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Everolimus improved PFS in neuroendocrine tumors
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SAN FRANCISCO — Everolimus may be a treatment option for patients with neuroendocrine tumors, although improvements in PFS were accompanied with increased adverse events, results from RADIANT-2 showed.
It is estimated that neuroendocrine tumors account for just more than 1% of all malignant cancers by incidence, and their incidence is on the rise. Most patients are diagnosed with advanced disease, and 65% of those will die within 5 years. Standard treatment with octreotide LAR (Sandostatin LAR, Novartis) has been shown to prolong time to progression in midgut carcinoid tumors, but there are no approved therapies for advanced carcinoid tumors.
James C. Yao, MD, associate professor in the department of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, presented results at the 2011 Gastrointestinal Cancers Symposium. He said the combination “demonstrates a clinically meaningful prolongation of median PFS.”
In reviewing the results, Mary F. Mulcahy, MD, associate professor in medicine, hematology/oncology, radiology and surgery at the Robert H. Lurie Comprehensive Cancer Center in Chicago, said the results showed efficacy with everolimus (Afinitor, Novartis), but those had to be weighed against toxicity associated with the drug.
“The activity of everolimus is demonstrated, but associated with significant adverse events,” Mulcahy said.
RADIANT-2 is a randomized, double blind, placebo-controlled, multicenter phase 3 trial of 10 mg daily everolimus plus 30 mg daily octreotide LAR (n=216) vs. 30 mg daily octreotide LAR and placebo (n=213). The primary endpoint was PFS.
“By central radiology review, everolimus was associated with a 5.1-month improvement in median PFS,” Yao said. “Median PFS was 16.4 months for the everolimus arm and 11.3 months for the placebo arm. This corresponded to an HR of 0.77, or a 23% reduction in the risk for progression.”
However, the P value (P=.026) missed the pre-specified boundary (P≤.0246), he added.
On local investigator review, median PFS was 12 months for the combination and 8.6 months for placebo (HR=0.78; 95% CI, 0.62-0.98). Yao said researchers observed benefits favoring everolimus across all subgroups.
He said treatment-related adverse events were consistent with the known safety profile of everolimus. However, Mulcahy said the discrepancy between the central review and the investigator review was troubling, and 70% of patients in the everolimus arm discontinued the study because of progression or adverse events compared with 75% in the placebo arm.
“Either way, that represents a failure of the therapy,” she said. “This is also demonstrated in the median duration and the range of exposure being exactly the same in both arms. There is a signal that there is a benefit, but I don’t think it’s well defined based on the data presented.”
Manisha H. Shah, MD, associate professor at the Ohio State University Comprehensive Cancer Center, presented results from RADIANT-3, which Yao presented at the European Society for Medical Oncology 35th Congress. Mulcahy said she was more positive regarding those results, which evaluated everolimus vs. placebo in patients with pancreatic neuroendocrine tumors.
Mulcahy said only 62% of patients assigned everolimus in RADIANT-3 discontinued the study because of adverse events or progression compared with 84% of patients assigned placebo and 70% assigned everolimus and octreotide LAR in RADIANT-2. That was despite a median duration of treatment that was twice as long in the experimental group in RADIANT-3 than in the placebo group.
“There is a significant and durable benefit of everolimus in previously treated patients,” she said. “The duration and sequencing of therapy remains undefined.”
For more information:
- Yao J. #159. Presented at: the 2011 Gastrointestinal Cancers Symposium; Jan. 20-22, 2011; San Francisco.
Disclosures: Dr. Shah reported receiving researcher support and serving on an advisory board for Novartis. Dr. Yao reported receiving honoraria and/or serving on advisory boards for Novartis, Ipsen and Pfizer, as well as receiving research support from Novartis. Dr. Mulcahy did not respond to requests for disclosure.