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Everolimus Extends PFS in GI NET/NET of Unknown Primary

Carlson, Robert H.

doi: 10.1097/01.COT.0000481872.17791.3e
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SAN FRANCISCO—The oral mTOR inhibitor everolimus reduced the risk of disease progression by at least 40 percent compared with placebo in patients with advanced, progressive gastrointestinal (GI) neuroendocrine tumors (NETs) or NETs of unknown primary origin, according to a subanalysis of the randomized Phase III RADIANT-4 trial.

The benefit was seen in previously untreated patients as well as those who had tumors that progressed on somatostatin analogues, surgery, or chemotherapy.

Median progression-free survival in patients with GI NET treated with everolimus was 13.1 months, versus 5.4 months for placebo, a 44 percent risk reduction. And in patients with NET of unknown primary, median progression-free survival was 13.6 months for everolimus versus 7.5 months for placebo, a 40 percent risk reduction.

The study results were presented here at the 2016 Gastrointestinal Cancers Symposium by Simron Singh, MD, a medical oncologist at Sunnybrook Health Sciences Centre, Toronto, Ontario (Abstract 315).

“We see a significant delay in the tumor's growth with everolimus, regardless of whether [patients] had prior somatostatin treatment for the NET,” Singh said in a presscast. “Everolimus is an effective and exciting treatment option in a disease where we've had very few treatments to date.”'

Everolimus is approved by the Food and Drug Administration for treatment of pancreatic NET.


The first RADIANT-4 report, presented at the 2015 European Cancer Congress (ECC) in Vienna, was on the whole population of patients with advanced, progressive, well-differentiated (G1/G2), nonfunctional GI or lung NET who were randomly assigned to receive everolimus 10 mg/day or placebo. In that analysis, median progression-free survival was 11 months with everolimus compared with 3.9 months for placebo, a 52-percent reduction.

The sub-analysis Singh presented here focused specifically on GI NETs and NETs of unknown primary. The unknown primary tumors were generally thought to be of the GI system, Singh said.

The sub-analysis included 302 patients with previously treated, advanced GI neuroendocrine tumors and neuroendocrine tumors of unknown origin. All tumors were non-functional and asymptomatic.

Among the 175 patients with GI NET, 118 were treated with everolimus and 57 received placebo; and among the 36 with NET of unknown primary, 23 received everolimus and 13 placebo. All patients also received best supportive care.

Median patient age was 63 years; 55 percent were females, 75 percent had grade-1 tumors, and 25 percent had grade-2 tumors.

Singh said the most common locations in the GI subgroup were ileum (41%), rectum (23%), and jejunum (13%).


Median progression-free survival for patients with GI NET treated with everolimus was 13.1 months, versus 5.4 months for placebo, a 44 percent risk reduction. In patients with NET of unknown primary, median progression-free survival was 13.6 months for everolimus versus 7.5 months for placebo.

Singh said the adverse drug reactions with everolimus in RADIANT-4 were not unexpected.

“These had been seen in prior studies of the drug in kidney and breast cancer and were easily managed,” he said. These included stomatitis, diarrhea, infections, and fatigue.

Singh concluded: “In consultation with their oncologist, patients with neuroendocrine tumors may consider this as one of the new standard treatment options.”

The study received funding from Novartis Pharmaceuticals.

Everolimus Plus Somatostatin Analogue?

The entire RADIANT-4 cohort included patients with NET of GI or lung origin, while RADIANT-3 compared everolimus versus placebo in patients with advanced pancreatic NET. RADIANT-2 compared everolimus plus ocreotide versus octreotide alone in patients with advanced functional (carcinoid) NET.

The question of when everolimus might be used in treatment of any NET was brought up after the RADIANT-4 ECC presentation in Vienna. The discussant for the study, Enrique Grande, MD, Director of Research, Medical Oncology Service at the Hospital Universitario Ramón y Cajal, Madrid, Spain, was quoted as saying RADIANT-4 results were positive, showing superiority versus placebo in progression-free survival, in a news release from the European Cancer Congress.

Figure. Everolimus
Figure. Everolimus

But despite the encouraging activity of everolimus, “we do not have the full picture yet,” Grande said. “Should everolimus be pushed after somatostatin analogue failure? If so, is single agent everolimus better than maintenance of somatostatin analogue plus adding on everolimus?”

Grande also noted there was no biomarker and no molecular selection of patients in the study, and he questioned the strategy in patients with functioning tumors or lower hepatic tumor burden or good prognosis by primary tumor origin.

Broader Group of NET Patients

At the presscast, moderator Smitha Krishnamurthi, MD, an ASCO spokesperson, said, “While everolimus is already approved to treat pancreatic neuroendocrine tumors, these results demonstrate that it may also be effective for a broader group of patients with neuroendocrine cancer. The findings may add a new treatment option for patients whose tumors have worsened despite other treatments.

Krishnamurthi, Associate Professor in the Department of Medicine-Hematology and Oncology at Case Western Reserve University School of Medicine and leader of the Gastrointestinal Oncology Disease team, said once GI NETs have progressed on somatostatin analogues, there are no good systemic treatments.

“This report, demonstrating an improvement in risk of progression and with very little toxicity, is a very welcome finding,” Krishmanurthi said.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association Institute, American Society for Radiation Oncology, American Society of Clinical Oncology, and Society of Surgical Oncology.

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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