CELESTIAL: Cabozantinib vs. Placebo increases Overall Survival and Progression-free Survival in Patients with Advanced Hepatocellular Carcinoma

25 Oct, 21

Introduction

Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor

receptors 1, 2, and 3, MET, and AXL, all of which are involved in the progression of

hepatocellular carcinoma. These receptors are also involved in the development of resistance to sorafenib, the standard initial treatment for advanced disease. Cabozantinib appeared to be clinical active in patients with advanced hepatocellular carcinoma, in phase II trial.

Aim

To evaluate cabozantinib in previously treated patients with advanced and progressing hepatocellular carcinoma

Patient Profile

Patients (aged ≥18 years) with a pathological diagnosis of hepatocellular carcinoma that was not amenable to curative treatment, and had Child–Pugh class A liver function (n=707).
Study participants had received previous treatment with sorafenib and had had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma.
Study participants had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1 (on a 5-point scale, with higher scores indicating greater disability), adequate hematologic measures, and adequate renal function.

Methods

Study Design

A randomized, double-blind, phase 3 trial

Treatment Strategy

The study participants were randomized 2:1 to receive cabozantinib (60 mg once daily; n=470) or placebo (n=237).
Adverse events (AEs) during the treatment were managed with treatment interruptions and dose reductions (to 40 mg and then to 20 mg)

Outcomes

Primary Outcome

Overall survival (time from randomization to death due to any cause)

Secondary Outcomes

Progression-free survival (time from randomization to radiographic progression or death due to any cause, whichever occurred first)
Objective response rate (ORR)

Results

Treatment with cabozantinib was associated with a 24% reduction in the risk of death versus placebo (median survival 10.2 months vs. 8.0 months; hazard ratio [HR]; 0.76; 95% confidence interval [CI]: 0.63 to 0.92; P=0.005). The trial showed significantly longer overall survival with cabozantinib versus placebo at the second planned interim analysis (Fig. 1).

Fig.1: Median survival in the study groups

Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (HR for disease progression or death: 0.44; 95% CI, 0.36 to 0.52; P<0.001)
The objective response rates were 4% with cabozantinib and less than 1%, with placebo (P = 0.009).
The incidence of grade 3 or 4 AEs was higher in the cabozantinib group versus the placebo group (68% vs. 36%). The most common high-grade AEs comprised palmar–plantar erythrodysesthesia (17% [cabozantinib] vs. 0% [placebo]), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%).

Conclusions

Cabozantinib treatment significantly prolonged the survival in patients with advanced hepatocellular carcinoma, when compared with placebo.
Cabozantinib treatment was also associated with longer progression-free survival, compared with placebo.
The incidence of high-grade AEs in the cabozantinib group was approximately twice than that seen in the placebo group.

N Engl J Med 2018;379:54-63.