233P - Phase 2 clinical evaluation of preclinically defined biomarkers for vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) tivoz...

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Renal Cell Cancer
Translational Research
Presenter Thomas Hutson
Citation Annals of Oncology (2014) 25 (suppl_4): iv58-iv84. 10.1093/annonc/mdu326
Authors T. Hutson1, W.K. Rathmell2, B. Feng3, M.O. Robinson3, J. Gyuris4, J. Lin3, T. Choueiri5
  • 1Gu Oncology Program, Baylor Sammons Cancer Center, 75246 - Dallas/US
  • 2Lineberger Comprehensive Cancer Center, North Carolina Cancer Hospital, University of North Carolina, 27599 - Chapel Hill/US
  • 3Clinical Research, AVEO Oncology, Cambridge/US
  • 4Clinical Research, AVEO Oncology, 02142 - Cambridge/US
  • 5Division Of Solid Tumor Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US



Despite significant effort, identifying predictive biomarkers for VEGF-targeted therapies remains a challenge. Using population-based tumor models, we identified a population of infiltrating myeloid cells associated with resistance to tivozanib, a selective VEGF receptor TKI. Myeloid cell biomarkers (immunohistochemistry [IHC] and RNA) from preclinical studies were evaluated in a phase 2 RCC clinical trial.


Prespecified biomarkers were evaluated in AV-951-10-202 (NCT01297244), a single-arm trial of tivozanib monotherapy in nephrectomized, targeted, therapy-naive RCC. RNA signatures were quantified using averaged qRT-PCR values on available tumor formalin-fixed paraffin-embedded archival tissues. CD68 (+)-infiltrating myeloid cells were quantified by IHC (Aperio Scanscope). RNA signatures were evaluated for prognostic impact in a dataset collected prior to the use of VEGF targeted therapies (Zhao et al. PLoS Med. 2006;3:e13).


Patients (n = 105) were enrolled (90 clear cell [cc] histology): intent-to-treat (ITT) progression-free survival (PFS), 9.7 mo; ccRCC PFS, 9.7 mo). ccRCC samples that passed quality check (RNA, 63; IHC, 66) were analyzed. Low myeloid signature score was associated with significantly longer PFS based on median cutoff (PFS 14.7 vs 8.3 mo, hazard ratio [HR] 0.49, P = .035; 95% CI 0.25-0.96), and as a continuous variable (P = .03; N = 63). The CD68 IHC score exhibited a similar trend but was not significant (median cutoff PFS 13.3 vs 9.2, HR 0.55, P = .067; 95% CI 0.28–1.05; continuous P = .057, N = 66). This gene signature exhibited a prognostic effect in a historical data set (Zhao, 2006).


A preclinically derived myeloid signature identified a ccRCC population with longer PFS on tivozanib and further provides a candidate VEGF pathway resistance mechanism amenable to inhibition. These results warrant the consideration of combination therapies targeting both the VEGF pathway and myeloid cells.


T. Hutson: Advisory boards; Corporate sponsored research: Pfizer, Bayer, GSK, AVEO, Novartis; B. Feng, J. Gyuris and J. Lin have declared: AVEO Oncology employee o Stock o Salary M.O. Robinson: • Former AVEO Oncology employee; T. Choueiri: Advisory boards: AVEO, GSK, Bayer, Novartis, Pfizer Corporate sponsored research: Pfizer . All other authors have declared no conflicts of interest.