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Treating hepatocellular carcinoma progression following first-line sorafenib: therapeutic options and clinical observations.

ABSTRACT: Despite the established efficacy of sorafenib in advanced hepatocellular carcinoma (HCC), a significant number of sorafenib-treated patients experience disease progression. Current guidelines recommend either best supportive care or clinical trial enrollment for this population. As such, there remains an unmet need for tolerable, life-prolonging strategies in the second-line setting. New information regarding the molecular pathogenesis of resistance to antiangiogenic therapy and positive post-progression experience with antiangiogenics in other tumor types has led to trials investigating the effect of continued use of sorafenib, alone or combined with other agents. Trials investigating the effect of switching from sorafenib to alternate antiangiogenic agents, phosphatidylinositol 3 kinase/AKT/mammalian target of rapamycin inhibitors, or cMet inhibitors are also underway. As these data emerge, clinicians may consider a new paradigm for managing advanced HCC. This article briefly reviews the mechanisms of disease resistance to antiangiogenic therapy as a vehicle for discussing clinical strategies to prolong survival in patients with advanced HCC that are currently employed at our institutions or are under investigation. Key ongoing trials investigating the use of molecularly targeted therapies in patients with progressive disease are also highlighted.

SUBMITTER: He AR

PROVIDER: S-EPMC3808569 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Treating hepatocellular carcinoma progression following first-line sorafenib: therapeutic options and clinical observations.

He A Ruth AR Goldenberg Alec S AS

Therapeutic advances in gastroenterology 20131101 6

Despite the established efficacy of sorafenib in advanced hepatocellular carcinoma (HCC), a significant number of sorafenib-treated patients experience disease progression. Current guidelines recommend either best supportive care or clinical trial enrollment for this population. As such, there remains an unmet need for tolerable, life-prolonging strategies in the second-line setting. New information regarding the molecular pathogenesis of resistance to antiangiogenic therapy and positive post-pr ...[more]

PMID: 24179481

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Project description:BackgroundCurrently, there are a few treatment options for unresectable hepatocellular carcinoma (HCC) after progression following sorafenib (SOR) therapy, but with limited benefit. The purpose of this study was to investigate the efficacy and safety of tyrosine kinase inhibitors (TKIs) combined with immune checkpoint inhibitors (ICIs) as second-line treatment.MethodsFrom May 2018 to May 2021, a total of 93 HCCs who failed SOR treatment were included in this study and divided into TKI group (n = 37) and TKI-ICI group (n = 56). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety were estimated among the two groups. In addition, univariate and multivariate Cox regression analyses were performed for OS and PFS to identify possible prognostic factors.ResultsWith a median follow-up time of 13.7 months, the median age of patients was 56 (range, 50-64) years and most were male. All of the patients were hepatitis virus-related HCC. Both median OS (7.63 months vs 19.23 months, P < 0.001) and median PFS (2.97 months vs 8.63 months, P < 0.001) were significantly improved in the TKI-ICI group compared to the TKI group. A significant increase in DCR was demonstrated in the TKI-ICI group compared to the TKI group (83.9% vs 45.9%, P = 0.0003), although no significant difference in ORR was reported (21.4% vs 8.1%, P = 0.1552). Multivariate Cox regression analysis of OS and PFS revealed that second-line regimen was an independent protective factor affecting death and progression in HCCs after SOR failure. In addition, Child-Pugh B7 was an independent risk factor of OS. Finally, there was no significant difference in the incidence of any grade or grade 3/4 adverse events (AEs) between the two groups, and no treatment-related deaths were observed.ConclusionThis real-world study suggests that the combination of TKIs and ICIs benefits more than mono-TKIs and is well tolerated in HCCs with hepatitis virus infection after SOR failure.

Project description:Lessons learnedTrebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang-2 levels' association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2.BackgroundAng-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC).MethodsPatients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2.ResultsThirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts.ConclusionThere was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

Project description:Objective: Nivolumab improves overall survival (OS) and is associated with fewer adverse events than sorafenib for the treatment of advanced hepatocellular carcinoma (aHCC). However, the cost-effectiveness of nivolumab compared with sorafenib treatment for aHCC remains unclear. This study evaluated the cost-effectiveness of nivolumab and sorafenib in the treatment of aHCC. Materials and methods: A partitioned survival model that included three mutually exclusive health states was used to evaluate the cost-effectiveness of nivolumab and sorafenib for treating aHCC. The clinical characteristics and outcomes of the patients in the model were obtained from the CheckMate 459. We performed deterministic one-way sensitivity and probabilistic sensitivity analyses to evaluate the robustness of the model. Subgroup analyses were also performed. Costs, life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were measured. Results: The base case analysis showed that compared with sorafenib, treatment with nivolumab was associated with an increment of 0.50 (2.45 vs. 1.95) life-years and an increment of 0.32 (1.59 vs. 1.27) QALYs, as well as a $69,762 increase in cost per patient. The ICER was $220,864/QALY. The INHB and INMB were -0.15 QALYs and -$22,362 at a willingness-to-pay (WTP) threshold of $150,000/QALY, respectively. The probabilistic sensitivity analysis demonstrated that the probability of nivolumab being cost-effective was only 10.38% at a WTP threshold of $150,000/QALY. The model was most sensitive to the costs of sorafenib and nivolumab according to the one-way sensitivity analysis. When the price of sorafenib exceeded $0.93/mg or nivolumab was less than $24.23/mg, nivolumab was more cost-effective. The subgroup analysis illustrated that the probability of cost-effectiveness was >50% in the Barcelona Clinic Liver Cancer Stage B subgroups for nivolumab at a WTP threshold of $150,000/QALY. This study also showed that the probability of cost-effectiveness was <50% in most subgroups. Conclusion: Nivolumab was not cost-effective, although it was associated with better clinical benefit and a favorable safety profile for the treatment of aHCC compared with sorafenib from the third-party payer perspective in the United States. If the price of nivolumab is substantially reduced, favorable cost-effectiveness can be achieved among patients with aHCC.

Project description:BackgroundIn a global, phase III, open-label, noninferiority trial (REFLECT), lenvatinib demonstrated noninferiority to sorafenib in overall survival and a statistically significant increase in progression-free survival in patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib became the first agent in more than 10 years to receive approval as first-line therapy for unresectable HCC, along with the previously approved sorafenib. The objective of this study was to determine the comparative cost-effectiveness of lenvatinib and sorafenib as a first-line therapy of unresectable HCC.Materials and methodsA state-transition model of unresectable HCC was developed in the form of a cost-utility analysis. The model time horizon was 5 years; the efficacy of the model was informed by the REFLECT trial, and costs and utilities were obtained from published literature. Probabilistic sensitivity analyses and subgroup analyses were performed to test the robustness of the model.ResultsLenvatinib dominated sorafenib in the base case analysis. A probabilistic sensitivity analysis indicated that lenvatinib remains a cost-saving measure in 64.87% of the simulations. However, if the cost of sorafenib was reduced by 57%, lenvatinib would no longer be the dominant strategy.ConclusionLenvatinib offered a similar clinical effectiveness at a lower cost than sorafenib, suggesting that lenvatinib would be a cost-saving alternative in treating unresectable HCC. However, lenvatinib may fail to remain cost-saving if a significantly cheaper generic sorafenib becomes available.Implications for practiceThis analysis suggests an actionable clinical policy that will achieve cost saving. This cost-utility analysis showed that lenvatinib had a similar clinical effectiveness at a lower cost than sorafenib, indicating that lenvatinib may be a cost-saving measure in patients with unresectable HCC, in which $23,719 could be saved per patient. The introduction of a new therapeutic option for the first time in 10 years in Canada provides an important opportunity for clinicians, researchers, and health care decision-makers to explore potential modifications in recommendations and practice guidelines.

Project description:ImportanceTreatment with atezolizumab plus bevacizumab may prolong overall survival among patients with unresectable hepatocellular carcinoma. However, to our knowledge, the cost-effectiveness of using this high-priced therapy for this indication is currently unknown.ObjectiveTo evaluate the cost-effectiveness of atezolizumab plus bevacizumab to treat unresectable hepatocellular carcinoma from the US payer perspective.Design, setting, and participantsThis economic evaluation used a partitioned survival model consisting of 3 discrete health states to assess the cost-effectiveness of treatment of hepatocellular carcinoma with atezolizumab plus bevacizumab vs sorafenib. The characteristics of patients in the model were similar to patients in a phase 3, open-label randomized clinical trial (IMbrave150) who had unresectable hepatocellular carcinoma and had not previously received systemic treatment. Key clinical data were generated from the IMbrave150 trial conducted between March 15, 2018, and January 30, 2019, and cost and health preference data were collected from the literature.Main outcomes and measuresCosts, quality-adjusted life-years (QALYs), incremental cost-utility ratios, incremental net health benefits, and incremental net monetary benefits were calculated for the 2 treatment strategies. Subgroup, 1-way sensitivity, and probabilistic sensitivity analyses were performed.ResultsTreatment of hepatocellular carcinoma with atezolizumab plus bevacizumab added 0.530 QALYs and resulted in an incremental cost of $89 807 compared with sorafenib therapy, which had an incremental cost-utility ratio of $169 223 per QALY gained. The incremental net health benefit was -0.068 QALYs, and the incremental net monetary benefit was -$10 202 at a willingness-to-pay threshold of $150 000/QALY. The probabilistic sensitivity analysis indicated that treatment with atezolizumab plus bevacizumab achieved a 35% probability of cost-effectiveness at a threshold of $150 000/QALY. One-way sensitivity analysis revealed that the results were most sensitive to the hazard ratio of overall survival. The subgroup analysis found that treatment with atezolizumab plus bevacizumab was associated with preferred incremental net health benefits in several subgroups, including patients with hepatitis B and C.Conclusions and relevanceAtezolizumab plus bevacizumab treatment is unlikely to be a cost-effective option compared with sorafenib for patients with unresectable hepatocellular carcinoma. Reducing the prices of atezolizumab and bevacizumab may improve cost-effectiveness. The economic outcomes also may be improved by tailoring treatments based on individual patient factors.

Dataset Information

Treating hepatocellular carcinoma progression following first-line sorafenib: therapeutic options and clinical observations.

Publications

Treating hepatocellular carcinoma progression following first-line sorafenib: therapeutic options and clinical observations.

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