Survival Outcomes and Safety of PD-1/PD-L1 Inhibitors for Unresectable Hepatocellular Carcinoma: Result from Phase III Trials

BACKGROUND: Determination of the comparative efficacy of one therapy over another for hepatocellular carcinoma (HCC) can be challenging. Application of a recognized value framework to published studies could objectively compare the potential benefit across available therapies. MATERIALS AND METHODS: An umbrella review of phase III trials for HCC therapies was performed. ASCO Value Framework Net Health Benefit Score version 2 (ASCO-NHB v2) scores, the primary analysis, and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 scores, the secondary analysis, were computed using selected drug registration trials. Both scores were compared between drugs that were Food and Drug Administration (FDA)-approved by 2020 and those that were not. RESULTS: Of the 22 studies identified, nine were FDA-approved and 13 were not. Across 22 trials, the median overall survival (OS) was 9.2 months (range, 1.9-16.4 months), with a median gain of 0.35 month (range, 2.3-3.3 months). HCC therapies that were FDA-approved showed longer OS (median 10.7 v 7.9 months, P < .01) and higher ASCO NHB scores (+18.4 v −5.7 scores, P < .01). The median gain in OS was 2.2 months in the approved treatments compared with −0.3 months in the unapproved group, with no difference in progression-free survival between the two groups. CONCLUSION: The nine FDA-approved therapies for HCC have higher mean NHB score than those that were not FDA-approved. The application of ASCO-NHB v2 and other proposed value frameworks could examine data of future therapies for HCC through a patient-oriented approach.

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The Cost-Effectiveness of Lenvatinib in the Treatment of Advanced or Unresectable Hepatocellular Carcinoma from a Canadian Perspective

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2021/8811018 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Brandon M. Meyers ◽

Arndt Vogel ◽

Paul Marotta ◽

Petr Kavan ◽

Laveena Kamboj ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Cost Effectiveness ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

Unresectable Hepatocellular Carcinoma ◽

Canadian Perspective ◽

The Cost ◽

First Line Treatment

Lenvatinib is an oral multikinase inhibitor indicated for the first-line treatment of unresectable hepatocellular carcinoma (uHCC). In the Phase III REFLECT trial, lenvatinib was noninferior in the primary endpoint of overall survival versus sorafenib, the only systemic therapy funded in Canada prior to the introduction of lenvatinib. Lenvatinib also demonstrated statistically significant improvement compared to sorafenib in secondary endpoint progression-free survival, time to progression, and objective response rate. The aim of this analysis was to estimate the cost-effectiveness of lenvatinib versus sorafenib for the first-line treatment of patients with uHCC from a Canadian perspective. A cost-utility analysis was conducted using partitioned survival modelling, with health states representing progression-free disease, progressed disease, and death. Health effects were measured using quality-adjusted life years (QALYs), and costs were represented in Canadian dollars. Clinical inputs were derived from the REFLECT trial, with outcomes extrapolated using parametric survival models. EQ-5D data collected in REFLECT were used to determine health state utility values, and estimates of resource use came from a survey of clinicians. The model predicted incremental costs of-$5,021 and incremental QALYs of 0.17, making lenvatinib dominant over sorafenib. The model demonstrates lenvatinib to be a cost-effective use of resources versus sorafenib in Canada for the treatment of uHCC. Overall costs are lower compared with sorafenib, while health benefits are greater, with modelled progression-free and overall survival extended by 4.1 and 2.6 months in the lenvatinib arm, respectively.

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Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups

Gut ◽

10.1136/gutjnl-2020-321702 ◽

2020 ◽

Vol 70 (1) ◽

pp. 204-214 ◽

Cited By ~ 4

Author(s):

Matthias Pinter ◽

Bernhard Scheiner ◽

Markus Peck-Radosavljevic

Keyword(s):

Hepatocellular Carcinoma ◽

Solid Organ Transplantation ◽

Progression Free Survival ◽

Standard Of Care ◽

The United States ◽

Phase Iii ◽

Advanced Hepatocellular Carcinoma ◽

Solid Organ ◽

United States Food ◽

Phase Iii Trials

Following the success of immune checkpoint blockers (ICBs) in different cancer types, a large number of studies are currently investigating ICBs in patients with hepatocellular carcinoma (HCC), alone or in combination with other treatments. Both nivolumab and pembrolizumab, as well as the combination of nivolumab plus ipilimumab have been granted accelerated approval by the United States Food and Drug Administration for sorafenib-pretreated patients. While nivolumab and pembrolizumab both failed to meet their primary endpoints in phase III trials, the combination of atezolizumab plus bevacizumab eventually improved overall and progression-free survival compared with sorafenib in a front-line phase III trial, and thus, will become the new standard of care in this setting. Despite this breakthrough, there are patient populations with certain underlying conditions that may not be ideal candidates for this new treatment either due to safety concerns or potential lack of efficacy. In this review, we discuss the safety of ICBs in patients with pre-existing autoimmune disease, IBD or a history of solid organ transplantation. Moreover, we summarise emerging preclinical and clinical data suggesting that ICBs may be less efficacious in patients with underlying non-alcoholic steatohepatitis or HCCs with activated Wnt/β-catenin signalling.

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Defining the Ideal Patient with Hepatocellular Carcinoma for Second-Line Treatment

Journal of Oncology ◽

10.1155/2020/8024124 ◽

2020 ◽

Vol 2020 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Giandomenico Roviello ◽

Andrea Casadei-Gardini ◽

Stefania Nobili ◽

Enrico Mini ◽

Sara Fancelli

Keyword(s):

Hepatocellular Carcinoma ◽

Pooled Analysis ◽

Phase Iii ◽

Novel Agents ◽

Line Treatment ◽

Second Line ◽

Novel Drugs ◽

Phase Iii Trials ◽

Male Patients ◽

Extrahepatic Metastases

Background. Second line of treatment of hepatocellular carcinoma (HCC) has notably changed in recent years as three novel drugs with a different mechanism of action have demonstrated to improve survival compared to placebo; thus, there is a need to better define the profile of optimal candidates to second-line treatment with these drugs in order to maximize clinical benefit. Materials and Methods. We performed a pooled analysis from the subgroup analysis of all published phase III trials for approved targeted therapy in the second line of treatment for HCC, with the aim to discover possible clinical-pathological predictive factors. Results. Four studies were included in the analysis for a total of 2137 cases whose results supported the use of these novel agents in male patients with ECOG: 0, extrahepatic metastases, and HBV infection. Conclusions. Future studies are awaited to define best candidates for novel agents approved in the second line of treatment for HCC.

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G06 : A randomized, double-blind, placebo-controlled phase III trial of TSU-68 (orantinib) combined with transcatheter arterial chemoembolization in patients with unresectable hepatocellular carcinoma

Journal of Hepatology ◽

10.1016/s0168-8278(15)30007-6 ◽

2015 ◽

Vol 62 ◽

pp. S189-S190 ◽

Cited By ~ 3

Author(s):

J.-W. Park ◽

A.-L. Cheng ◽

M. Kudo ◽

J.H. Park ◽

P.-C. Liang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Transcatheter Arterial Chemoembolization ◽

Phase Iii ◽

Double Blind ◽

Phase Iii Trial ◽

Double Blind Placebo ◽

Unresectable Hepatocellular Carcinoma ◽

Arterial Chemoembolization

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Outcomes of hepatocellular carcinoma patients treated with sorafenib: a meta-analysis of Phase III trials

Future Oncology ◽

10.2217/fon-2019-0287 ◽

2019 ◽

Vol 15 (29) ◽

pp. 3411-3422 ◽

Cited By ~ 4

Author(s):

Giuseppe Cabibbo ◽

Alessandro Cucchetti ◽

Calogero Cammà ◽

Andrea Casadei-Gardini ◽

Ciro Celsa ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Survival Data ◽

Meta Analysis ◽

Phase Iii ◽

Advanced Hepatocellular Carcinoma ◽

Radiological Progression ◽

Kaplan Meier ◽

Phase Iii Trials ◽

Individual Participant ◽

Multivariable Analyses

Aim: To benchmark overall survival (OS) and time to radiological progression (TTP) of patients enrolled in randomized controlled trials (RCTs) assessing sorafenib in advanced hepatocellular carcinoma using individual participant survival data, and to meta-analyze prognostic factors for OS and TTP. Methods: RCTs were identified through literature search until December 2018. Individual participant survival was reconstructed with an algorithm from published Kaplan–Meier curves. Results: Ten RCTs were included. Median OS was 10.0 months (95% CI: 9.6–10.5), and median TTP was 4.1 months (95% CI: 3.8–4.3). Multivariable analyses showed HCV positivity, absence of macrovascular invasion and extra-hepatic disease as predictors of longer OS. Conclusion: We provided a benchmark for future studies on sorafenib. The present results can be used in the decision making for the early shift to second-line strategy.

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