CELESTIAL: a phase III trial of CABOMETYX® (cabozantinib) in advanced HCC

The safety and efficacy of CABOMETYX® (cabozantinib) were evaluated in patients with advanced hepatocellular carcinoma (HCC) not amenable to curative treatment and who had previously received sorafenib in the randomised, double-blind, placebo-controlled phase III CELESTIAL study.^1,10

View the CELESTIAL trial publication

The CELESTIAL trial was a phase III, double blind, randomised controlled trial, conducted in a previously-treated advanced hepatocellular carcinoma (HCC) population.¹⁰

In total, 1023 patients were assessed for eligibility and 707 patients were randomly assigned in 2:1 ratio to receive cabozantinib 60 mg/day (n=470) or a matched placebo (n=237). Patients were stratified according to pre-specified categories: disease aetiology, region and the presence of macrovascular invasion (MVI) and/or extrahepatic spread (EHS).¹⁰

Within the cabozantinib treatment group, 71% of patients received cabozantinib as second-line treatment and 28% as a third-line treatment. These patients had previously undergone one systemic anticancer regimen for advanced HCC.¹⁰

The primary endpoint was OS. The secondary endpoints were progression-free survival (PFS),  the objective response rate (ORR), and safety. Tumour assessment took place every 8 weeks using computed tomography or magnetic resonance imaging (MRI). Measurable disease was defined by the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Assessments took place until 8 weeks after radiographic progression or until CABOMETYX^®or placebo had been discontinued, which ever occurred later.¹⁰

Design of the CELESTIAL phase III trial

^{HCC, hepatocellular carcinoma; ORR, objective response rate; OS, overall survival; PFS, progression-free survival}

_{Adapted from Abou-Alfa GK, et al. 2018}¹⁰

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The study population included 707 patients previously treated for advanced HCC.¹⁰

Patients were included if they met the following criteria:¹⁰

• Age ≥18 years of age
• Pathological diagnosis of HCC that was not amenable to curative treatment
• Child-Pugh class A liver function (a score of 5-6 points out of 15)
• Received previous treatment with sorafenib
• Disease progression after at least one systemic treatment for HCC
• An Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1 (on a five-point scale)
• Adequate renal function
• Adequate haematological measures

Patients were excluded if they met the following criteria:¹⁰

• More than two previous systemic treatments
• Previous treatment with cabozantinib
• Uncontrolled clinically significant illness

Baseline characteristics were balanced between the cabozantinib and placebo groups as shown in the table.¹⁰

Patient demographic and baseline characteristics in the CELESTIAL phase III trial

Characteristic	Cabozantinib (n=470)	Placebo (n=237)
Gender, n (%)
Male	378 (81)	202 (85)
Female	91 (19)	35 (15)
Age, years
Median	64	64
Range	22-86	24-86
ECOG PS, n (%)
0	245 (52)	131 (55)
1	224 (48)	106 (45)
2	1 (<1)	0 (0)
Etiologic factor, n (%)
HBV	178 (38)	89 (38)
HCV	113 (24)	55 (23)
Dual HBV and HCV infection	8 (2)	4 (2)
Alcohol use	112 (24)	39 (16)
Nonalcoholic steatohepatitis	43 (9)	23 (10)
Other	24 (5)	16 (7)
Unknown	75 (16)	47 (20)
EHS of disease, n (%)
	369 (79)	182 (77)
MVI, n (%)
	129 (27)	81 (34)
EHS of disease, MVI or both, n (%)
	398 (85)	200 (84)

^{ECOG PS, Eastern Cooperative Oncology Group performance score; EHS, extrahepatic spread; HBV, hepatitis B virus; HCV, hepatitis C virus, MVI, macrovascular invasion.}

_{Adapted from Abou-Alfa GK, et al. 2018}¹⁰

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Primary endpoint: OS

Cabozantinib significantly extended OS in advanced HCC patients vs. placebo: 10.2 months (95% CI: 9.1–12.0) for cabozantinib vs. 8.0 months (95% CI: 6.8–9.4) for placebo.¹⁰

OS in the advanced HCC population in the CELESTIAL phase III trial

^{OS, overall survival}

_{Adapted from Abou-Alfa GK, et al. 2018}¹⁰

In the subgroup analysis of patients previously treated with sorafenib only, cabozantinib provided an additional 4.1 months of OS vs. placebo (11.3 months for cabozantinib and 7.2 months for placebo). Risk of death was reduced by 30% in this population (stratified hazard ratio [HR] for death: 0.70; 95% CI: 0.55-0.88).¹⁰

OS in patients previously treated with sorafenib only in the CELESTIAL phase III trial

^{OS, overall survival}

_{Adapted from Abou-Alfa GK, et al. 2018}¹⁰

PFS

Cabozantinib significantly improved PFS in advanced HCC patients: 5.2 months (95% CI: 4.0–5.5) vs. 1.9 months (95% CI: 1.9–1.9) for placebo.¹⁰

PFS in the advanced HCC population in the CELESTIAL phase III trial

^{PFS, progression-free survival}

_{Adapted from Abou-Alfa GK, et al. 2018}¹⁰

In the subgroup analysis of patients previously treated with sorafenib only, cabozantinib provided an additional 3.6 months without signs of advanced HCC recurrence vs. placebo (5.5 months for cabozantinib and 1.9 months for placebo; HR for disease progression or death: 0.40; 95% CI: 0.32-0.50).¹⁰

PFS in patients previously treated with sorafenib only in the CELESTIAL phase III trial

^{PFS, progression-free survival}

_{Adapted from Abou-Alfa GK, et al. 2018}¹⁰

Disease Control

The objective response rate according to RECIST, version 1.1, was 4% (18 partial responses among 470 patients) in the cabozantinib group and less than 1% (1 partial response among 237 patients) in the placebo group (P= 0.009). Cabozantinib enabled a high number of patients to achieve stable disease control versus placebo (64% vs. 33%, respectively).¹⁰

Disease Control in the Celestial phase III trial

^{Disease Control}

_{Adapted from Abou-Alfa GK, et al. 2018}¹⁰

OS and PFS in subgroups of the CELESTIAL phase III trial

OS in subgroups of the CELESTIAL phase III trial

 

PFS in subgroups of the CELESTIAL phase III trial

^{AFP, alpha-fetoprotein; ECOG, Eastern Cooperative Oncology Group; EHS, extrahepatic spread of disease; HBV, hepatitis B virus; HCV, hepatitis C virus; MVI, macrovascular invasion}

_{Adapted from Abou-Alfa GK, et al. 2018}¹⁰

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Please see the ‘What are the adverse events of CABOMETYX^®’ and ‘What are the dosing recommendations for CABOMETYX^®’ sections of this website.

Please also refer to the CABOMETYX^® Summary of Product Characteristics for a full list of adverse events and dose reduction recommendations.

For further information on the CELESTIAL trial, please refer to the full published clinical paper.¹⁰

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