Biomarkers May Predict TKI Response in Metastatic RCC

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Circulating blood biomarkers related to angiogenesis may help clinicians predict who will have a robust response to sunitinib.
Circulating blood biomarkers related to angiogenesis may help clinicians predict who will have a robust response to sunitinib.

Angiogenesis-related biomarkers regulated by hypoxia were found to be strong predictors of primary renal tumor response (PRT), progression-free survival (PFS), and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) who were being treated with sunitinib prior to kidney removal, according to research published in Clinical Cancer Research.1

The prospective phase 2 PREINSUT study (ClinicalTrials.gov Identifier: NCT00930345), conducted by the French Ministry of Health, Pfizer France, the Institut National du Cancer, and sponsored by Assistance Publique-Hôpitaux de Paris, enrolled 32 patients scheduled for nephrectomy and examined their response to treatment with two cycles of sunitinib to see if the presence of certain biomarkers circulating in their blood could provide clues about if the tyrosine kinase inhibitor was working.

The primary end point of the study was a reduction in the size of primary renal tumors (PRT), and secondary end points were PFS and OS.

Of the 27 patients who were evaluable for PRT, one-third (33.3%) had at least a 10% decrease in PRT size. OS was significantly longer in patients who responded to sunitinib compared with those who did not (28.8 months vs 11.1 months, respectively, P = .03).

At baseline, biomarkers found to be significantly associated with a response to treatment with sunitinib were endothelial progenitor cells (P=.029), which are thought to contribute most to changes in renal tumor size, or PRT. High levels of vascular endothelial growth factor (VEGF)-A, stromal cell-derived factor-1 (SDF-1), and soluble VEGF receptor 1 (sVEGFR1) — as well as low levels of soluble VEGF receptor 2 (sVEGFR2) — were linked to significantly worse outcomes related to PFS (P ≤ .001).

During sunitinib treatment cycle 1, the smaller the increase in sVEGFR1, and the greater the increase of SDF-1, the longer the OS (.01< P≤ .05). Sunitinib-related adverse events were reported in 27 patients (84%), though most of the effects were mild or moderate.

Following treatment initiation, the plasma factors thought to best predict PRT were SDF-1 and platelet-derived growth factor (PDGF)-BB. sVEGFR2 was a predictor of PFS, whereas OS was most closely linked to levels of sVEGFR1 circulating in the blood.

Targeted therapies in mRCC outside of sunitinib that also inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGFR) include sorafenib, bevacizumab, pazopanib, and axitinib.2 Everolimus and temsirolimus also target the VEGF pathway. Other treatments for mRCC that focus on targets outside of this pathway include cabozantinib and nivolumab (either alone or combined with ipilimumab).1

The investigators concluded that poorly vascularized tumors appeared to be associated with worse outcomes, and “angiogenesis-related parameters have a promising place in therapy guidance and should be evaluated on a larger scale.”

References

  1. Mauge L, Mejean 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
  2. Hsieh JJ, Purdue MP, Signoretti S, et al. Renal cell carcinoma. Nat Rev Dis Primers. 2017;3:17009. doi 10.1038/nrdp.2017.9
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