Important pipelines in development of the Liver Cancer Drug

Important pipelines in development

The angiogenesis inhibitors and immune checkpoint inhibitors are the directions of main liver cancer drugs in development, and the drug combinations are also in development (Fig. 3).

The oral MKI cabozantinib (Cabometyx; Exelixis / Ipsen / Takeda) has a primary endpoint (OS) similar to placebo in the advanced recurrent HCC (Phase III; CELESTIAL); compared to those who only took sorafenib, cabozantinib could improve OS; the grade 3 or 4 adverse reaction, such as drug discontinuation rate and ORR (4%), of cabozantinib was equal to other MKIs approved for HCC treatment. Cabozantinib is under regulatory review in the U.S. and Europe, and its PDUFA date has been determined to be Jan. 14, 2019 by FDA.

Ramucirumab (Cyramza; Eli Lilly) is a monoclonal antibody (mAb) targeting vascular endothelial growth factor receptor 2 (VEGFR2), and reached the primary endpoint OS in the Phase III clinical trial (REACH-2). Same as regorafenib and cabozantinib, ramucirumab (in combination with the best supportive care (BSC)) could improve OS in patients who have previously received sorafenib treatment, however, different from other trials with same conditions, the alpha-fetoprotein (AFP) level of the participants was higher. In the Phase III REACH trial with prespecified subgroup analysis, REACH-2 was triggered, but ramucirumab failed to significantly improve OS in unselected patients. Generally, the AFP content is high in about a half of advanced HCC patients. The human trial results of ramucirumab used for such biomarker will be submitted to the regulator in 2018.

The PD-1 inhibitor pembrolizumab (Keytruda; Merck＆Co) is in the clinical trial for recurrent advanced liver cancer patients after sorafenib treatment (Phase III; KEYNOTE-240). Pembrolizumab received the priority review designation of FDA for recurrent advanced liver cancer in July 2018. Merck, based on the Phase II data, is seeking for accelerated approval, and FDA’s target PDUFA review date therefor is determined to be Nov. 9, 2018.

Other PD-1 inhibitors in development for liver cancer include tislelizumab (BeiGene / Celgene), and spartalizumab (Novartis Oncology), etc. Tislelizumab is in the trial for patients with previously treated or untreated locally advanced or metastatic cancer. Spartalizumab is in the trial for advanced liver cancer treatment as monotherapy or in combination with c-MET (also known as HGFR) inhibitor: capmatinib (Novartis Oncology).

Fig. 3 Important Pipelines in Development for Liver Cancer

Many targeted drugs including tislelizumab are in phase III head-to-head trials with sorafenib in patients who have previously not received treatment, and many MKIs fail to significantly improve the OS. Like ramucirumab, bevacizumab (Avastin; Roche / Genentech / Chugai) is a mAb angiogenesis inhibitor targeting VEGF ligand. Atezolizumab (Tecentriq; Roche / Genentech / Chugai) is used in combination with programmed death-ligand 1 (PD-L1) inhibitor to treat locally advanced or metastatic HCC patients who have not received any systemic treatment, and in the IMbrave150 trial; according to the Phase Ib data, FDA approved atezolizumab to be used in combination with bevacizumab as a breakthrough therapy to serve as a first-line therapy for the advanced or metastatic liver cancer in July 2018.

The PD-L1 inhibitor durvalumab (Imfinzi; AstraZeneca) is in the HIMALAYA trial for unresectable advanced or metastatic liver cancer. Other combination therapies underway include the transforming growth factor beta receptor (TGFβR1) inhibitor: galunisertib (Eli Lilly) in combination with nivolumab, ramucirumab, sorafenib, and the mAb bavituximab (Oncologie) that targets the converted phosphatidylserine. Like ramucirumab, galunisertib can also be used as a monotherapy for elevated AFP patients with recurrence or poor performance after sorafenib treatment.

Read More:

Nature Review: Current Situation of the Global Liver Cancer Drug Market

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

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