Systemic Therapy and Sequencing Options in Advanced Hepatocellular Carcinoma

Abstract

The treatment landscape for advanced hepatocellular carcinoma (HCC) has recently changed and become relatively confusing. Head-to-head comparisons between most of the available agents have not been performed and are less likely to be examined in a prospective fashion in the future. Therefore, a network meta-analysis (NMA) is helpful to compare different agents from across different trials.OBJECTIVE To evaluate comparative effectiveness of different systemic treatments in advanced patients with HCC across lines of therapy.DATA SOURCES We searched various databases for abstracts and full-text articles published from database inception through March 2020.STUDY SELECTION We included phase 3 trials evaluating different vascular endothelial growth factor inhibitors (VEGFis), checkpoint inhibitors (CPIs), or their combinations in advanced HCC, in the first-line or refractory setting. DATA EXTRACTION AND SYNTHESISThe reporting of this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The overall effect was pooled using the random effects model. MAIN OUTCOMES AND MEASURES Outcomes of interest included overall (OS) and progression-free survival (PFS).FINDINGS Fourteen trials (8 in the first-line setting and 6 in the second-line setting) at low risk of bias were included. The 8 trials in the first-line setting encompassed a total of 6290 patients, with an age range of 18 to 89 years. The 5 trials included in the second-line analysis encompassed a total of 2653 patients, with an age range of 18 to 91 years. Network meta-analysis showed the combination of atezolizumab and bevacizumab was superior in patients with HCC treated in the first-line setting compared with lenvatinib (HR, 0.63; 95% CI, 0.44-0.89), sorafenib (HR, 0.58; 95% CI, 0.42-0.80), and nivolumab (HR, 0.68; 95% CI, 0.48-0.98). In the refractory setting, NMA showed that all studied drugs had PFS benefit compared with placebo. However, this only translated into OS benefit with regorafenib (HR, 0.62; 95% CI, 0.51-0.75) and cabozantinib (HR, 0.76; 95% CI, 0.63-0.92) compared with placebo. In the NMA of patients with α-fetoprotein (AFP) levels of 400 ng/mL or greater, regorafenib, cabozantinib, and ramucirumab showed PFS and OS benefit compared with placebo with no superiority of an active drug compared with any others.CONCLUSIONS AND RELEVANCE This systematic review and NMA of 14 trials found that atezolizumab and bevacizumab in combination is now considered the standard of care in the first-line setting in patients with advanced HCC. Regorafenib and cabozantinib are preferred options in refractory patients, with ramucirumab as an additional option in those with levels of AFP of 400 ng/mL or higher. Future trials should focus on other potential combinations and best treatment strategy in patients with prior VEGFi/CPI exposure.

Immunotherapy and Targeted Therapy for Hepatocellular Carcinoma: A Literature Review and Treatment Perspectives

“…Regorafenib and cabozantinib clinical trials did not include patients previously treated with immunotherapies [ 41 , 42 ], that now comprise the standard first line. Further complicating this issue, some specialists also consider that sorafenib or lenvatinib could be used as the first-line tyrosine kinase inhibitor following immunotherapy-based regimens [ 85 ].…”

FGF/FGFR Signaling in Hepatocellular Carcinoma: From Carcinogenesis to Recent Therapeutic Intervention

“…Regorafenib prolonged the median survival time of HCC patients to 10.6 months (7.8 months for a placebo) and significantly reduced the risk of death of sorafenib-resistance patients [ 109 ]. Regorafenib and cabozantinib exhibited the best PFS and OS benefits and are preferable in refractory HCC patients compared to other agents [ 110 ]. These drugs have now been applied in second-line treatment to help HCC patients who show failure after first-line intervention.…”

Beyond First-Line Immune Checkpoint Inhibitor Therapy in Patients With Hepatocellular Carcinoma

“…The majority of advanced HCC patients will invariably progress and a looming question is what should be used in the second-line setting following combination ICI therapy. The recently updated European Society of Medical Oncology position regorafenib, cabozantinib, and ramucirumab as therapeutic options following failure of atezolizumab and bevacizumab, a stance that has been adopted by a number of healthcare systems ( 18 , 19 ), and is supported by a recent network analysis ( 42 ). Evidence of efficacy of TKIs following ICI in HCC is limited.…”