Circulating biomarkers and outcomes in a single-arm phase II trial of first-line sunitinib alternating with everolimus for advanced renal cell carcinoma (aRCC): EVERSUN ANZUP trial 0901

Background: We sought biomarkers at baseline associated with clinically important outcomes in this trial of alternating sunitinib and everolimus.

Methods: Baseline blood was tested for circulating tumor cells (CTCs) using CellSearch CTC system (Veridex). Baseline serum was tested for protein biomarkers: bFGF, CAIX; e-selectin; HIF1; IL8; NGAL; PDGF; PLGF; vCAM; VEGF-A, C and D; VEGFR1-3; by multiplex immunoassays (Bio-Plex system BioRad) or ELISA (R&D Systems DuoSets). Biomarker levels were dichotomised according to median or limit of detectability. Outcomes were progression free, overall survival (PFS, OS), objective tumour response (OTR) and toxicity (cycle 1 grade 3-5 AEs). Regression models were used for hazard ratios (HR), odds ratios (OR), p-values (p) in univariable analysis, adjusted for established prognostic factors in multivariable analysis.

Results: Patient (n=55) characteristics were mean age 61 yrs: male 71%; MSKCC good risk 16%, intermediate risk 84%. There were 47 progression events and 30 deaths after a median follow-up of 20 mos. CTCs were detected in 5/31 (16%). Univariable analysis showed associations between OTR and low levels of bFGF (6 v 0, p 0.009); shorter OS and high levels of both NGAL (HR 2.5, p 0.02) and IL8 (HR 2.3, p 0.04); toxicity with detectable levels of CAIX (OR 4.7, p 0.03); none was associated with PFS. Adjusting for MSKCC prognostic score, age, gender and presence of liver or bone metastases: shorter PFS was associated with high bFGF (HR 2.0, p 0.03), low vCAM1 (HR 0.50, p 0.04), undetectable HIF1 (HR 0.33, p 0.01), shorter OS was associated with high NGAL (HR 2.5, p 0.03) and undetectable HIF1 (HR 0.35, p 0.04). Toxicity was associated with detectable CAIX (OR 5.8, p 0.04). None were statistically significant after adjusting for multi-comparisons.

Conclusions: This exploratory study did not find strong statistical evidence for the prognostic value of these circulating baseline biomarkers. Prognostic value of changes from baseline during therapy remains an important area of study. EVERSUN is an ANZUP Cancer Trials Group Ltd trial coordinated by NHMRC Clinical Trials Centre (ACTRN12609000643279).