Serum lactate dehydrogenase (LDH) as a biomarker for survival with mTOR inhibition in patients with metastatic renal cell carcinoma (RCC).

Abstract

4631 Background: No predictive biomarkers currently exist in GU cancers. LDH is an enzyme detectable in serum that is often elevated in multiple cancers including RCC, has prognostic importance and is regulated by the PI3 kinase/Akt/mTOR pathway and tumor hypoxia/necrosis. We sought to evaluate pretreatment LDH as a predictive biomarker in patients with metastatic RCC. Methods: We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk RCC subjects treated with the mTOR inhibitor temsirolimus or interferon alpha (IFN) in an international phase III randomized trial. Kaplan-Meier estimator and the proportional hazards model were used to examine the association of LDH with overall survival. Results: Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (range 0.05 to 28.5x ULN). Among 140 subjects with elevated LDH, survival was significantly improved with temsirolimus (6.9 vs. 4.2 months, log- rank p<0.002). Among 264 subjects with normal LDH, survival was not improved with temsirolimus as compared to interferon therapy (11.7 vs. 10.4 months, log-rank p=0.514). There was a statistically significant interaction effect noted between normalized LDH and treatment group (p=0.031). The hazard ratio (HR) for death was 1.98 (95% confidence interval (CI) 1.6-2.5, p<0.0001) for patients with LDH>1x ULN compared to patients whose LDH ≤ 1x ULN. Adjusting for known prognostic factors, the HR for death was 2.01 for patients with LDH>1 ULN vs. ≤1 ULN (95% CI=1.6-2.6, p<0.0001). Post- treatment LDH at 2 months increased 1.7% vs. 27% in the IFN and temsirolimus arms, respectively. A decline in LDH with therapy was prognostic of OS (p<0.0001) but this association was weak (HR=1.00). Conclusions: Serum LDH is a potential pretreatment predictive biomarker for the survival benefit conferred by mTOR inhibition in patients with poor risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with mTOR inhibition in other RCC risk groups and other tumor types is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer-Wyeth, Wyeth Pfizer Pfizer, Wyeth