Baseline lactate dehydrogenase (LDH) and overall survival (OS) in metastatic renal cell carcinoma (mRCC) patients (pts) treated with everolimus (EVE) versus sunitinib (SUN): Predictive biomarker analysis from the RECORD-3 trial

Background: Data from a randomized mRCC trial of temsirolimus vs interferon reported elevated baseline LDH to be a favorable predictive marker for OS with mTOR inhibitors (Armstrong, JCO 2012). As a product of anaerobic glycolysis, LDH was hypothesized to reflect mTOR activation in tumor cells. We explored this association in the RECORD-3 trial, which randomly assigned untreated pts to the mTOR inhibitor EVE vs the VEGFR TKI SUN without difference in OS (Knox, ASCO 2015). Methods: Pts were grouped by baseline LDH (low, 1xULN; high, > 1xULN). Treatment arms were stratified by MSKCC risk group. Cox proportional hazards and log-rank tests were used to test the association of LDH category with OS and progression-free survival (PFS). Correlation between LDH category and genomically defined subgroups (somatic mutations in BAP1 or PBRM1, both commonly altered in RCC with reported effects on OS for EVE-treated pts) was tested using Fisher exact test. Results: Among 468 randomly assigned pts, 13% were LDH high and 87% LDH low, with a median of 0.73xULN (range, 0.15-10.54xULN). High baseline LDH adversely affected OS for pts receiving EVE (HR 2.96; P< .0001) but showed no association for those receiving SUN (HR 1.18; P= .09). When comparing outcomes with first-line EVE vs SUN, OS was shorter for EVE in LDH-high pts but was not different in LDH-low pts. Associations between LDH and PFS were seen for EVE (HR 2.3; P< .0001) but not for SUN (HR 1.04; P.33). No statistically significant association was seen between LDH category and mutation status of BAP1 (P= .54) or PBRM1 (P= .47). Conclusions: Elevated baseline LDH correlated adversely with PFS and OS for first-line EVE but not SUN. Notably, this predictive effect for EVE is opposite that previously reported in the randomized trial for the mTOR inhibitor temsirolimus vs interferon.