Host-mediated changes in patients receiving antiangiogenic therapy for resected RCC.

Abstract

4557 Background: VEGFR TKIs show activity in patients (pts) with metastatic RCC; however, their activity in the adjuvant setting is unknown. VEGFR TKI-targeted tx of pts with advanced cancer induces changes in circulating proangiogenic cyts; the source of these molecules is unknown. In order to see if these changes were host dependent we performed plasma analysis of circulating cyts in pts treated with adjuvant sunitinib (Su), sorafenib (So) or placebo (P) on ECOG E2805. Methods: 1,943 pts were enrolled in E2805, study of adjuvant tx in pts with resected RCC. Pts were randomized to Su 50mg po qd for 4 of 6 wks; So 400mg po BID qd; or P). Plasma was collected at the start of tx (4-12 wks post nephrectomy) and at either 4 or 6 wks into tx. Levels of circulating VEGF, bFGF, sFLT1, and placental growth factor (PlGF) were measured by multiplex array (Meso-Scale Disc.). Mixed models were used to estimate log-transformed cyt levels in each group, adjusting for effects due to plate and processing day and accounting for within-subject correlation. P values are from model-based tests of fixed effects (F tests). Results: 1,416 samples from 352 pts were included; table shows results in ng/ml. VEGF levels increased from baseline to post-cycle 1 in Su pts (measured at 4 wks) and in So pts, and remained stable in P pts. No consistent patterns of change between arms for bFGF, sFLT or PlGF were seen, after adjusting for processing effects. Conclusions: Of cyts measured, the most consistent changes were seen in VEGF levels. Treatment with Su and So increased VEGF levels in pts with no evidence of cancer, signifying that levels are mediated at least in part by the host. No difference from baseline to post-tx among Su patients with samples drawn at 6 wks was observed, suggesting that changes are reversible. On the contrary, So-treated pts maintained elevated VEGF levels at wk 6 (2 wks off tx), consistent with the continuous dosing schedule. Further study of the relationship among VEGF levels, tx outcomes and side effects is warranted. Arm Follow-up sample drawn at wk Patients Adj mean VEGF baseline Adj mean VEGF follow-up P value (F test) Sunitinib 4 66 0.10 0.22 <0.0001 6 61 0.12 0.12 0.90 Sorafenib 4 71 0.14 0.17 <0.0001 6 65 0.11 0.16 <0.0001 Placebo 4 75 0.11 0.11 0.27 6 66 0.11 0.11 0.30