Objective response by mRECIST to predict survival in hepatocellular carcinoma: A multivariate, time-dependent analysis from the phase III BRISK-PS study.

4084 Background: mRECIST (modified Response Evaluation Criteria In Solid Tumors) was developed to overcome the limitations of standard RECIST in hepatocellular carcinoma (HCC) response assessment. Retrospective studies have correlated objective response (OR) by mRECIST with overall survival (OS) in patients treated by loco-regional therapies. We investigated whether OR by mRECIST predicted OS using data from a double-blind, placebo-controlled, randomized phase III trial. Methods: In the BRISK-PS study, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib plus best supportive care (BSC) or placebo plus BSC. Tumor assessments were performed every 6 weeks by contrast-enhanced computed tomography or magnetic resonance imaging. Assessment of response was done by central radiological review using mRECIST. Multivariate models using time-dependent covariate analysis defined variables with independent prognostic value (SPSS 18 and SAS 9.2). Results: 210/226 (93%) patients in the brivanib arm and 101/108 (94%) in the placebo arm, who had baseline and on-study scans available for central blinded review, were evaluable according to mRECIST. 26/210 patients on brivanib and 2/101 on placebo achieved partial response (p < 0.01). At the end of follow up, 284 patients had died, the median OS for the brivanib arm being 9.4 months. As per mRECIST response assessment, median OS was 16.4 months (n = 26; 95% CI, 15.7 – NA) for brivanib responders and 8.3 months (n = 237; 95% CI, 7.2 – 9.7) for brivanib non-responders (hazard ratio, 0.28; 95% CI, 0.14 – 0.55, p < 0.01). Independent predictors of OS at multivariate time-dependent analysis were ORR by mRECIST, vascular invasion/extrahepatic spread, AFP > 200 ng/mL and bilirubin > 1.5 mg/dl. Conclusions: ORR by mRECIST is an independent predictor of OS in HCC patients receiving a systemic multikinase inhibitor, brivanib. mRECIST response is a marker of antitumor activity and warrants further evaluation in prospective clinical trials exploring novel agents in HCC patients. Clinical trial information: NCT0901901.