Hepatocellular carcinoma (HCC) is the most common primary malignant tumor in liver, with chronic viral infection (hepatitis B or hepatitis C) or alcoholic cirrhosis being the major potential risk factors. Most patients can be treated through surgery, local ablation, or targeted arterial embolization therapy, etc. when diagnosed in early stage or middle stage, however, the recurrence rate is high. Liver cancer has become one of the tumors with high fatality rate among cancers in the U.S., and is mainly treated through systemic palliative care in the advanced stage.

Existing treatment methods

There have been three oral multi-kinase inhibitors (MKIs) approved for systemic therapy, including two as first-line therapy. Sorafenib (Nexavar; Bayer) has been used as a first-line drug for advanced HCC in patients with good liver function and performance since 2007, being the first targeted drug with better overall survival (OS) compared to the placebo, however, with lower objective response rate (ORR) than the placebo (2%).

The MKI regorafenib (Stivarga; Bayer, Fig. 1) was approved in Apr. 2017 by FDA for liver cancer patients who have failed sorafenib treatment. It's worth noting that regorafenib will cause occurrence of hepatotoxicity or dose interruption or reduction.

Fig. 1 Molecular Structural Formula of Regorafenib

The other MKI lenvatinib (Lenvima; Eisai and Merck & Co., Fig. 2) was approved in Japan, and the U.S. and Europe separately in Mar. 2018 and Aug. 2018, as a first-line therapy for unresectable HCC, which was based on the data of a Phase III clinical study REFLECT (Study 304): lenvatinib reached the noninferiority statistical standard compared to sorafenib in terms of OS.

Fig. 2 Molecular Structural Formula of Lenvatinib

The programmed cell death 1 (PD-1) inhibitor: nivolumab (Opdivo; Bristol-Myers Squibb / Ono Pharmaceutical) is the one and only biologic approved for HCC. The drug received FDA’s accelerated approval in Sep. 2017 for treatment of patients with recurrence who have been previously treated with sorafenib based on the ORR and drug resistance results of the Phase I / II trial (CheckMate-040).

Despite the promising data, Bristol-Myers Squibb withdrew the application for using nivolumab for liver cancer recurrent after sorafenib treatment in July 2017 in the Europe, because the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) considered there to be uncertainties in the non-comparative design of CheckMate-040. And later the company improved CheckMate-040 (CheckMate-459), and nivolumab has been assessed as a first-line therapy after sorafenib treatment in Phase III (CheckMate-459) trial, and the only targeted drug after resection or ablation adjuvant therapy in Phase III (CheckMate-9DX).

Read More:

Nature Review: Market Forecast of the Global Liver Cancer Drug Market

Important pipelines in development of the Liver Cancer Drug

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