Cabozantinib as a Second-Line Agent in Advanced Hepatocellular Carcinoma

Kudo, Masatoshi

doi:10.1159/000488542

Cited by 21 publications

(11 citation statements)

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“…Lenvatinib is a novel first-line drug in the treatment of advanced HCC, and cabozantinib can act as a second-line option to the first-line drugs sorafenib and lenvatinib and the second-line drug regorafenib in advanced HCC. 32 Thus, whether lenvatinib or cabozantinib combines with RAN-based molecular therapy to overcome sorafenib resistance in HCC still needs further study.…”

Section: Discussionmentioning

confidence: 99%

<p>LncRNA HEIH Confers Cell Sorafenib Resistance in Hepatocellular Carcinoma by Regulating miR-98-5p/PI3K/AKT Pathway</p>

Shen

Jiang²,

Wu³

et al. 2020

CMAR

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Background The hepatocellular carcinoma up-regulated EZH2-associated long non-coding RNA (HEIH) has been identified to act as an oncogene to promote cell tumorigenesis in hepatocellular carcinoma (HCC); however, the roles of HEIH in sorafenib resistance in HCC cells remain elusive. Materials and Methods The expression of HEIH and microRNA (miR)-98-5p was detected using quantitative real-time polymerase chain reaction. Cell viability, apoptosis, migration and invasion were analyzed using cell counting kit-8 assay, flow cytometry and transwell assay. Western blot was used to measure the levels of apoptosis-related protein and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway-related protein. The interaction between HEIH and miR-98-5p was confirmed by dual-luciferase reporter and RNA immunoprecipitation assay. In vivo experiments were performed using murine xenograft models. Results HEIH was up-regulated in sorafenib-resistant HCC tissues and cell lines, and HEIH silence weakened sorafenib resistance by suppressing cell viability, invasion and migration, decreasing the IC 50 values to sorafenib, and increasing apoptosis in sorafenib-resistant HCC cells in vitro and reinforced the anti-tumor eﬀects of sorafenib in vivo. HEIH was a sponge of miR-98-5p, and miR-98-5p inhibition reversed the sorafenib sensitivity induced by HEIH deletion in sorafenib-resistant HCC cells. MiR-98-5p inhibition could activate PI3K/AKT pathway, and enhanced sorafenib resistance by regulating the activation of PI3K/AKT pathway in sorafenib-resistant HCC cells. Besides, HEIH also activated PI3K/AKT pathway through regulating miR-98-5p in sorafenib-resistant HCC cells. Conclusion HEIH conferred an advantage to sorafenib resistance in HCC by the activation of PI3K/AKT pathway through miR-98-5p, indicating a potential therapeutic strategy for HCC chemotherapy.

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Section: Discussionmentioning

confidence: 99%

<p>LncRNA HEIH Confers Cell Sorafenib Resistance in Hepatocellular Carcinoma by Regulating miR-98-5p/PI3K/AKT Pathway</p>

Shen

Jiang²,

Wu³

et al. 2020

CMAR

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“…10 A recent phase III trial (CELESTIAL trial), demonstrated a statistically significant benefit for cabozantinib compared to placebo, in overall survival (OS; median 10.2 versus 8.2 months) and in progression-free survival (PFS; median 5.2 months versus 1.9 months). 11,12 The inclusion criteria for the trial were patients with Child-Pugh A cirrhosis and advanced HCC who had failed prior therapy. However, despite the demonstration of a statistically significant survival benefit, the high cost of the drug as well as its substantial side effects, mandate a thorough analysis of its cost-effectiveness.…”

Section: Introductionmentioning

confidence: 99%

Cabozantinib for patients with advanced hepatocellular carcinoma: a cost-effectiveness analysis

Shlomai

Leshno

Goldstein

2019

Therap Adv Gastroenterol

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Background and aims: The multi-kinase inhibitor sorafenib is a first-line drug for patients with advanced hepatocellular carcinoma (HCC). Treatment options for patients whose disease has progressed on sorafenib are limited. In a recent randomized controlled trial (CELESTIAL trial), patients with advanced HCC who had failed prior systemic therapy had moderate progression-free survival and overall survival advantages when treated with the multi-kinase inhibitor cabozantinib. However, since this treatment is costly and is accompanied by significant adverse events in a large proportion of patients, its cost-effectiveness in these patients should be determined. Methods: We developed a Markov model incorporating health outcomes, measured by life-years and quality-adjusted life-years (QALYs) to evaluate the cost-effectiveness of cabozantinib compared with placebo in patients who have failed prior systemic therapy. Results: Treatment with cabozantinib results in a mean gain of 11.6 weeks of life (0.22 life-years) as compared with placebo. When quality of life was incorporated, treatment with cabozantinib produced a gain of 0.16 QALYs. The total mean incremental cost of cabozantinib was US$76,406 per patient. The incremental cost-effectiveness ratio for cabozantinib compared with best supportive care was US$469,374/QALY using the recommended dose of 60 mg cabozantinib daily. Conclusion: Our results suggest that the use of cabozantinib in patients with advanced HCC who have progressed on prior treatment, results in a modest incremental benefit with high incremental costs, suggesting that it is not cost-effective at conventional willingness to pay thresholds.

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“…The CELESTIAL study showed the highest increase in progression‐free survival (3.3 months) and overall survival (2.2 months) vs placebo when compared with other second‐line therapy options. As Kudo M mentioned, the sample size of 470 patients in CELESTIAL was fairly larger than that of other second‐line trials (379 patients in RESORCE, 214 patients in CheckMate 040 expansion cohort) and thus had power to detect small differences as significant. Cabozantinib as well as immunotherapy proved to have statistically significant improvements as second‐line options.…”

Section: Discussionmentioning

confidence: 99%

Cost‐effectiveness analysis of cabozantinib as second‐line therapy in advanced hepatocellular carcinoma

Liao

Huang

Hutton

et al. 2019

Liver International

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Background: In the CELESTIAL trial for patients with advanced hepatocellular carcinoma (HCC), cabozantinib showed improved survival compared with placebo but comes at a price. We aimed to investigate the cost-effectiveness of cabozantinib for sorafenib-resistant HCC from the payer's perspective of the USA, UK and China. Methods:We developed Markov models to simulate the patients pre-treated with first-line sorafenib following the CELESTIAL trial. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated for the treatment with cabozantinib or best supportive care. The list price for drugs was acquired from the Red Book, the British National Formulary, West China hospital and reported literature. Adverse events, utilities weights, and transition likelihood between states were sourced from the published randomized phase III trial. A willing-to-pay threshold was set $150 000/QALY in the USA, $70 671/QALY (£50 000/QALY) in the UK and $26 481/QALY (3x GDP per capita) in China. Deterministic and probabilistic sensitivity analyses were developed to test the models' uncertainty. Results:In the base case, treatment with cabozantinib increased effectiveness by 0.13 QALYs, resulting in an ICER vs best supportive care of $833 497/QALY in the USA, $304 177/QALY in the UK and $156 437/QALY in China. The models were most sensitive to assumptions about transitions to progression with both cabozantinib and best supportive care, the utility associated with being progression free. These results were robust across a range of scenarios and sensitivity analyses, including deterministic and probabilistic analyses.Conclusions: Cabozantinib at its current cost would not be a cost-effective treatment option for patients with sorafenib-resistant HCC from the payer's perspective in the USA, UK or China. Substantial discounts are necessary to meet conventional costeffectiveness thresholds. K E Y W O R D S cabozantinib, cost-effective, hepatocellular carcinoma, incremental cost-effectiveness ratio, Markov model, second-line therapy S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Liao W, Huang J, Hutton D, et al. Cost-effectiveness analysis of cabozantinib as second-line therapy in advanced hepatocellular carcinoma. Liver Int.

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Cabozantinib as a Second-Line Agent in Advanced Hepatocellular Carcinoma

Cited by 21 publications

References 20 publications

<p>LncRNA HEIH Confers Cell Sorafenib Resistance in Hepatocellular Carcinoma by Regulating miR-98-5p/PI3K/AKT Pathway</p>

<p>LncRNA HEIH Confers Cell Sorafenib Resistance in Hepatocellular Carcinoma by Regulating miR-98-5p/PI3K/AKT Pathway</p>

Cabozantinib for patients with advanced hepatocellular carcinoma: a cost-effectiveness analysis

Cost‐effectiveness analysis of cabozantinib as second‐line therapy in advanced hepatocellular carcinoma

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