Neuroendocrine tumors are highly vascular, expressing vascular endothelial growth factor (VEGF) and demonstrating angiogenesis. Since the mTOR inhibitor everolimus has antiangiogenic activity, RADIANT-3 investigators evaluated several VEGF pathway tumor markers for their prognostic and predictive potential. The results were presented by James C. Yao, MD, in an abstract presentation at ESMO.1
Yao and colleagues evaluated pretreatment plasma samples for levels of the angiogenic cytokines VEGF-A, soluble VEGF receptors (sVEGFR1 and sVEGFR2), and placental growth factor (PlGF). The multivariate analysis showed that sVEGFR1 and PlGF were significant prognostic markers, with lower baseline levels associated with longer progression-free survival (PFS). This means that patients with high sVEGFR1 and high PlGF are likely to have a worse prognosis. None of the markers, however, proved predictive of a benefit with everolimus, he reported.
“PFS was significantly improved to a similar extent in patients receiving everolimus, compared with patients who received placebo, regardless of baseline levels of these markers,” he said, “suggesting that none of these markers are associated with the efficacy of everolimus in patients with pNET. The markers are prognostic but not predictive.”
An updated overall survival (OS) analysis of the phase 3 sunitinib trial was also reported at ESMO by Sandrine Faivre, MD, of Clichy, France.2
“At trial closure, there was an advantage for sunitinib over placebo in OS, a secondary end point. At that time 69% of patients on placebo crossed over to sunitinib upon disease progression or trial closure, potentially confounding the OS analysis. We now present OS data 2 years after study closure and after adjusting for crossover,” she said.
The intent-to-treat analysis without adjustment for crossover showed OS to be 33 months with sunitinib and 26.7 months with placebo (hazard ratio [HR], 0.71). The investigators then adjusted for crossover using 4 different statistical methods, which showed median OS with sunitinib to range from 16.4 months (HR, 0.43) to 26.7 months (HR, 0.49), depending on the model employed. This yielded an OS benefit that ranges from 6.3 to 16.7 months.
“Four methods of adjusting for crossover suggested that the effect of sunitinib on OS may have been more pronounced had no crossover occurred,” she said. “These analyses demonstrate a survival advantage and further support the clinical benefit of sunitinib for patients with advanced, progressive pNET.”
- Yao JC, Shah M, Panneerselvam A, et al. The VEGF pathway in patients with pancreatic neuroendocrine tumors: efficacy of everolimus by baseline marker level, and prognostic and predictive effect analyses from RADIANT-3. Presented at: European Society for Medical Oncology 2012 Congress; September 29, 2012; Vienna, Austria. Abstract 11540.
- Niccoli P, Faivre S, Raoul J, et al. Updated overall survival (OS) analysis from a phase III study of sunitinib vs. placebo in patients (Pts) with advanced, unresectable pancreatic neuroendocrine tumor (NET). Presented at: European Society for Medical Oncology 2012 Congress; September 29, 2012; Vienna, Austria. Abstract 11550.