794PD - Novel circulating proteins, single nucleotide polymorphisms (SNPS), and molecular tumor markers as potential biomarkers of sunitinib efficacy in tre...

Date 01 October 2012
Event ESMO Congress 2012
Session Genitourinary tumors, non-prostate (renal cancer)
Topics Renal Cell Cancer
Translational Research
Presenter Robert Motzer
Authors R.J. Motzer1, T. Hutson2, G.R. Hudes3, R.A. Figlin4, J. Martini5, P.A. English6, L. Wood7, X. Huang8, O. Valota9, J.A. Williams5
  • 1Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, 10021 - New York/US
  • 2Gu Oncology Program, Baylor Simmons Cancer Center-Texas Oncology, PA, 75246 - Dallas/US
  • 3Genitourinary Malignancies Program, Fox Chase Cancer Center, 19111 - Philadelphia/US
  • 4Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 90048 - Los Angeles/US
  • 5Translational Oncology, Pfizer, 92121 - La Jolla/US
  • 6Translational Oncology Statistics, Pfizer, 92121 - La Jolla/US
  • 7Global Research And Development, Pfizer, 06340 - Groton/US
  • 8Statistics, Pfizer, 92130 - La Jolla/US
  • 9Oncology, Pfizer, 20152 - Milano/IT

Abstract

Background

In a randomized, phase II trial of sunitinib on the approved intermittent schedule vs. continuous daily dosing (CDD) in treatment-naïve pts with advanced RCC, median TTP (primary endpoint) was 9.9 vs. 7.1 mo, respectively (P = 0.090; J Clin Oncol 2012;30:1371). Here we report three separate exploratory biomarker analyses conducted as part of this study.

Methods

Pts received sunitinib 50 mg/d on the 4-wk-on-2-wk-off schedule (Schedule 4/2; n = 146) or 37.5 mg/d on the CDD schedule (n = 146). The following were performed: (1) analysis of a broad base of soluble proteins (up to c.1000) in serum samples via two distinct multiplex platforms, correlating protein levels with response; (2) germline genotyping to explore potential associations between five SNPs in the VEGF-A (2 SNPs) and VEGFR-3 (3 SNPs) genes with response and survival; and (3) tumor IHC for HIF-1α and CA-IX plus analysis of tumor VHL gene inactivation status to explore their correlation with response and survival.

Results

Using 74 baseline samples from Schedule 4/2, lower Ang-2 and higher MMP-2 baseline levels were identified by both multiplex platforms as significantly associated with better overall response. In 202 pts who were genotyped (both schedules combined), there were no significant correlations between VEGF-A or VEGFR3 SNPs and outcome. In 149 IHC-evaluable pts (both schedules combined), PFS was higher for HIF-1a percent of tumor expression values of 0–2 vs. 3–4 (P = 0.034). For VHL inactivation (up to 143 evaluable pts), there were no significant associations with outcome by inactivation mechanism (mutation [86% of VHL inactive pts], methylation [14%], or large deletion [7%]) or when the inactivation mechanisms were grouped together.

Conclusions

Using a multi-method approach, serum Ang-2 and MMP-2 and tumor HIF-1α have been identified for further research as potential biomarkers for sunitinib efficacy in advanced RCC. No association with outcome was observed for SNPs selected for investigation based on prior reports of their prognostic value (Eur J Cancer 2011;47[suppl 1]:S505; Lancet Oncol 2011;12:1143).

Disclosure

R.J. Motzer: Advisory role with Pfizer. Research funding from Pfizer.

T.E. Hutson: Advisory relationship with Pfizer, GlaxoSmithKline, AVEO, Bayer, and Novartis. Honoraria from Pfizer, GlaxoSmithKline, Bayer, and Novartis. Research funding from Pfizer, GlaxoSmithKline, AVEO, Bayer, and Novartis.

G.R. Hudes: Advisory relationship with Pfizer.

R.A. Figlin: Research funding from Novartis.

J. Martini: Employed by Pfizer as a Director of Translational Oncology and holds Pfizer stock.

P.A. English: Employed by Pfizer as a Director of Translational Oncology Statistics and hold Pfizer stock.

L. Wood: Employed by Pfizer as a Principal Scientist and holds Pfizer stock.

X. Huang: Employed by Pfizer as a statistician and holds Pfizer stock.

O. Valota: Employed by Pfizer as a Clinician and holds Pfizer stock.

J.A. Williams: Employed by Pfizer as a Director of Translational Oncology and holds Pfizer stock.