Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study

Abstract

Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.

Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence

“…In addition, elevated baseline CgA and NSE levels were associated with shorter PFS and OS with everolimus treatment[141]. Similarly, sub-analysis of RADIANT-3 trial also showed that high baseline CgA, NSE, placental growth factor (PIGF) or soluble vascular endothelial growth factor receptor 1 (sVEGFR1) levels were associated with poor OS[65], however, baseline CgA levels were not predictive for everolimus treatment effect on OS in the RADIANT-2 trial[59]. Another study genotyped the fibroblast growth factor receptor 4 (FGFR4) using DNA isolated from tissue or blood in panNETs, and found that patients homozygous for FGFR-G388 demonstrated greater tumor shrinkage with everolimus treatment than those harboring only one FGFR4-R388 allele[142].…”

The European Society for Medical Oncology 'Magnitude of Clinical Benefit Scale' field-tested in infrequent tumour entities: an extended analysis of its feasibility at the Medical University of Vienna

“…Noteworthy, in none of these trials a significant OS benefit was demonstrated. [8][9][10][11][12][13][14][15] Conclusion: To date, published trials are comparable in design and efficacy, and the corresponding MCBS-FT score of 2-3 is consistent with the moderate clinical benefit seen while treating patients with advanced or metastatic NET. The fact that all trials rated equally in quite similar clinical settings reflects however one difficulty of the scale in its current version: as only one trial may be considered at once (except for meta-analyses), there is no additional information for optimal sequencing of treatment options added by the ESMO-MCBS scoring system; this has also previously been discussed for colorectal cancer and renal cell cancer in our pilot analysis.…”

“…[8][9][10][11][12][13][14][15] Assessment of ESMO-MCBS scores for advanced NET revealed comparable results in all available data (all trials placebo controlled). The CLARINET and the PROMID trial represent two proof of principle studies demonstrating for the first time direct antiproliferative effects of somatostatin analogues for advanced midgut and pancreatic NET irrespective of progression status.…”

“…In NETs, for example, all current trials resulted in a MCBS-FT score of 2 or 3 reflecting the moderate PFS benefit aligned with a favourable toxicity profile quintessential for the treatment of this specific disease. [8][9][10][11][12][13][14][15] However, a maximum score of 3 is clearly inferior to results achieved for metastatic breast or colorectal Kiesewetter cancer. 5 This fact might possibly be related to the inferior power of trials in infrequent diseases.…”

Pancreatic neuroendocrine tumors

“…The oral mTOR inhibitor everolimus has been extensively studied in GEP-NETs. A randomized phase III study evaluating the efficacy of everolimus in advanced pNENs had been demonstrated to prolong PFS duration in patients with advanced-stage pNENs when compared with placebo (67). As a result of the significant improvement in PFS, everolimus was approved by the FDA for treatment of patients with advanced pancreatic NETs.…”