1154O - The VEGF pathway in patients with pancreatic neuroendocrine tumors: efficacy of everolimus by baseline marker level, and prognostic and predictive e...

Date 29 September 2012
Event ESMO Congress 2012
Session NETs and endocrine tumors
Topics Anti-Cancer Agents & Biologic Therapy
Neuroendocrine Cancers
Presenter James Yao
Authors J.C. Yao1, M. Shah2, A. Panneerselvam3, S. Stergiopoulos4, D. Chen5, T. Ito6, M. Pavel7
  • 1Gastrointestinal Medical Oncology, MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 2Medical Oncology, Ohio State University, Columbus/US
  • 3Oncology Biometrics And Data, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 4Oncology, Novartis Pharmaceuticals, East Hanover/US
  • 5Oncology Biometrics And Data, Novartis Pharmaceuticals Corporation, Florham Park/US
  • 6Medicine And Bioregulatory Science, National Cancer Center Hospital, Tokyo/JP
  • 7Dept Of Gastroenterology & Hepatology, Charité Universitätsmedizin Berlin, 13353 - Berlin/DE

Abstract

Background

RADIANT-3 was a phase III study investigating the effect of the mammalian target of rapamycin inhibitor everolimus on progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (pNET; Yao et al, NEJM, 2011). Everolimus significantly improved PFS compared with placebo (11 vs 4.6 months, P < .001). Here we investigate the predictive and prognostic effect of soluble VEGF pathway biomarkers among patients treated in this study.

Methods

Baseline plasma levels of VEGF-A, PlGF, sVEGFR1, and sVEGFR2 were determined by ELISA using multiplexed MSD platform. The optimal cutoffs for these markers were explored using the “survival tree analysis” method. Interaction of treatment and baseline marker status (< or ≥ cutoff) was analyzed using a Cox proportional hazards model to assess predictive effects of these markers. P values and hazard ratios for prognostic effects were obtained using stratified log rank test and Cox proportional hazards model, stratified by treatment.

Results

PFS was significantly improved to a similar extent in patients receiving everolimus compared with patients who received placebo, regardless of baseline levels of markers (P < .001, all analyses; Table), suggesting that none of these markers are associated with the efficacy of everolimus in patients with pNET. However, significantly longer PFS was seen in those with lower VEGF-A, PlGF, and sVEGFR1 levels, suggesting these three markers are prognostic in pNET (Table).

Conclusions

These exploratory analyses demonstrated consistent everolimus efficacy in all patients with advanced pNET irrespective of their baseline VEGF pathway biomarker levels. However, levels of VEGF-A, PlGP, and sVEGFR1 are potential prognostic factors for pNET.

Marker Cutoff (pg/mL) Median PFS Prognostic effect HR [95% CI]; P value Treatment effect P value
VEGF-A 246.1 8.3 vs 5.5 1.50 [1.17-1.92]; <.001 <.001
PlGF 32.06 8.0 vs 4.2 1.52 [1.14-2.02]; .004 <.001
SVEGFR1 226.2 8.3 vs 5.5 1.62 [1.27-2.07]; <.001 <.001
SVEGFR2 24503.1 10.8 vs 5.7 1.30 [0.96-1.76]; .090 <.001

Disclosure

J.C. Yao: Consultant/advisory role for Novartis, Ipsen, Pfizer, Endo; Honoraria from Novartis; Research funding from Novartis, Genentech.

M. Shah: Honoraria for presentations and participation in Advisory Board Meetings: Novartis, Ipsen, Pfizer Research grant: Novartis.

A. Panneerselvam: Novartis employee.

S. Stergiopoulos: Novartis employee.

D. Chen: Novartis employee.

M. Pavel: Honoraria for presentations and participation in Advisory Board Meetings: Novartis, Ipsen, Pfizer Research grant: Novartis.

All other authors have declared no conflicts of interest.