Assessment of tumor response, alpha-fetoprotein (AFP) response, and time to progression (TTP) in the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (HCC)

Background: C inhibits tyrosine kinases including MET, VEGFR, and AXL. In the CELESTIAL trial (NCT01908426), C significantly improved overall survival (median OS 10.2 mo vs 8.0 mo; HR 0.76, 95% CI 0.63-0.92; P = 0.0049), progression-free survival (median PFS 5.2 mo vs 1.9 mo; HR 0.44, 95% CI 0.36-0.52; P < 0.0001), and objective response rate (4% vs 0.4%, P = 0.0086) vs P in patients (pts) with previously treated advanced HCC. Here, we report a secondary analysis of tumor response including best percent change in sum of tumor target lesion diameters (SOD), best percent change in AFP levels, and TTP. Methods: A total of 707 pts, stratified by disease etiology, geographic region, and extent of disease, were randomized 2:1 to C 60 mg once daily (N = 470) or P (N = 237). Eligible pts had a pathologic diagnosis of HCC, Child-Pugh score A, and ECOG performance status ≤1. Pts must have received prior sorafenib; up to 2 lines of prior systemic therapy for HCC were allowed. Tumors were assessed by the investigator at baseline and every 8 wks thereafter; serum AFP levels were measured centrally on the same schedule. Best percent change in SOD or AFP was defined as the maximum reduction from baseline at any timepoint. TTP, determined retrospectively, was defined as the time from randomization to radiological progression or clinical deterioration attributed to cancer progression. Results: Based on the intent-to-treat population, 222 of 470 pts (47%) in the C arm and 27 of 237 pts (11%) in the P arm had any reduction in SOD from baseline as best response. Thirtynine of 470 pts in the C arm (8%) and 3 of 237 pts (1%) in the P arm had ≥30% reduction in SOD as best response. In the C arm, 9% (26/278) of pts with baseline AFP <400 ng/mL and 7% (13/192) of pts with AFP ≥400 ng/mL achieved a ≥ 30% reduction in SOD. Overall, 109 of 470 pts (23%) in the C arm and 13 of 237 pts (5%) in the P arm had a ≥ 50% decrease from baseline in AFP levels. Median TTP was 5.4 mo with C vs 1.9 mo with P (HR 0.41, 95% CI 0.34- 0.49). Conclusions: C is associated with improved TTP, greater rates of target lesion regression, and AFP response compared with P in pts with previously treated advanced HCC.