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

2019 ◽  
Vol 15 (29) ◽  
pp. 3411-3422 ◽  
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.

scholarly journals Efficacy and Safety of Systemic Therapies for Advanced Hepatocellular Carcinoma: A Network Meta-Analysis of Phase III Trials

Liver Cancer ◽  
2017 ◽  
Vol 6 (4) ◽  
pp. 337-348 ◽  
Author(s):  
Alessandro Cucchetti ◽  
Fabio Piscaglia ◽  
Antonio Daniele Pinna ◽  
Benjamin Djulbegovic ◽  
Federico Mazzotti ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Meta Analysis ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Efficacy And Safety ◽  
Phase Iii Trials ◽  
Systemic Therapies

scholarly journals Comparing the efficacy and safety of second-line therapies for advanced hepatocellular carcinoma: a network meta-analysis of phase III trials

2020 ◽  
Vol 13 ◽  
pp. 175628482093248
Author(s):  
Dongxu Wang ◽  
Xu Yang ◽  
Jianzhen Lin ◽  
Yi Bai ◽  
Junyu Long ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Comparative Investigation ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Second Line ◽  
Significant Difference ◽  
Phase Iii Trials

Background: The prospect for targeted therapies in advanced hepatocellular carcinoma (HCC) has dramatically changed since several recent clinical trials have yielded promising results. The number of second-line therapies is increasing, though the consequent challenge is to consider differences between these interventions. This is a comparative investigation of presently approved second-line drugs for HCC based on findings from phase III randomized controlled trials. Methods: Data related to treatment efficacy including overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were extracted and compared using a Bayesian approach. Adverse events (AEs) and the rate of discontinuation due to AEs were assessed and compared with provide a more complete understanding. OS and PFS in patients with alpha fetoprotein (AFP) values greater than 400 were compared and ranked as a subgroup. Results: A total of five trials involving 2571 patients were included. The comparison suggests that regorafenib and cabozantinib significantly prolong OS compared with placebo. The rate of AEs and treatment discontinuation did not significantly differ, although the types of AEs varied substantially. Subgroup analysis did not highlight a significant OS difference between regorafenib [hazard ratio (HR) 0.68; 95% confidence interval (CI) 0.50–0.92], cabozantinib (HR 0.71; CI 0.54–0.94) and ramucirumab (HR 0.69; CI 0.57–0.84). Conclusion: Among the four second-line HCC therapies compared, regorafenib and cabozantinib appear to be better choices in terms of OS. Cabozantinib, regorafenib and ramucirumab have similar levels of efficacy for those with AFP >400, although ramucirumab has fewer side effects. No significant difference was observed in AEs, but some AEs related to each of these interventions should be given further consideration.

scholarly journals A systematic review and network meta-analysis of second-line therapy in hepatocellular carcinoma

2020 ◽  
Vol 27 (6) ◽  
Author(s):  
S. Delos Santos ◽  
S. Udayakumar ◽  
A. Nguyen ◽  
Y.J. Ko ◽  
S. Berry ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Systematic Review ◽  
Meta Analysis ◽  
Objective Response ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Second Line ◽  
Clinical Benefits ◽  
Baseline Characteristics ◽  
Grade 3

Background In patients with advanced hepatocellular carcinoma (hcc) following sorafenib failure, it is unclear which treatment is most efficacious, as treatments in the second-line setting have not been directly compared and no standard therapy exists. This systematic review and network meta-analysis (nma) aimed to compare the clinical benefits and toxicities of these treatments. Methods A systematic review of randomized controlled trials (rcts) was conducted to identify phase iii rcts in advanced hcc following sorafenib failure. Baseline characteristics and outcomes of placebo were examined for het­erogeneity. Primary outcomes of interest were extracted for results, including overall survival (os), progression-free survival (pfs), objective response rate (orr), grade 3/4 toxicities, and subgroups. An nma was conducted to compare both drugs through the intermediate placebo. Comparisons were expressed as hazard ratios (hrs) for os and pfs, and as risk difference (rd) for orr and toxicities. Subgroup analyses for os and pfs were also performed. Results Two rcts were identified (1280 patients) and compared through an indirect network; celestial (cabozantinib vs. placebo) and resorce (regorafenib vs. placebo). Baseline characteristics of patients in both trials were similar. Both trials also had similar placebo outcomes. Cabozantinib, compared with regorafenib, showed similar os [hazard ratio (hr): 1.21; 95% confidence interval (ci): 0.90 to 1.62], pfs (hr: 1.02; 95% ci: 0.78 to 1.34) and orr (−3.0%; 95% ci: −7.6% to 1.7%). Both treatments showed similar toxicities, but there were marginally higher risks of grade 3/4 hand–foot syndrome (5%; 95% ci: 0.1% to 9.8%), diarrhea (4.8%; 95% ci: 1.1% to 8.5%), and anorexia (4.4%; 95% ci: 0.8% to 8.0%) for cabozantinib. Subgroup results for os and pfs were consistent with overall results. Conclusions Overall, this nma determined that cabozantinib and regorafenib have similar clinical benefits and toxicities for second-line hcc.

scholarly journals Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups

Gut ◽  
2020 ◽  
Vol 70 (1) ◽  
pp. 204-214 ◽  
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.

Prognostic and predictive factors in patients treated with ramucirumab (RAM) with advanced hepatocellular carcinoma (aHCC) and elevated alpha-fetoprotein (AFP): Results from two phase III trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4146-4146
Author(s):  
Josep M. Llovet ◽  
Amit G. Singal ◽  
Augusto Villanueva ◽  
Richard S. Finn ◽  
Masatoshi Kudo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Meta Analysis ◽  
Performance Status ◽  
Phase Iii ◽  
P Value ◽  
Vegf Receptor ◽  
Advanced Hepatocellular Carcinoma ◽  
Poor Prognostic Factor ◽  
Molecular Features ◽  
Phase Iii Trials

4146 Background: Elevated AFP in patients with aHCC is a poor prognostic factor with distinct molecular features, including high vascular endothelial growth factor (VEGF) signalling and increased angiogenesis. RAM, a human IgG1 monoclonal antibody, VEGF receptor 2 (VEGFR2) inhibitor, demonstrated improved survival vs placebo among patients with elevated AFP in the REACH-2 trial and is accepted as a standard of care for management of aHCC. We analyzed prognostic factors in patients with AFP ≥400 ng/mL and predictors of clinical benefit to RAM in an individual participant data (IPD) meta-analysis of the REACH and REACH-2 Phase III trials. Methods: Patients with aHCC, Child-Pugh A, ECOG performance status (PS) ≤1, and prior sorafenib were randomized (REACH 1:1; REACH-2 2:1) to RAM 8 mg/kg or Placebo Q2W. Meta-analysis was conducted in patients with AFP ≥400 ng/mL (n = 542). Univariate (UV) and multivariate (MV) analyses were performed using a Cox proportional hazard regression model. MV used the cut-off p-value < 0.1 from UV, irrespective of treatment arm. Overall survival (OS) was evaluated by Kaplan-Meier estimator and Cox models. To define predictors of RAM benefit, treatment-by-covariate interactions terms were evaluated. Results: In terms of prognosis assessed by MV analysis in patients with AFP ≥400 ng/mL, 6 variables among demographic and baseline disease characteristics were associated with poor OS in the RAM cohort (ECOG PS 1, AFP > 1000 ng/mL, Child-Pugh > A5, Extrahepatic site > 1, neutrophil-to-lymphocyte ratio > 3.2 and aspartate aminotransferase > 57 U/L) with an additional 3 factors identified within the whole cohort (macrovascular invasion presence, etiology HCV vs. Other and alkaline phosphatase ≥146). RAM benefit was present across all subgroups, including patients with very aggressive HCCs (AFP > 4000 ng/mL; HR: 0.64; 95% CI: 0.49-0.84) and those with nonalcoholic steatohepatitis /alcohol related aHCC (HR: 0.56; 95% CI: 0.40-0.79). Of note, two treatment-emergent (TE) events were the only factors that were significantly associated with improved RAM-related survival: TE-hypertension (p interaction = 0.0392) and TE-ascites (p interaction = 0.0001). However, these results should be interpreted with caution given that TE events are factors only observed after randomization. Conclusions: Several poor prognostic factors for OS were identified in patients with aHCC and elevated AFP. RAM provided an OS benefit irrespective of baseline prognostic covariates, with greater benefit observed in patients with aggressive HCC and those who experienced TE-hypertension or TE-ascites. Clinical trial information: NCT01140347; NCT02435433.

scholarly journals Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Ziyu Liu ◽  
Yan Lin ◽  
Jinyan Zhang ◽  
Yumei Zhang ◽  
Yongqiang Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Line Treatment ◽  
Phase Ii Trials ◽  
Advanced Hcc ◽  
Phase Iii Trials ◽  
Asian Pacific

Abstract Molecular targeted therapy for advanced hepatocellular carcinoma (HCC) has changed markedly. Although sorafenib was used in clinical practice as the first molecular targeted agent in 2007, the SHARPE and Asian-Pacific trials demonstrated that sorafenib only improved overall survival (OS) by approximately 3 months in patients with advanced HCC compared with placebo. Molecular targeted agents were developed during the 10-year period from 2007 to 2016, but every test of these agents from phase II or phase III clinical trial failed due to a low response rate and high toxicity. In the 2 years after, 2017 through 2018, four successful novel drugs emerged from clinical trials for clinical use. As recommended by updated Barcelona Clinical Liver cancer (BCLC) treatment algorithms, lenvatinib is now feasible as an alternative to sorafenib as a first-line treatment for advanced HCC. Regorafenib, cabozantinib, and ramucirumab are appropriate supplements for sorafenib as second-line treatment for patients with advanced HCC who are resistant, show progression or do not tolerate sorafenib. In addition, with promising outcomes in phase II trials, immune PD-1/PD-L1 checkpoint inhibitors nivolumab and pembrolizumab have been applied for HCC treatment. Despite phase III trials for nivolumab and pembrolizumab, the primary endpoints of improved OS were not statistically significant, immune PD-1/PD-L1 checkpoint therapy remains to be further investigated. This review summarizes the development and progression of molecular targeted and immune-based checkpoint therapies in HCC.

scholarly journals Optimizing Survival and the Changing Landscape of Targeted Therapy for Intermediate and Advanced Hepatocellular Carcinoma: A Systematic Review

2020 ◽  
Author(s):  
Howard Lim ◽  
Ravi Ramjeesingh ◽  
Dave Liu ◽  
Vincent C Tam ◽  
Jennifer J Knox ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Targeted Therapy ◽  
Kinase Inhibitor ◽  
Hepatocellular Cancer ◽  
Phase Iii ◽  
Locoregional Therapy ◽  
Advanced Hepatocellular Carcinoma ◽  
First Line ◽  
Patient Reported ◽  
Phase Iii Trials

Abstract Background Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice Methods Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms “hepatocellular cancer” AND “advanced” AND “targeted therapy” AND “phase III” OR respective aliases (PRISMA). Results Ten phase III trials assessed targeted therapy first-line and eight following sorafenib. In the first-line, atezolizumab plus bevacizumab statistically significantly improved overall survival (OS) and patient-reported outcomes (PROs) compared with sorafenib, while lenvatinib demonstrated non-inferior OS. Following progression on sorafenib, statistically significant OS improvements over placebo were seen for cabozantinib and regorafenib in unselected patients and for ramucirumab in those with baseline α-fetoprotein≥400 ng/mL. Based on improved OS and PROs, atezolizumab plus bevacizumab appears to be a preferred first-line treatment option for intermediate or advanced non-LRT eligible HCC. Phase III data informing sequencing of later lines of treatment is lacking. Therefore, sequencing principles are proposed that can be used to guide treatment selection. Conclusions Ongoing trials will continue to inform optimal therapy. Multiple targeted therapies have improved OS in intermediate or advanced non-LRT eligible HCC, although optimal sequencing is an area of ongoing investigation.

Sign in / Sign up

Export Citation Format

Share Document