Angiogenesis-Related Parameters Regulated by Hypoxia May Predict Poorer Survival in Metastatic RCC

The presence of biomarkers including SDF-1, VEGF-A, and sVEGFR1 and 2 at baseline were associated with poorer progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with sunitinib (Sutent) prior to nephrectomy.

According to results from the PREINSUT (NCT00930345) trial, endothelial progenitor cells were significantly associated with primary renal tumor (PRT) response at baseline. VEGF-A, SDF-1, soluble VEGF receptors (sVEGFR) 1 and 2 were associated with PFS, and SDF-1 and sVEGFR1 were significantly associated with OS.

Changes in SDF-1 and PDGF-BB during treatment were also associated with PRT response. Changes during treatment in sVEGFR2 were associated with PFS, and changes in SDF-1 and sVEGFR1 were associated with OS.

“Several angiogenesis-related parameters regulated by hypoxia, assessed at baseline or during sunitinib treatment, were significant predictors of PRT response, PFS, and OS,” wrote corresponding author Stéphane Oudard, MD, PhD, department of Medical Oncology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Université Paris Descartes, and colleagues. “Because these blood biomarkers are not influenced by tumor heterogeneity, and can be easily assessed during follow-up, they have a promising role for guiding sunitinib therapy, but need to be validated in larger trials.”

Investigators found no correlation between clinical outcome and plasma sunitinib or its active metabolite steady-state trough concentrations.

In the multicenter, prospective, open-label, phase II PREINSUT trial, 32 treatment-naïve adults received 2 cycles of sunitinib prior to nephrectomy. Eligible patients had an ECOG score ≤1, and adequate hepatic, hematologic, and renal function.

Investigators’ primary aim was to determine if biomarkers could identify responders based on PRT size change. Response was defined as a ≥10% decrease in PRT size from baseline to the end of sunitinib treatment as assessed by modified RECIST criteria. The ability of biomarkers to predict PFS and OS were secondary objectives.

Twenty patients proceeded to nephrectomy. Sixteen progression-free patients restarted sunitinib following surgery.

Oudard et al used dynamic contrast-enhanced computed tomography (DCE-CT) to determine whether angiogenic tumoral status prior to treatment could predict which patients were likely to have a response to sunitinib. They also used DCE-CT to determine whether biomarkers could assess the VEGF inhibitor’s efficacy before a change in PRT size could be detected (C1d28), and at study’s end (C2d42).

Twenty-seven patients were evaluable for response, and C2d42 was available for 17. A total of 9 (33.3%) patients were considered to be responders. The median relative difference in tumor size from baseline to the end treatment was —5.9% (range, –13.5 to 1.2).

The median PFS was 4.5 months (95% CI, 1.7-12.3) at a median follow-up of 56.3 months (95% CI, 48.0-67.9). The median OS was 12.4 months (95% CI, 7.3-24.0). OS was nearly 3 times greater in responding patients compared with nonresponders (28.8 vs. 11.1 months; HR, 0.35; 95% CI, 0.14-0.92;P= .030).

Oudard et al observed a median SDF-1 increase of 31.9% among 9 responders (range, 23.7%-71.1%) in cycle 1 of treatment compared with an increase of 12.4% among the 16 nonresponders (range, 3.9%-31.5%). In cycle 2, decrease in PDGF-BB was greater among nonresponders than in responders (—51.1% vs 7.3%;P= .030).

Low baseline levels of sVEGFR2 and high levels of VEGF-A, SDF-1 and sVEGFR1, and were significantly associated with a shorter PFS. High levels of SDF-1 and sVEGFR1 correlated to significantly shorter OS.

“At baseline, high levels of VEGF-A, SDF-1, sVEGFR1, possibly reflecting hypoxia, and a low level of sVEGFR2 seems to be associated with a worse outcome,” investigators wrote. “Hypoxia-induced synthesis (VEGF-A and SDF-1) and alternative splicing (sVEGFR1) indeed represent the common features between those molecules.”

Investigators found that OS was longer when decreases in sVEGFR1 were smaller (<32.5%) and SDF-1 increase was larger (>18%) during cycle 1. PFS was significantly shorter when sVEGFR2 decreased slightly during cycle 2.

Reference:

Mauge L, M&eacute;jean A, Fournier L, et al. Sunitinib prior to planned nephrectomy in metastatic renal cell carcinoma: angiogenesis biomarkers predict clinical outcome in the prospective Phase 2 PREINSUT trial [published online July 30, 2018].Clin Cancer Res. doi: 10.1158/1078-0432.CCR-18-1045. doi:10.1038/nm.4118.

Patents who had a PRT response had a significantly higher level of circulating endothelial progenitor cells at baseline compared with nonresponders (67.0 cells/mL vs 20.9 cells/mL). Oudard et al determined the data on circulating endothelial cells was not extensive enough to &ldquo;perform relevant statistical analysis.&rdquo;