Better response in survival were observed in patients with Child-Pugh B cirrhosis, a patient population that has limited treatment options, when given cabozantinib in the phase 3 CELESTIAL study.
Anthony B. El-Khoueiry, MD
Better response in survival were observed in patients with Child-Pugh B cirrhosis, a patient population that has limited treatment options, when given cabozantinib (Cabometyx). These patients are often underrepresented in clinical trials and have worse outcomes in overall survival (OS) and adverse events (AEs) compared with their Child-Pugh A counterparts.1
“There [are] limited prospective data about the safety and efficacy of various systemic therapies in patients with advanced HCC and Child-Pugh B cirrhosis,” Anthony B. El-Khoueiry, MD, said in his presentation at the International Liver Cancer Association 2020 Virtual Conference. "The Child-Pugh B population is quite heterogenous and generally has [a] poorer prognosis than patients with Child-Pugh A.” According to the data from a retrospective exploratory analysis, patients with HCC and Child-Pugh B liver function in the CELESTIAL trial (NCT01908426) experienced clinical benefit in terms of OS and progression-free survival (PFS) hazard ratios and a manageable safety profile when receiving cabozantinib by week 8.2
El-Khoueiry, an associate professor of clinical medicine in the Division of Medical Oncology at the Keck School of Medicine of the University of Southern California in Los Angeles, briefly recounted the phase 3 CELESTIAL study of patients with advanced HCC who were previously treated for their disease.3 The trial demonstrated that cabozantinib improved OS and PFS compared with placebo in these patients.
Patients with Child-Pugh B had an 8.5-month median OS on cabozantinib (95% CI, 7.7-12.2) versus 3.8 months on placebo (95% CI, 3.3-4.8), with a hazard ratio of 0.32 (95% CI, 0.18-0.58). The overall population had a median OS of 10.2 months and 8.0 months for cabozantinib compared with placebo, respectively (P = .005).2
“Similarly, when we look at PFS in the Child-Pugh B subgroup, cabozantinib resulted in a median PFS of 3.7 months versus 1.9 with placebo and a hazard ratio of 0.44 [95% CI, 0.25-0.76],” El-Khoueiry said. The overall population had a median PFS of 5.2 months on cabozantinib and 1.9 months on placebo, with the same hazard ratio as those in the subgroup (P <.001).
Sixty-one percent of patients in the Child-Pugh B subgroup required a reduction in cabozantinib, which was comparable to the rate of the overall population at 62%, as well as discontinuations due to treatment-related AEs in 18% and 16%, respectively. The all-causality grade 3/4 AEs were alike, at 71% and 68%.
In the cabozantinib arm, 51 of 470 patients had investigator-assessed Child-Pugh B cirrhosis and 22 of 237 patients in the placebo arm had advanced to Child-Pugh B at week 8.
"The breakdown at study entry was that 75% of patients had Child-Pugh A6 and 25% had A5. The deterioration from Child-Pugh A to Child-Pugh B at week 8 was mostly related to changes from baseline in albumin, bilirubin, and ascites [TABLE 2 ],” El-Khoueiry explained.2
Patients in the Child-Pugh B subgroup receiving cabozantinib had higher rates of macrovascular invasion, which was present in 43% of patients compared with 32% of those on placebo and 27% in the overall population receiving cabozantinib, at baseline. Investigators also noted higher rates of extrahepatic spread of disease, which they observed in 82% of patients compared with 68% and 79%, respectively, and an elevated α-fetoprotein level—above 400 ng/mL—at 39% versus 27% and 41%.
In CELESTIAL, 760 patients with advanced HCC, Child-Pugh A score, an ECOG performance status of 0 or 1, and previous treatment with sorafenib (Nexavar) and up to 2 prior systemic regimens for their disease with progression following at least 1 of them, were randomized 2:1 to cabozantinib versus placebo.3
The stratification factors were etiology—either hepatitis B virus or hepatitis C virus, both, or other—region, and presence of macrovascular invasion and/or extrahepatic spread. Patients randomized to cabozantinib were given 60 mg by mouth daily or placebo by mouth daily. Treatment was continued until loss of clinical benefit or intolerable toxicity. Additionally, crossover was not allowed on the study.
The primary end point of the trial was OS, and secondary end points included PFS, overall response rate, and safety. Investigators performed a tumor assessment every 8 weeks per RECIST 1.1 criteria. “Further prospective studies are warranted in Child-Pugh B patients with HCC, a population with considerable unmet need[s],” El-Khoueiry concluded.
1. Zhou K, Fountzilas C. Outcomes and quality of life of systemic therapy in advanced hepatocellular carcinoma. Cancers (Basel). 2019;11(6):861. doi:10.3390/ cancers11060861
2. El-Khoueiry AB, Meyer T, Cheng AL, et al. Outcomes for patients with advanced hepatocellular carcinoma and Child-Pugh B liver function in the phase 3 CELESTIAL study of cabozantinib versus placebo. Slides presented at: International Liver Cancer Association 2020 Virtual Conference; September 11-13, 2020. Abstract 0-24.
3. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63.