417PD - A phase 2 trial of the multitargeted kinase inhibitor lenvatinib (E7080) in patients (pts) with recurrent glioblastoma (GBM) and disease progression...

Date 29 September 2012
Event ESMO Congress 2012
Session CNS tumors
Topics Cytotoxic agents
Central Nervous System Malignancies
Therapy
Biological therapy
Presenter David Reardon
Authors D.A. Reardon1, E. Pan2, J. Fan3, J. Mink3, D.P. Barboriak4, J.J. Vredenburgh5, A. Desjardins5, K. Peters5, J. O'Brien3, P.Y. Wen1
  • 1Neuro-oncology Department, Dana-Farber Cancer Insitute, 02215 - Boston/US
  • 2Neuro-oncology, Moffitt Cancer Center, 33647 - Tampa/US
  • 3Pcu, Eisai Inc., Woodcliff Lake/US
  • 4Radiology, Duke University Medical Center, Durham/US
  • 5Medicine, The Preston Robert Tisch Brain Tumor Center at Duke, Durham/US

Abstract

Background

There is no effective therapy for recurrent GBM pts following progression on the vascular endothelial growth factor (VEGF)-targeting agent bevacizumab (BV), with historical series reporting progression-free survival at 6 months (PFS-6) of only 2%. Several mechanisms of tumor adaptation following anti-VEGF therapy have been proposed, including upregulation of alternative angiogenic cytokines. We therefore performed a single-arm phase 2 study to evaluate lenvatinib (L), an oral tyrosine kinase inhibitor targeting FGFR1-4, PDGFR�, VEGFR1-3, RET, and KIT, in pts with recurrent GBM progressing on BV.

Methods

32 pts with recurrent GBM (≤2 prior progressions) and progression on BV received L 24 mg once daily in 28-day cycles until PD or unacceptable toxicity. Dynamic contrast-enhanced MRI was performed before and after 1 day of L on a subset of pts (n = 16). Response was assessed using Response Assessment in Neuro-Oncology criteria. Primary endpoint was PFS-6. This cohort has completed enrollment; 1 pt is still ongoing.

Results

Median age was 52 y, 56% were male, and 19% had a KPS <80; 16% required dose reduction for toxicity and 25% withdrew from therapy due to treatment-related toxicity. Most common AEs were hypertension 47% (Gr 3: 18.8%), fatigue 44% (Gr 3: 15.6%), headache 41%, proteinuria 31% (Gr 3: 6.3%), and diarrhea 31%; 2 pts (6.3%) experienced Gr 4 fatigue and hypertension, respectively. One patient died due to pulmonary embolism; 28% of pts achieved stable disease. No objective responses were observed. PFS-6 rate was 8.3%; median PFS was 1.9 months (95% CI: 0.95-2.73); 6-month overall survival (OS) rate was 28%; median OS was 4.11 months (95% CI: 3.02-5.88). A ≥33% reduction in mean Ktrans was observed in 10 pts (63%) and a significant decrease in lesion volume (mean reduction: 33%, P = 0.00287) was found 1 day after therapy, indicating L affected tumor vascularity and vascular permeability.

Conclusions

Lenvatinib has modest activity and a similar toxicity profile when compared with other tyrosine kinase inhibitors. Further study of VEGF therapy failure mechanisms as well as biomarkers of outcome is needed.

Disclosure

D.A. Reardon: D. Reardon discloses reimbursement for serving as an advisory board member for Genentech/Roche and Schering/Merck in the past year.

E. Pan: E. Pan has been reimbursed as an advisory board member for Genentech in the past year. He has also been on the Speakers' Bureau for Genentech, Merck, and Sigma Tau in the past year.

J. Fan: J. Fan is an Eisai employee.

J. Mink: J. Mink is an employee of Eisai.

D.P. Barboriak: D. Barboriak discloses receiving imaging core lab support from Eisai Pharmaceuticals, ACRIN, NIBIB / RSNA QIBA Member of GE Medical Systems Neuro MRI advisory board Pulse sequence support from Siemens Healthcare.

J.J. Vredenburgh: J.J. Vredenburgh received financial compensation from Genentech/Roche for Speakers Bureau participation and consultation.

A. Desjardins: A. Desjardins received financial compensation from Genentech/Roche for Speakers Bureau participation.

J.P. O'Brien: J. P. O'Brien is an employee of Eisai.

P.Y. Wen: P. Wen discloses research support from Eisai.

All other authors have declared no conflicts of interest.