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.

Trial registration: ClinicalTrials.gov NCT00510068.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Figures

Fig 1.

Patient disposition. OS, overall survival. (*) Concurrent use of somatostatin analogs was allowed but not mandated. (†) At the time of progression during the double-blind phase, patients were unblinded and those randomly assigned to the placebo arm were allowed to cross over to open-label everolimus after assessment of benefit-risk by investigator on a case-by-case basis. (‡) All ongoing patients were unblinded at the end of the core phase (cutoff date, June 3, 2010) and were switched over to open-label everolimus. (§) At the time of study termination, 16 patients receiving everolimus were rolled over to study RAD001C2X01B (ClinicalTrials.gov identifier, NCT01789281) or commercial everolimus; one patient entered a compassionate use program in Canada.

Fig 2.

Kaplan-Meier plot of overall survival (full analysis set).

Fig 3.

Overall survival analysis by RPSFT (full analysis set). NA, not assessable; RPSFT, Rank-Preserving Structural Failure Time. (*) Reconstructed placebo data as if never treated with everolimus.

Fig 4.

Prognostic effects of baseline chromogranin A (CgA), neuron-specific enolase (NSE), and angiogenic biomarkers. bFGF, basic fibroblast growth factor; PIGF, placental growth factor; SVEGFR, soluble VEGF receptor; VEGF, vascular endothelial growth factor. (*) Elevated baseline CgA was defined as > 2× upper limit of normal. (†) Elevated baseline NSE was defined as > 1× upper limit of normal. (‡) P values are nominal without adjustment for multiple testing. For all angiogenic biomarkers, the median of distribution was used to define the threshold for elevated biomarker levels.