Advances in systemic therapy for the first-line treatment of unresectable HCC

ABSTRACT

Introduction: Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancers worldwide. In recent years, several drugs have been approved in first- and second-line setting. Currently, several phase-III trials are ongoing with combinations of checkpoint inhibitors, tyrosine kinase inhibitors (TKI) and anti-angiogenic antibodies, which will most likely increase therapeutic options in frontline therapy in the near future.

Areas covered: This review summarizes the standard of care in first-line systemic therapy for patients with advanced HCC and provides an outlook on the most promising combinations currently tested in prospective trials.

Expert opinion: The recent approval of novel substances has substantially changed the field of palliative treatment strategies in patients with advanced HCC. Immuno-oncology (IO)-based combination therapies will become the next standard of care in frontline HCC. The potent anti-tumor efficacy and good tolerability of these therapies will increase the use of upfront systemic therapy in patients with intermediate stage HCC.

KEYWORDS:

• Advanced hepatocellular carcinoma
• immunotherapy
• immune checkpoint inhibitor
• locoregional therapy
• systemic therapy
• tyrosine kinase inhibitors

Article highlights

• Sorafenib was the first systemic drug, which showed efficacy in advanced HCC and remained the standard of care in first-line therapy over 10 years.

• The approvals of lenvatinib in first-line and of regorafenib, cabozantinib and ramucirumab in second-line paved the way to sequential systemic therapy in HCC.

• The combination of atezolizumab and bevacizumab was the first treatment that achieved statistically significant and clinically meaningful improvement in overall survival compared to sorafenib.

• Pivotal phase III studies based on promising data from phase Ib and II studies (such as Nivolumab/Ipilimumab, Durvalumab/Tremelimumab and Lenvatinib/Pembrolizumab) are currently ongoing.

• With the availability of different options in frontline HCC, cross trial comparisons of efficacy and safety data will be required for daily decision making.

• Locoregional therapies will remain a mainstay of HCC therapy, but systemic therapies will be increasingly used in intermediate stage HCC.

Declaration of interest

A Vogel holds speaker, consultancy and advisory roles for: Roche, Bayer, Sanofi, BMS, Lilly, Novartis, EISAI, AstraZeneca, Merck, Medac, Ipsen. Servier, PierreFabre and MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received honorariums, consulted or advised the following companies: Bayer, Lilly, BMS, MSD, Eisai, Ipsen and Roche. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

AS and AV have received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - SFB/TRR 209 – 314905040. AV is supported by the European-Latin- American ESCALON consortium, funded by the EU Horizon2020 program.