203P - Placental growth factor (PIGF) as a biomarker in patients (pts) with solid tumors treated with linifanib (ABT-869)

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Drug Development
Presenter Evelyn Mc Keegan
Authors E.M. Mc Keegan1, B.C. Goh2, H.C. Toh3, N. Tannir4, A. Chakravartty5, P.J. Ansell1, S. Datwyler6, M.D. McKee7, J. Ricker7, D.M. Carlson7
  • 1Cancer Discovery, Abbott, 60064 - Abbott Park/US
  • 2Cancer Science Institute Of Singapore, National University Hospital, Singapore, Singapore/SG
  • 3Medical Oncology, National Cancer Centre Singapore, Singapore/SG
  • 4Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston/US
  • 5Exploratory Statistics, Abbott, Abbott Park/US
  • 6Abbott Diagnostics, Abbott, Abbott Park/US
  • 7Clinical Oncology, Abbott, Abbott Park/US

Abstract

Introduction

Linifanib is a VEGF/PDGF receptor tyrosine kinase inhibitor (TKI). PlGF is a member of the VEGF family and is induced upon inhibition of VEGF signaling. We explored whether changes in PlGF levels during linifanib therapy could predict clinical outcome.

Methods

An exploratory, retrospective analysis was performed for pts enrolled internationally in phase (P) 1 (solid tumor) and hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) P2 linifanib monotherapy trials. Efficacy was assessed by RECIST and safety by NCI-CTCAE. Plasma PlGF levels were analyzed using the Architect system (Abbott) and relationships between PlGF levels, time-to-progression (TTP) or progression-free survival (PFS), and overall survival (OS) were determined.

Results

130 pts were enrolled; 33 in P1; 44 HCC in P2 and 53 RCC in P2 studies. Across all studies, PlGF levels were induced in a dose and time- dependent manner by linifanib in pts with multiple solid tumor types. P1 pts were assessed for an association for PlGF with TTP. Of the pts assessed in P1 at day (D) 15, those with PlGF levels > 40 pg/ml had improved TTP (328 D; p = 0.01), compared to those with PlGF levels <40 pg/ml (96 D). Due to these findings in P1, we explored PlGF levels further in P2 in uniform populations. In HCC, an efficacy threshold was calculated for mean ΔPlGF between D 8-22. Pt with ΔPlGF > 66.3 pg/ml at D8-56 had improved PFS (p = 0.029) and OS (p = 0.02). In RCC, 5 pts with ΔPlGF below this threshold had median PFS of 100 D vs 207 D in the remaining pts (p = NS). Across the P2 studies, toxicity thresholds were determined using PlGF levels at D8 and toxicity events resulting in dose reductions or interruptions. The efficacy and toxicity thresholds were used to identify optimal ΔPlGF levels associated with improved OS in HCC (p = 0.01) and RCC pts (p = 0.001).

Conclusions

Optimal ΔPlGF plasma levels were identified and associated with improved outcome in HCC and RCC pts receiving linifanib. Monitoring of PlGF levels may allow clinicians to identify pts with increased sensitivity or toxicity risk on linifanib. Further evaluation in randomized linifanib studies is warranted, including dose adjustments based on ΔPlGF levels.

Disclosure

E.M. Mc Keegan: Full time Abbott employee who owns stock.

A. Chakravartty: Full time Abbott employee who owns stock.

P.J. Ansell: Full time Abbott employee who owns stock.

S. Datwyler: Full time Abbott employee who owns stock.

M.D. McKee: Full time Abbott employee who owns stock.

J.L. Ricker: Full time Abbott employee who owns stock.

D.M. Carlson: Full time Abbott employee who owns stock.

All other authors have declared no conflicts of interest.