Prognostic factors in patients with advanced renal cell carcinoma treated with VEGF-targeted agents

Abstract

The medical treatment of metastatic renal cell carcinoma (mRCC) has undergone a paradigm shift during the last decade with the approval of five drugs targeting vascular endothelial growth factor (VEGF) or its receptors (bevacizumab, sunitinib, sorafenib, pazopanib and axitinib) and of two drugs inhibiting the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway (temsirolimus and everolimus). Median survival has now reached 2 years in mRCC patients receiving first-line targeted treatment. A considerable body of work was conducted on the identification of prognostic factors of survival in the earlier era of immunotherapy of mRCC. The current challenge is to pursue this work on biomarkers of prognosis for targeted therapy and, even more importantly, to identify predictive factors of response to such therapy. This review provides an overview of recent key work on prognostic and predictive factors in patients with advanced clear cell RCC treated with VEGF-targeted agents.

Keywords::

• mTOR
• predictive factor
• prognostic factor
• renal cell carcinoma
• TKI
• VEGF-targeted therapy

Financial & competing interests disclosure

YA Vano has received honoraria for consulting from Sanofi, Pfizer, Hospira and Novartis; E Tartour has received a laboratory grant from GSK; L Fournier has received speaker and author honoraria from Pfizer, and author honoraria from Merck; S Oudard has received honoraria for consulting from Pfizer, Sanofi, Novartis and Bayer; B Beuselinck has received research funding from Pfizer; A Mejean has received honoraria for consulting from Novartis, Pfizer and GSK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• A better understanding of renal tumor biology has led to the development and approval within the last 5 years of seven targeted therapies, of which five directly target VEGF(R).

• The Memorial Sloan Kettering Cancer Center prognostic model developed during the immunotherapy era has been validated during the VEGF(R)-targeted therapy era. The main prognostic factors are predictors of short survival, time from diagnosis to treatment, baseline hemoglobin, neutrophilia, thrombocytopenia, lactate dehydrogenase, baseline corrected calcium and the presence of bone metastases.

• Hypoxia-related proteins (carbonic anhydrase IX, VEGF(R), hypoxia-inducible factor, tissue inhibitor of metalloproteinase-1) and biomarkers of inflammation (C-reactive protein, IL6, neutrophil-to-lymphocyte ratio) have been shown to be prognostic of survival in metastatic renal cell carcinoma patients, but only two of these biomarkers (C-reactive protein, neutrophil-to-lymphocyte ratio) are in current routine use.

• Hypertension induced by antiangiogenic therapy seems to be strongly correlated with efficacy. The evidence for other AEs (treatment-induced hypothyroidism, hand–foot syndrome and fatigue) being potential prognostic factors is limited. However, these AEs seem to be able to predict response to antiangiogenic therapy. The dose titration arm in the Phase II trial of first-line axitinib therapy suggested that dose in patients without hypertension has to be increased to improve survival.

• New imaging techniques (FDG-PET/CT, DCE-US, DCE-MRI) and/or new criteria (modified Choi, tumor burden and tumor growth rate) show promise as ways of assessing response to VEGF(R)-targeted therapy. The Descartes criteria, with a 10% cutoff for response on CT scans, would seem to be superior to conventional criteria in identifying patients surviving longer while on antiangiogenic therapy. These new criteria are simple to use and can be implemented as of now though, like newer imaging, they need to undergo further validation.

• Single nucleotide polymorphisms in genes such as NR1/2, VEGFR, ABCB1 and FGFR2 seem to be of value in predicting response to sunitinib and survival.

• New antibodies (anti-PD-1/anti-PDL1 antibody) have sparked renewed interest in tumor immunity. Unlike in other solid tumors, intratumoral CD8+ Tcells are strongly correlated with short survival in primary renal cell carcinoma and metastatic renal cell carcinoma.

• Sarcomatoid component is a factor signaling poor prognosis, but there are no data on a difference in the efficacy of multityrosine kinase receptor inhibitors in patients with or without a sarcomatoid component.

• Von Hippel Landau mutation or hypermethylation status provides no predictive information on multityrosine kinase receptor inhibitor efficacy.