tyrosine kinase inhibitors, or the continuation of imatinib or sunitinib therapy despite progression.

Dr. Demetri and several coauthors report financial relationships with industry, as noted in the abstract.

2012 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract LBA10008. Presented June 4, 2012.

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