1550P - Investigating the combination of bevacizumab and the EGF receptor inhibitor erlotinib for the treatment of metastatic renal cell carcinoma

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Renaud Grepin
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors R. Grepin1, M. Guyot2, J. Durivault1, B. Front1, D. Ambrosetti3, G. Pagès2
  • 1Medical Biology, Centre Scientifique de Monaco, 98000 - Monaco/MC
  • 2Cnrs Umr 7284/inserm U 1081, University Nice Sophia Antipolis, Institute for Research on Cancer and Aging, Nice/FR
  • 3Laboratoire Central D’anatomopathologie, Hôpital Pasteur, Nice/FR

Abstract

Background

One of the major characteristics of metastatic clear cell renal cell carcinomas (RCC) is the over-expression of the Vascular Endothelial Growth Factor (VEGF). Several treatments against this pro-angiogenic factor are usually used such as sunitinib or the anti-VEGF bevacizumab (BVZ). In a mouse experimental model of RCC we have described that BVZ accelerated tumor growth. A down-regulation of phospho tyrosine phosphatase receptor kappa (PTPRk) by tumor cells under the selection pressure exerted during BVZ treatment is a potential explanation for this accelerated growth. The main target of PTPRk is the Epidermal Growth Factor Receptor (EGFR). Thus, down-regulation of PTPRk leads to a constitutive activation of the EGFR. According to the literature BVZ combined with ERLO does not benefit patients. However, the EGFR mutations were not checked in this clinical study. Considering these data, a combination of an inhibitor of EGFR (erlotinib/Tarceva) with the BVZ/interferon alpha (INF) treatment could be more efficient against RCC growth.

Methods

Tumor cells were injected subcutaneously, bioluminescence was quantified by using an in vivo Imaging System.

Results

The BVZ/INF/ERLO treatment strongly reduced tumor volume and no tumor relapse has been observed compared to the reference treatment sunitinib. The triple combination reduces the production of redundant pro-angiogenic/pro-inflammatory cytokines of the ELR + CXCL family and induces a polarization of macrophages towards the M1 phenotype. The number of lymphatic vessels is inferior in tumors receiving this combination compared to the tumors of BVZ/INF or ERLO treated mice. Although no study has shown that BVZ combined with ERLO does not benefit patients, the EGFR mutations were not checked in this clinical study. Based on cells isolated from human RCC tumors we have identified a new mutation of the EGFR in human RCC, which could discriminate sensitive and insensitive patients to ERLO.

Conclusions

Together, our results indicate that BVZ/INF treatment could be more efficient in RCC if it is coupled to ERLO when a specific mutation of the EGFR is present. In conclusion BVZ/INF/ERLO is a relevant combination that deserves to be tested for the treatment of RCC.

Clinical trial identification

Legal entity responsible for the study

Centre Scientifique Monaco

Funding

Centre Scientifique Monaco

Disclosure

All authors have declared no conflicts of interest.