Second-line Treatment Of Advanced Hepatocellular Carcinoma Research Articles

Regorafenib with immunotherapy versus regorafenib alone as second-line treatment for hepatocellular carcinoma: A multicenter real-world study.

Regorafenib remains the standard and widely used second-line strategy for advanced hepatocellular carcinoma (HCC). There is still a lack of large-scale multicenter real-world evidence concerning the concurrent use of regorafenib with immune checkpoint inhibitors (ICI). This study aims to evaluate whether combining regorafenib with ICI provides greater clinical benefit than regorafenib monotherapy as second-line therapy for advanced HCC under real-world circumstances. The study included 208 patients from five medical facilities. One hundred forty-three patients received regorafenib plus ICI combination therapy, while 65 patients received regorafenib monotherapy. Propensity score matching (PSM) analysis was employed. The regorafenib plus ICI group demonstrated significantly higher objective response rate (24.3% vs. 10.3%, after PSM, p = 0.030) and disease control rate (79.4% vs. 50.0%, after PSM, p < 0.001) compared to the regorafenib monotherapy group based on mRECIST criteria. Median progression-free survival (7.9 vs. 3.2 months, after PSM, p < 0.001) and overall survival (25.6 vs. 16.4 months, p = 0.010, after PSM) were also considerably longer in the regorafenib plus ICI group. The incidence of Grades 3-4 treatment-related adverse events (TRAEs) was marginally greater in the regorafenib plus ICI group than in the regorafenib group (23.8% vs. 20.0%, p = 0.546). Notably, there were no instances of treatment-related mortality or emergence of new TRAEs in any treatment group. The combination of regorafenib and ICI shows potential as a viable second-line treatment for advanced HCC, exhibiting favorable efficacy while maintaining a tolerable safety profile in contrast to regorafenib monotherapy.

Regorafenib combined with a PD-1 inhibitor in the second-line setting for unresectable hepatocellular carcinoma in real-world practice.

Most advanced hepatocellular carcinoma (HCC) cases administered molecular targeted agents and/or anti-programmed cell death-1 (PD-1) inhibitors have no response or develop resistance. Moreover, second-line therapies still cannot provide beneficial clinical outcomes. A pilot study assessing combined regorafenib and PD-1 inhibitor as second-line treatment of advanced HCC reported promising effectiveness. The current single-center, retrospective, real-world study was carried out between January 2019 and July 2021. Advanced HCC cases were administered second-line regorafenib combined with a PD-1 inhibitor or regorafenib alone were assessed. Progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were determined. Totally 46 HCC cases were analyzed, most of whom underwent previous systemic treatment comprising targeted therapy and immunotherapy. Tumor response was evaluated in 25 and 21 individuals in the regorafenib + PD-1 inhibitor and regorafenib monotherapy groups, respectively: ORRs were 21.7% and 8.7%, and DCRs were 47.8% and 32.6%, respectively. Median PFS was markedly longer in the regorafenib plus PD-1 inhibitor group (11.5 months) compared with the regorafenib monotherapy group (5.1 months, P=0.049). This study suggested regorafenib and a PD-1 inhibitor in combination may provide significant clinical benefits in HCC cases showing progression following first-line treatment. Further analysis in real-world studies with large cohorts is warranted to confirm these findings.

Lenvatinib plus anti-PD-1 antibodies as conversion therapy for patients with unresectable intermediate-advanced hepatocellular carcinoma: a single-arm, phase II trial

BackgroundOver 70% of the patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage and lose the opportunity for radical surgery. Combination therapy of tyrosine kinase inhibitors (TKIs) and...

Efficacy and safety of regorafenib alone or in combinations in the second-line setting for advanced hepatocellular carcinoma: A multicenter real-world study.

e16172 Background: Due to drug resistance or intolerable adverse events, most hepatocellular carcinoma (HCC) patients tend to experience TKI-based first-line therapy failure. However, there is no unified choice of second-line treatment after this. Different authors have demonstrated that the combination of regorafenib and PD-1 inhibitors or TACE depicts synergistic effect. Therefore, the major goal of this research is to explore the efficacy and safety of regorafenib alone or in combinations as second-line therapy for advanced HCC in a real-world setting. Methods: In this study 94 advanced HCC patients (84 male and 10 females, average age of 59.8 years) were included from 3 Chinese centers between September 2018 and August 2022. It includes pathologically or clinically diagnosed advanced HCC patients who received regorafenib alone or in combinations in the second-line setting for at least 28 consecutive days. The primary endpoints were objective response rate (ORR, mRECIST criteria), and progression-free survival (PFS), however, the secondary endpoints included overall survival (OS) rate at 12-month, disease control rate (DCR) and treatment-related adverse events (TRAEs). Statistical analysis was performed with Kaplan-Meier method by using log-rank test. Results: 32 (34.0%) patients had BCLC stage B (others had BCLC stage C) and 72 (76.6%) patients were of Child-Pugh A (others were of Child-Pugh B). Half of the patients received regorafenib 160mg once daily during weeks 1–3 of each 4-week cycle. The proportions of patients received single drug regorafenib therapy (REGO) and combination therapies (COM) were 26.6% and 73.4%, respectively. The combination treatment regimens included regorafenib plus PD-1 inhibitors (36.2%), regorafenib combined with TACE (11.7%), and triple therapy (regorafenib, PD-1 inhibitors, TACE) (25.5%). The ORR and DCR were 28.7% and 72.3% with a median PFS of 8.4 months (range 6.33-10.47) and 12-month OS rate was 92.6%. The median PFS of COM group was 8.7 months ranging from 7.09-10.32, which was significantly longer compared to REGO group (4.2 months, range 0.45-7.95) (P = 0.031). Moreover, 66 (70.2%) recipients had TRAEs and most frequent TEAEs (≥5%) included hand-foot syndrome (31.9%), diarrhea (20.2%), rash (13.8%), fatigue (7.4%), oral mucositis (7.4%) and arthralgia (5.3%). 12 (12.8%) recipients had grade 3 TRAEs, including hand-foot syndrome (8.5%), hypertension (2.1%), diarrhea (1.1%) and rash (1.1%). No Grade 4 TRAE and new safety signal were identified. Conclusions: In the second-line treatment of advanced HCC, regorafenib alone or in combinations is effective and well-tolerated. The combination therapy showed a longer survival than regorafenib alone.

Regorafenib combined with transarterial chemoembolization and PD-1 antibody as a second-line therapy for hepatocellular carcinoma: A real-world study.

e16167 Background: The benefits and tolerability of regorafenib combined with transarterial chemoembolization (TACE) and programmed death-1 (PD-1) antibody as a second-line therapy for advanced hepatocellular carcinoma (HCC) is unclear. We aimed to determine the efficacy and safety of regorafenib combined with TACE and PD-1 antibody as second-line treatment for advanced HCC. Methods: This study was approved by our institutional review board. In this retrospective study, a total of 55 consecutive advanced HCC patients who had tumor progression after first-line sorafenib treatment, and then treated with regorafenib plus TACE and programmed death-1 (PD-1) antibody between January 2017 and December 2020 were evaluated. The overall survival (OS), tumor response and adverse events (AEs) were analyzed. Statistical analysis was performed with the Kaplan-Meier method using the log-rank test and Cox regression models. Results: The median follow-up period was 35.5 months (range 6.0-52.0 months). The median age was 50 (range 18, 72) years. There were 49 (89.0%) males. The initial doses of regorafenib were 80 mg/d (n = 18, 32.7%) and 120 mg/d (n = 37, 67.3%). The patients underwent a median of two TACE sessions (range 1–5). The median OS after second-line treatment was 16.0 months (range 3.6-33.5 months), and the median PFS was 9.0 months (95%CI 6.1-11.7 months). According to modified RECIST criteria, complete response and partial response were found in 3 (5.5%) and 29 (45.5%) patients. The incidence of all grade 3/4 AEs was 29.6%, and the three main AEs were abdominal pain (10.9%), hypertension (7.3%) and hand-foot-skin reaction (5.5%). Two patients stopped PD-1 antibody and one stopped regorafenib due to AEs. Conclusions: Regorafenib combined with TACE and PD-1 antibody were tolerable and resulted in a promising OS and ORR in the second-line treatment of advanced HCC.

Antitumor Effect of Regorafenib on MicroRNA Expression in Hepatocellular Carcinoma Cell Lines.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is one of the leading causes of cancer-related deaths worldwide. Regorafenib, a multi-kinase inhibitor, is used as a second-line treatment for advanced HCC. Here, we aimed to investigate the mechanism of the antitumor effect of regorafenib on HCC and evaluate altered microRNA (miRNA) expression. Cell proliferation was examined in six HCC cell lines (HuH-7, HepG2, HLF, PLC/PRF/5, Hep3B, and Li-7) using the Cell Counting Kit-8 assay. Xenografted mouse models were used to assess the effects of regorafenib in vivo. Cell cycle analysis, western blotting analysis, and miRNA expression analysis were performed to identify the antitumor inhibitory potential of regorafenib on HCC cells. Regorafenib suppressed proliferation in HuH-7 cell and induced G0/G1 cell cycle arrest and cyclin D1 downregulation in regorafenib-sensitive cells. During miRNA analysis, miRNA molecules associated with the antitumor effect of regorafenib were found. Regorafenib suppresses cell proliferation and tumor growth in HCC by decreasing cyclin D1 via alterations in intracellular and exosomal miRNAs in HCC.

P-61 Relatlimab + nivolumab in patients with advanced hepatocellular carcinoma who are naive to immuno-oncology therapy but progressed on tyrosine kinase inhibitors, a phase 2, randomized, open-label study: RELATIVITY-073

Immuno-oncology (IO) therapies, used alone or in combination, have improved outcomes in advanced hepatocellular carcinoma (HCC); however, not all patients benefit and novel IO combinations are needed to further enhance the benefit-risk profile. Lymphocyte-activation gene 3 (LAG-3) regulates an inhibitory immune checkpoint pathway, limiting T-cell activity, and is a marker for T-cell exhaustion and resistance to IO therapies. LAG-3 is upregulated in many tumors including HCC. Relatlimab (RELA), a LAG-3-blocking antibody, restores effector function of exhausted T cells. Nivolumab (NIVO) is a programmed death-1 (PD-1)-blocking antibody approved for second-line treatment of advanced HCC. Preclinical data indicate that dual inhibition of LAG-3 and PD-1 pathways with RELA + NIVO, respectively, may leverage potentially synergistic pathways to enable T-cell activation and improve immune response. RELATIVITY-073 will evaluate preliminary efficacy and safety of RELA + NIVO in previously treated IO-naive HCC. RELATIVITY-073 is an open-label, randomized, phase 2 study in IO-naive patients with advanced HCC who progressed on prior tyrosine kinase inhibitor therapy in the advanced/metastatic setting. Patients aged ≥ 18 years must have histologically confirmed, advanced HCC of any etiology, not eligible for curative surgical and/or locoregional therapy, Child-Pugh score of 5 or 6, and ECOG performance status 0 or 1. Tumor tissue must be provided for biomarker analysis and patients must have evaluable tumor LAG-3 expression status prior to randomization. Patients with active brain metastases or leptomeningeal metastases, uncontrolled or significant cardiovascular disease, and clinically significant ascites are excluded. Approximately 250 patients will be randomized 2:1:2 to NIVO (treatment arm A) or one of two regimens of RELA + NIVO (treatment arms B and C) to assess different RELA dose levels. The primary endpoint is objective response rate (ORR) per RECIST v1.1 as assessed by blinded independent central review. Other endpoints include safety and tolerability, disease control rate, duration of response, progression-free survival, overall survival, dose-response relationship using best overall response, and ORR by LAG-3 expression status. This study is enrolling patients globally. NCT04567615. All authors contributed to and approved the abstract; writing and editorial assistance was provided by Kathryn Woods and Adam Paton of Complete HealthVizion, funded by Bristol Myers Squibb. Bristol Myers Squibb.

Second-line treatments for Advanced Hepatocellular Carcinoma: A Systematic Review and Bayesian Network Meta-analysis

Background & AimsA plethora of second-line therapies have been recently introduced for hepatocellular carcinoma (HCC) treatment with promising results. A meta-analysis of second-line treatments for HCC has been performed to better tailor their use based on improved patient stratification and to identify the best available option.MethodsPubmed, Scopus, Web of Science, and ClinicalTrials.gov were searched for randomized controlled trials evaluating second-line treatment for advanced HCC in patients already treated with sorafenib. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and drug withdrawal due to adverse events. Network meta-analyses were performed considering placebo as the basis for comparison in efficacy and safety analyses. Subgroup stratification considered gender, age, sorafenib-responsiveness and drug tolerability, viral infection, macrovascular invasion, HCC extrahepatic spread, performance status, and alpha-fetoprotein levels.ResultsFourteen phase II or III randomized controlled trials, involving 5,488 patients and 12 regimens, were included in the analysis. Regorafenib (hazard ratio (HR) = 0.63, 95% confidence interval (CI) = 0.50–0.79), cabozantinib (HR = 0.76, 95% CI = 0.63–0.92), and ramucirumab (HR = 0.82, 95% CI = 0.70–0.76) significantly prolonged OS compared with placebo. Cabozantinib (HR = 0.44, 95% CI = 0.36–0.52), regorafenib (HR = 0.46, 95% CI = 0.37–0.56), ramucirumab (HR = 0.54, 95% CI = 0.43–0.68), brivanib (HR = 0.56, 95% CI = 0.42–0.76), S-1 (HR = 0.60, 95% CI = 0.46–0.77), axitinib (HR = 0.62, 95% CI = 0.44–0.87), and pembrolizumab (HR = 0.72, 95% CI = 0.57–0.90) significantly improved PFS compared with placebo. None of the compared drugs deemed undoubtedly superior after having performed a patients’ stratification.ConclusionsThe results of this network meta-analysis suggest the use of regorafenib and cabozantinib as second-line treatments in HCC.

Nivolumab + Ipilimumab for patients with hepatocellular carcinoma previously treated with Sorafenib

ABSTRACT Introduction The systemic treatment of advanced, unresectable hepatocellular carcinoma (HCC) has undergone an evolution in recent years. In March 2020, a combination of nivolumab and ipilimumab was approved by the FDA for treatment of patients with advanced HCC who received prior sorafenib. This was based on the results of the phase I/II CheckMate-040 cohort 4 trials, which showed a promising overall response rate and encouraging overall survival with a manageable safety profile. Areas covered This article reviews the pharmacology, efficacy and safety of nivolumab-ipilimumab in advanced HCC with prior sorafenib. Other existing systemic treatment options for advanced HCC will be described and compared to nivolumab-ipilimumab. Impact of different dose regimes, ongoing research and future developments of nivolumab-ipilimumab will be discussed. We focus on the analysis from the aforementioned CheckMate-040 cohort 4 registration trial. Expert opinion The approval of nivolumab-ipilimumab in the second-line treatment of advanced HCC by the FDA is an important development for treatment of advanced HCC. However, further investigations are needed to optimize dosing regimens and explore the use of nivolumab-ipilimumab in other combinations and settings.

Safety and efficacy of combination of GT90001, an anti-activin receptor-like kinase-1 (ALK-1) antibody, and nivolumab in patients with metastatic hepatocellular carcinoma (HCC).

326 Background: GT90001, a fully human anti-ALK-1 mAb (IgG2) that may inhibit ALK-1/ TGF-β signaling and tumor angiogenesis, has shown good single-agent safety profile in humans. This study aimed to assess the safety and efficacy of GT90001 in combination with nivolumab in patients with advanced HCC who had progressive disease after or were intolerant to first-line sorafenib or lenvatinib therapy (NCT03893695). Methods: We did a phase I/II, open-label, single arm, dose de-escalation and expansion trial of GT90001 in combination with nivolumab in patients with histologically or cytologically confirmed HCC with Child-Pugh class A, ECOG performance status of 0 or 1 at three sites in Taiwan. Patients previously treated with immune checkpoint inhibitors were excluded. Stage 1 (dose de-escalation cohort) tested 3 doses of GT90001 (7 (starting dose), 4.5, and 3 mg/kg every 2 weeks) plus nivolumab 3 mg/kg every 2 weeks in 6 subjects at each dose level. Dose-limiting toxicity (DLT) was defined as any treatment-emergent grade 3-4 adverse events (AEs) (CTCAE V5.0) in the first 28 days of treatment. Stage 2 (expansion cohort) tested the combination regimen in 14 patients until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was investigator-assessed objective response as per RECIST v1.1. Results: Between July 9th, 2019 and June 26th, 2020, twenty eligible patients were treated. No DLT was observed in stage 1, and GT90001 7.0 mg/kg + nivolumab 3.0 mg/kg every 2 weeks were given in stage 2. The pharmacokinetics of GT90001 and nivolumab were similar to those observed in monotherapy. As of June 26, 2020, 20 patients were evaluable for safety. The common AEs (occurring to more than 20%) included platelet count decreased, rash, fatigue, dizziness, peripheral edema, and constipation. Three patients had treatment-related serious AEs (renal dysfunction, autoimmune hepatitis, hyperamylasemia). Nine patients had GT90001 dose interruption due to AEs and the most common reasons were platelet count decrease (3 patients). No patient discontinued the treatment due to AEs. The median duration of follow-up was 3.7 months (range 0.6-11.1). An objective response assessed was observed in 7 patients (43.75%) out of 16 evaluable patients, all were partial response and 4 of them had confirmed responses. The disease control rate (complete response + partial response + stable disease) was 56.2%. Updated efficacy data will be presented at the congress. Conclusions: The combination of GT90001 with nivolumab showed a manageable safety profile, and no new safety signals were identified. The promising preliminary antitumor activities show the potential of GT90001 combined with nivolumab as second-line treatment for advanced HCC. Clinical trial information: NCT03893695.

Novel systemic therapy for hepatocellular carcinoma.

Systemic therapy for hepatocellular carcinoma (HCC) used to be limited to patients with advanced diseases and multi-kinase inhibitors targeting tumor angiogenesis the major approach of developing new treatment options. In the past 3years, new data from trials of both molecular targeted therapy and immune checkpoint inhibitors (ICI) provided many new options of first- and second-line treatment for advanced HCC. Most notably, combination of ICI targeting the program cell death-1 (PD-1) pathway with other novel agents or conventional anti-cancer therapy may further improve treatment efficacy in different clinical settings. In thispaper updated data of clinical trials of systemic therapy in the first- and second-line settings for advanced HCC were reviewed and the following issues werediscussed: (1) lessons of trial design learned from positive and negative trials; (2) the balance between efficacy and safety in clinical practice; and (3) impact on future multi-disciplinary management of HCC.

Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials

BackgroundSymptoms of advanced hepatocellular carcinoma (HCC) represent a substantial burden for the patient and are important endpoints to assess when evaluating treatment. Patient-reported outcomes were evaluated in subjects with advanced HCC and baseline alpha-fetoprotein (AFP) ≥400 ng/mL treated with second-line ramucirumab.Patients and methodsPatients with AFP≥400 ng/mL enrolled in the REACH or REACH-2 phase 3 studies were used in this analysis. Eligible patients had advanced HCC, Child-Pugh A, Eastern Cooperative Oncology Group performance status 0/1 and prior sorafenib. Patients received ramucirumab 8 mg/kg or placebo once every 2 weeks. Disease-related symptoms and health-related quality of life (HRQoL) were assessed with the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL-5-Dimensions (EQ-5D) instruments, respectively. Time to deterioration (TTD) (≥3-point decrease in FHSI-8 total score;≥0.06-point decrease in EQ-5D score, from randomisation to first date of deterioration) was determined using Kaplan-Meier estimation and the Cox proportional hazards model. Both separate and pooled analyses for REACH AFP≥400 ng/mL and REACH-2 patients were conducted.ResultsIn the pooled population with AFP ≥400 ng/mL (n=542; ramucirumab, n=316; placebo, n=226), median TTD in FHSI-8 total score was prolonged with ramucirumab relative to placebo (3.3 vs 1.9 months; HR 0.725; (95% CI 0.559 to 0.941); p=0.0152), including significant differences in back pain (0.668; (0.497 to 0.899); p=0.0044), weight loss (0.699; (0.505 to 0.969); p=0.0231) and pain (0.769; (0.588 to 1.005); p=0.0248) symptoms. TTD in EQ-5D score was not significantly different between ramucirumab and placebo groups (median 2.9 vs 1.9 months). Results in the individual trials were consistent with these findings.ConclusionsRamucirumab in second-line treatment of advanced HCC demonstrates consistent benefit in the delay of deterioration in disease-related symptoms with no worsening of HRQoL. Taken with previously demonstrated ramucirumab-driven survival benefits in this setting, these data may inform patient–clinician discussions about the benefit–risk profile of this therapy.Trial registration numberNCT01140347; NCT02435433, NCT02435433.

Lenvatinib (len) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 3 LEAP-002 study.

TPS4152 Background: Len, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, is approved for first-line treatment of unresectable HCC (uHCC) based on the open-label phase 3 REFLECT study in which len showed noninferior overall survival (OS) and significantly improved objective response rate (ORR), progression-free survival (PFS), and time-to-progression (TTP) vs sorafenib. In the phase 2 KEYNOTE-224 study of pembro (a PD-1 inhibitor) as second-line treatment of advanced HCC, pembro showed meaningful clinical efficacy in pts previously treated with sorafenib, with median PFS 4.9 mo, median OS 12.9 mo, and a manageable safety profile. In results from the phase 1b KEYNOTE-524 trial, len+pembro was well-tolerated, with promising antitumor activity in pts with uHCC. LEAP-002 is a phase 3 study to evaluate the safety and efficacy of len+pembro vs len+placebo as first-line therapy for advanced HCC. Methods: Eligible pts are ≥18 y and have HCC confirmed by radiology, histology, or cytology; ECOG PS 0/1; BCLC stage C or stage B disease not amenable to locoregional therapy or curative treatment approach; CP class A liver score within 7 days before study; and ≥1 measurable lesion by RECIST v1.1. Pts with past or ongoing HCV infection and those with controlled HBV are eligible. 750 pts will be randomized 1:1 to receive len 12 mg (body weight [BW] ≥60 kg) or 8 mg (BW &lt;60 kg) orally once daily plus pembro 200 mg or placebo IV Q3W. Pembro and len will be administered until disease progression or unacceptable toxicity, with a maximum 35 cycles for pembro. Stratification will be by geographic region (Asia vs Japan and Western regions); macroscopic portal vein invasion or extrahepatic spread or both (yes or no); alpha fetoprotein ≤400 ng/mL vs &gt;400 ng/mL; and ECOG PS 0/1. Primary end points are PFS per RECIST v1.1 by blinded independent central review (BICR) and OS. Secondary end points are ORR, duration of response, disease control rate, and TTP per RECIST v1.1 by BICR, efficacy per modified RECIST, pharmacokinetics, and safety. Imaging assessments will be performed Q9W on study. AEs will be graded per CTCAE v4.0 and monitored up to 90 days after last dose. Clinical trial information: NCT03713593.

Second-line Treatments of Advanced Hepatocellular Carcinoma: Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Advanced hepatocellular carcinoma (HCC) constitutes the second leading cause of cancer-related deaths. First-line therapy is either sorafenib or lenvatinib. Several treatment options have been recently added to the second-line treatment of advanced HCC. The aim of this network meta-analysis of randomized controlled trials was to compare the second-line treatments of advanced HCC. Network meta-analyses were computed for overall survival (OS), progression-free survival, rates of grade 3 to 5 adverse events, and for treatment discontinuation due to adverse events. OS was considered to be the primary outcome of this study, and everolimus was chosen to be the common comparator for efficacy analyses and placebo for safety analyses. Subgroup analyses were computed for OS in patients with hepatitis B, patients with hepatitis C, Asian patients, patients with macrovascular invasion, and patients with extrahepatic metastases. Thirteen randomized controlled trials including 5076 patients and evaluating 11 agents were found to be eligible. Regorafenib [hazard ratio (HR)=0.60, 95% confidence interval (CI)=0.44-0.81] and cabozantinib (HR=0.72, 95% CI=0.55-0.95) were found to significantly prolong OS compared with everolimus. The effect of regorafenib on OS tended to be conserved across patient subgroups. Regorafenib was also found to significantly prolong progression-free survival (HR=0.46, 95% CI=0.35-0.62) and significantly increase the rates of grade 3 to 5 adverse events (odds ratios=3.18, 95% CI=2.22-4.54) and treatment discontinuation due to adverse events (odds ratios=2.67, 95% CI=1.21-5.87). This network meta-analysis concludes that, based on current evidence, regorafenib could be the agent of choice in the second-line treatment of HCC, with cabozantinib as a possible alternative for sorafenib-intolerant patients.

Immunotherapy for hepatocellular carcinoma treatment

Hepatocellular carcinoma (HCC) is a malignancy with rapidly progressive and poor prognosis. Data from the Thai national public health survey in 2016, liver cancer became the number one leadingcause of death. Strategies using immunotherapy, including immune checkpoint inhibitors, have shown promising results as the second-line treatment for advanced HCC after the standard of care andtargeted therapy. This review is the update on the important clinical studies, current clinical application, and future perspectives on the immunotherapy in HCC.&#x0D;

Emerging Targeted Strategies in Advanced Hepatocellular Carcinoma

Treatment of advanced-stage hepatocellular carcinoma (HCC) remains a challenge because of the complex nature of the disease and the lack of available therapies. The antiangiogenic multikinase inhibitor sorafenib is the first therapy to demonstrate a significant overall survival benefit in advanced HCC. However, new agents for both first- and second-line treatment of advanced HCC are needed. The multiple pathways involved in HCC oncogenesis, proliferation, and survival provide many opportunities for the development of molecularly targeted therapies. Many novel agents are under investigation in phase III trials in advanced HCC, including antiangiogenic multikinase inhibitors (e.g., brivanib, sunitinib, linifanib) and inhibitors of the mammalian target of rapamycin (mTOR) pathway (e.g., everolimus). Although these therapies have demonstrated some utility as single agents in advanced HCC, rational combinations of therapies are likely to provide greater success. Current research efforts are directed at combining agents targeting different molecular pathways (e.g., sorafenib in combination with erlotinib) and combining molecularly targeted agents with systemic chemotherapy or transarterial chemoembolization (TACE). Therapies targeting other molecular pathways in HCC are in early development; future research will focus on discovering additional targets for therapy and identifying biomarkers that predict the success of current therapies.