Second line systemic therapy options for advanced hepatocellular carcinoma; a systematic review

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.

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Comparison of systemic therapy efficacy in advanced hepatocellular carcinoma: Systematic review and frequentist network meta-analysis of randomized controlled trials.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.293 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 293-293

Author(s):

Robin Park ◽

Laércio Lopes da Silva ◽

Voravech Nissaisorakarn ◽

Ivy Riano ◽

Anwaar Saeed

Keyword(s):

Hepatocellular Carcinoma ◽

Systematic Review ◽

Meta Analysis ◽

Objective Response ◽

Indirect Comparison ◽

Advanced Hepatocellular Carcinoma ◽

Second Line ◽

First Line ◽

Line Setting ◽

Systemic Agents

293 Background: Several systemic agents are approved for use in the first line and second line treatment settings for advanced hepatocellular carcinoma (aHCC). However, choosing among available options in both first and second line settings remain difficult due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings. Methods: Published clinical trials that have evaluated systemic agents in the first line and second line settings in advanced HCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and abstracts presented in the main annual ASCO and ESMO conferences from 2017 to 2020. Studies published in English providing clinical outcomes data including overall survival (OS), progression free survival (PFS) and objective response rate (ORR) were included in the analysis. The primary outcomes of interest were pooled hazard ratios (HR) of OS and OR of ORR in first line studies and HR of PFS and OR of ORR for second line studies. OS for second line agents were synthesized in a qualitative analysis. Results: Overall, 8,335 patients (13 studies) and 4,612 patients (11 studies) were analyzed in phase II/III trials for first line and second line settings respectively. In the first line setting, atezolizumab plus bevacizumab and lenvatinib were ranked highest as the regimens associated with the greatest OS (A+B, HR 0.58, 95% CI, 0.42-0.80; P-score 0.993) and ORR (lenva, OR 3.34, 95% CI, 2.17-5.14; P-score 0.080) respectively. In the second line setting, cabozantinib showed the highest probability of greatest PFS benefit (HR 0.44, 95% CI, 0.29-0.66; P-score 0.854) as well as the highest probability of greatest ORR benefit (cabo, OR 9.40, 95% CI, 1.25-70.83, P-score, 0.266). Conclusions: In the first line setting, atezolizumab plus bevacizumab may be the superior regimen whereas lenvatinib may be considered as the initial option when robust tumor responses are preferred. In the second line setting, cabozantinib may be the preferred option including in cases when robust tumor responses are favored.

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Surrogacy of Time to Progression for Overall Survival in Advanced Hepatocellular Carcinoma Treated with Systemic Therapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Liver Cancer ◽

10.1159/000489505 ◽

2018 ◽

Vol 8 (2) ◽

pp. 130-139 ◽

Cited By ~ 8

Author(s):

Takeshi Terashima ◽

Tatsuya Yamashita ◽

Tadashi Toyama ◽

Kuniaki Arai ◽

Kazunori Kawaguchi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Systematic Review ◽

Overall Survival ◽

Randomized Controlled Trials ◽

Systemic Therapy ◽

Meta Analysis ◽

Controlled Trials ◽

Advanced Hepatocellular Carcinoma ◽

Time To Progression ◽

Randomized Controlled

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Therapy in Advanced Hepatocellular Carcinoma

Seminars in Interventional Radiology ◽

10.1055/s-0040-1719187 ◽

2020 ◽

Vol 37 (05) ◽

pp. 466-474

Author(s):

Hanna Javan ◽

Farshid Dayyani ◽

Nadine Abi-Jaoudeh

Keyword(s):

Hepatocellular Carcinoma ◽

Systemic Therapy ◽

Randomized Clinical Trials ◽

Adoptive Cell Transfer ◽

Oncolytic Viruses ◽

Locoregional Therapy ◽

Advanced Hepatocellular Carcinoma ◽

Second Line ◽

First Line ◽

Advanced Hcc

AbstractTreatment of advanced hepatocellular carcinoma (HCC) is challenging. Several randomized clinical trials are investigating the efficacy of systemic therapy, immunotherapy, and locoregional therapy as monotherapy or combined with other modalities in the treatment of HCC. Systemic therapy is the preferred treatment in advanced disease. To date, multiple first-line and second-line agents received Food and Drug Administration approval. For over a decade, sorafenib was the only first-line agent. In May 2020, combination of atezolizumab and bevacizumab has been approved as a first-line systemic regimen. Lenvatinib is another first-line agent that has multikinase activity. Second-line agents include cabozantinib, regorafenib, ramucirumab, and nivolumab. Adoptive cell transfer therapy is a highly specific immunotherapy that has shown antitumor activity against HCC. Oncolytic viruses are genetically modified viruses that infect cancer cells and induce apoptosis. Locoregional therapies such as transarterial chemoembolization and radioembolization have shown a potential benefit in selected patients with advanced HCC. In this review, we aim to summarize the treatment options available for advanced HCC.

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Clinical Outcomes with Multikinase Inhibitors after Progression on First-Line Atezolizumab plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma: A Multinational Multicenter Retrospective Study

Liver Cancer ◽

10.1159/000512781 ◽

2021 ◽

Vol 10 (2) ◽

pp. 107-114

Author(s):

Changhoon Yoo ◽

Jwa Hoon Kim ◽

Min-Hee Ryu ◽

Sook Ryun Park ◽

Danbi Lee ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Retrospective Study ◽

Disease Progression ◽

Clinical Outcomes ◽

Systemic Therapy ◽

Advanced Hepatocellular Carcinoma ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Advanced Hcc

Introduction: Atezolizumab-bevacizumab is the new standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, the optimal sequence of therapy after disease progression on atezolizumab-bevacizumab is unclear. Methods: This multinational, multicenter, and retrospective study assessed clinical outcomes of patients with advanced HCC who received subsequent systemic therapy after progression on atezolizumab-bevacizumab between July 2016 and April 2019. Results: Among 71 patients treated with atezolizumab-bevacizumab, a total of 49 patients who received subsequent systemic therapy were included in this analysis; the median age was 60 years (range, 37–80) and 73.5% were male. All patients were classified as Child-Pugh A and Barcelona-Clinic Liver Cancer stage C. Multikinase inhibitors (MKIs), including sorafenib (n = 29), lenvatinib (n = 19), and cabozantinib (n = 1), were used as second-line therapy for all patients. The objective response rate and disease control rate were 6.1 and 63.3%, respectively, in all patients. With a median follow-up duration of 11.0 months, median progression-free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI] 1.8–4.9) and 14.7 months (95% CI 8.1–21.2) in all patients. Median PFS with lenvatinib was significantly longer than that with sorafenib (6.1 vs. 2.5 months; p = 0.004), although there was no significant difference in median OS (16.6 vs. 11.2 months; p = 0.347). Treatment-related adverse events (TRAEs) of any grade and grade 3 occurred in 42 (85.7) and 8 (16.3%) of patients. Common TRAEs included hand-foot syndrome (n = 26, 53.1%), fatigue (n = 14, 28.6%), hypertension (n = 14, 28.6%), and diarrhea (n = 12, 24.5%). Conclusion: Second-line treatment with MKIs, mostly sorafenib and lenvatinib, showed comparable efficacy and manageable toxicities in patients with advanced HCC after disease progression on atezolizumab-bevacizumab.

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