Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study)
There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma
(mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients
with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In
an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and
polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at
baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progressionfree survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher
lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L),
associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival
(OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS
(HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH
levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR
polymorphisms appeared to be associated with therapy response but were not significant. Hence, we
identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus
after failure of one VEGF-targeted therapy in patients with clear cell mRCC