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Everolimus Effect on Gastrin and Glucagon in Pancreatic Neuroendocrine Tumors
Marianne E Pavel1, David Chen, Wei He
1From the *Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin/Campus Virchow Klinikum, Berlin, Germany; †Novartis Pharmaceuticals Corporation, East Hanover, NJ; ‡Department of Medical Oncology, University Medical Center, University of Groningen, Groningen, The Netherlands; §Oncologie Endocrinienne et Médecine Nucléaire, Institut Gustave-Roussy, Villejuif, France; and ∥Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX.
Objectives:
The pharmacodynamic effects of everolimus on gastrointestinal hormone levels have not been described in patients with pancreatic neuroendocrine tumors (pNETs). We report the effects of everolimus on gastrin and glucagon levels in patients with progressive pNET in RADIANT-1 (a single-arm phase II trial) and RADIANT-3 (a placebo-controlled, randomized, phase III trial).
Methods:
Serum gastrin and glucagon levels were determined by immunoassay at baseline and at predose in subsequent treatment cycles in patients with elevated baseline hormone levels. The analyses included 158 patients from RADIANT-1 and 404 patients from RADIANT-3.
Results:
In RADIANT-1, everolimus induced a rapid, sustained decrease in median gastrin and glucagon levels to approximately 60% and 70% of baseline levels, respectively. In RADIANT-3, everolimus consistently reduced median gastrin and glucagon levels by greater than 50% and approximately 40%, respectively (everolimus vs placebo, P < 0.0001), whereas with placebo, both hormones at each time point were essentially the same as their baseline levels. In patients with concomitant octreotide long-acting repeatable treatment, the moderate pharmacodynamic effect on lowering gastrin was greater than that seen with everolimus alone.
Conclusions:
In addition to prolonging progression-free survival in patients with pNET, everolimus down-regulates excess production of 2 gastrointestinal hormones, which may help control their associated clinical syndromes.
Insights
Everolimus significantly reduces elevated gastrin and glucagon levels in patients with pancreatic neuroendocrine tumors (pNETs). This effect may help manage clinical syndromes associated with these hormones.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Pancreatic neuroendocrine tumors (pNETs) can cause excess gastrointestinal hormone production.
- The pharmacodynamic effects of everolimus on these hormones in pNET patients were previously undescribed.
Purpose of the Study:
- To investigate the effects of everolimus on serum gastrin and glucagon levels in patients with progressive pNET.
- To analyze these effects in the context of RADIANT-1 and RADIANT-3 clinical trials.
Main Methods:
- Serum gastrin and glucagon levels were measured by immunoassay at baseline and during treatment cycles.
- Analysis included 158 patients from RADIANT-1 and 404 patients from RADIANT-3 with elevated baseline hormone levels.
Main Results:
- Everolimus led to a rapid and sustained decrease in gastrin and glucagon levels in RADIANT-1.
- In RADIANT-3, everolimus significantly reduced gastrin and glucagon compared to placebo (P < 0.0001).
- Concomitant octreotide use enhanced the gastrin-lowering effect of everolimus.
Conclusions:
- Everolimus down-regulates excess gastrin and glucagon production in pNET patients.
- These pharmacodynamic effects may contribute to controlling associated clinical syndromes.
- Everolimus offers benefits beyond progression-free survival in pNET management.
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