Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial.

Abstract

207 Background: C, an inhibitor of MET, VEGFR, and AXL, has previously shown clinical activity in pts with advanced HCC. This phase 3 trial (NCT01908426) evaluated C vs P in previously treated pts with advanced HCC. Methods: In this double-blind, global, phase 3 trial, pts were randomized 2:1 to receive C (60 mg qd) or matched P stratified by disease etiology (HBV, HCV, other), geographic region (Asia, other), and presence of extrahepatic spread and/or macrovascular invasion (EHS/MVI). Eligible pts had pathologic diagnosis of HCC, Child-Pugh score A, ECOG PS ≤1, and must have received prior sorafenib. Pts received up to two lines of prior systemic therapy for HCC and must have progressed following at least one. The primary endpoint was overall survival (OS). Secondary endpoints were investigator-assessed progression-free survival (PFS) and objective response rate (ORR) per RECIST 1.1. The study was designed to detect a hazard ratio (HR) for OS of 0.76 (90% power, 2-sided α = 0.05) at the final analysis with two prespecified interim analyses at 50% and 75% of the planned 621 events. Results: As of 1 Jun 2017, 707 pts were randomized, and 484 deaths had occurred (317 out of 470 for C; 167 out of 237 for P). Baseline characteristics were balanced between the two arms: median age was 64 years, 82% were male, 38% had HBV, 24% had HCV, 25% enrolled in Asia, 78% had EHS, 30% had MVI, 85% had EHS/MVI, and 27% had received two prior systemic therapy regimens for advanced HCC. The study met the primary endpoint at the second planned interim analysis with median OS 10.2 mo for C vs 8.0 mo for P (HR 0.76, 95% CI 0.63-0.92; p = 0.0049). Median PFS was 5.2 mo for C vs 1.9 mo for P (HR 0.44, 95% CI 0.36-0.52; p < 0.001), and ORR was 4% vs 0.4% (p = 0.0086). The most common grade 3/4 adverse events (predominantly grade 3) with higher incidence in the C vs P arm included hand-foot skin reaction (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%). Conclusion: C significantly improved OS and PFS vs P in previously treated pts with advanced HCC. Adverse events were consistent with the known safety profile of C. Clinical trial information: NCT01908426.

Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases

“…In a recent phase II study of 41 patients with HCC, the overall response rate was 5% with a week 12 disease control rate of 66% and reductions in AFP . A phase III randomized trial of cabozantinib in advanced HCC patients as a second‐line agent has been completed (Table ). A total of 707 patients with advanced HCC randomized in a 2:1 ratio received cabozantinib at 60 mg daily (n = 470) or placebo (n = 237).…”

Inhibition of Cyclin‐Dependent Kinase 5

“…For example, Regorafenib has recently been approved as second‐line treatment for patients with HCC progressing under sorafenib treatment . Further, Lenvatinib, as first‐line treatment, and Cabozantinib, as second‐line treatment, have shown promising results in clinical phase 3 trials and are expected to be approved for HCC treatment . However, sorafenib is still the only approved first‐line treatment for patients with advanced‐stage HCC.…”

“…(7) Further, Lenvatinib, as first-line treatment, and Cabozantinib, as second-line treatment, have shown promising results in clinical phase 3 trials and are expected to be approved for HCC treatment. (8,9) However, sorafenib is still the only approved first-line treatment for patients with advanced-stage HCC. Therefore, the search for new therapeutic approaches is urgent.…”

Recent clinical applications of external beam radiotherapy for hepatocellular carcinoma according to guidelines, major trials and meta‐analyses

“…It has been the only approved molecular target therapeutic agent until the recent approval of lenvatinib as another first‐line drug for advanced HCC . Regorafenib and cabozantinib, the second‐line drugs after treatment failure with sorafenib, have recently shown their survival benefits 10 years after the sorafenib landmark trial …”

“…17 Regorafenib and cabozantinib, the second-line drugs after treatment failure with sorafenib, have recently shown their survival benefits 10 years after the sorafenib landmark trial. 18,19 Regarding radiation therapy (RT), which mostly refers to external beam radiotherapy (EBRT) in this review, irradiation of the whole liver is highly likely to result in toxicities such as radiation-induced liver disease (RILD); in addition, the available dose to the tumour is too limited (<30-35 Gy) to result in meaningful tumour control. 20,21 Therefore, the treatment efficacy was unsatisfactory in the old era when RT was performed with guidance from plain X-ray views, bony landmarks and organ shadows.…”