Circulating protein biomarkers of sunitinib (SU) and interferon-α (IFN-α) efficacy in treatment (Tx)-naive patients (pts) with metastatic renal cell carcinoma (mRCC).

Abstract

10525 Background: In a randomized phase 3 trial, SU demonstrated superior PFS (primary endpoint) over IFN-α as first-line mRCC therapy, with a median OS of >2 yrs (Motzer, 2009). Here, we report an investigation of potential biomarkers of SU efficacy through assessment of plasma levels of 4 soluble proteins from this trial: VEGF-A, VEGF-C, sVEGFR-3 and IL-8. Methods: 750 Tx-naïve mRCC pts were randomized 1:1 to receive oral SU 50 mg/d on a 4-week-on/2-week-off schedule or IFN-α 9 MU subcutaneously thrice weekly. Pre-dose plasma samples were collected on days 1 and 28 of cycles 1–4 and at end of Tx and analyzed via ELISA. Possible correlations between plasma protein levels and PFS or OS were assessed by univariate Cox regression analysis. Results: Baseline characteristics of biomarker-evaluated pts in the SU (n=33) and IFN-α (n=30) arms were comparable to their respective ITT populations. Compared with baseline levels, VEGF-A reversibly increased >4-fold and sVEGFR-3 reversibly decreased by >50% with SU Tx, but was unchanged with IFN-α Tx. In both Tx arms, VEGF-C changes were minimal, while IL-8 increased >50% at all time points. For each of the following regression analysis results, low soluble protein levels at baseline were associated with a lower risk of progression and/or death. In the SU arm, baseline VEGF-A, sVEGFR-3 (both P<0.005) and VEGF-C (P=0.022) correlated with PFS, while baseline VEGF-A, sVEGFR-3, and IL-8 (all P<0.0005) correlated with OS, with a trend for VEGF-C (P=0.135). In the IFN-α arm, baseline VEGF-A, IL-8 (both P<0.0001) and VEGF-C (P=0.006) correlated with PFS, while baseline VEGF-A (P=0.002), IL-8 (P<0.001) and sVEGFR-3 (P=0.048) correlated with OS, with a trend for VEGF-C (P=0.0634). Pharmacodynamic changes were not associated with PFS or OS for any plasma protein. Conclusions: Analysis of a subset of pts in a randomized phase 3 RCC study support literature evidence that high circulating VEGF-A levels are associated with poor prognosis in RCC. Results further suggest that high baseline levels of VEGF-C and IL-8 may be associated with poor prognosis in RCC, and that low plasma sVEGFR-3 levels may predict improved outcome following SU Tx.