Hepatocellular carcinoma (HCC) is the most frequent type of malignant neoplasm occurring in the liver. It accounts for roughly 75% of all liver cancer cases and has one of the lowest five-year survival rates across all of oncology. Resection, locoregional therapy and liver transplantation have been the standard of care for treating less severe HCC, namely stage A and B HCC in the Barcelona Clinic Liver Cancer (BCLC) grading system. For less fortunate patients with metastatic or unresectable tumours in the advanced stages C and D of the BCLC system, which could make up 47% of all US HCC patients, targeted therapies and immunotherapies are the first- and second-line standard of care in the US.
Despite the increasing therapy options for patients, there is a significant unmet clinical need for treating advanced HCC. First, drug resistance against currently approved agents may severely limit available therapeutic options for patients. The existing landscape of first and second-line settings for treating metastatic/unresectable HCC consists predominantly of tyrosine kinase inhibitors (TKIs) and programmed death 1 (PD-1) inhibitors. The two first-line TKIs, Bayer’s Nexavar (sorafenib) and Eisai’s Lenvima (lenvatinib), suffer from acquired drug resistance, which negatively impacts the durability of the therapy and results in highly suboptimal patient outcomes. Similarly, there are resistance mechanisms against PD-1 inhibitors, such as interferon-γ pathway defects minimising PD-L1 expression in tumours, the presence of inhibitory metabolites in the tumour microenvironment suppressing T-cell antitumour function, and upregulation of other immune checkpoints to downplay the influence of the therapy.
This problem is likely to persist due to the increasing population of pipeline agents with the anti-PD1 mechanism of action (MoA), and there are no clear indicators that these novel agents can overcome resistance. GlobalData’s Pharma Intelligence Centre showed that PD-(L)1 inhibition is the most used MoA by upcoming pipeline agents, in five out of nine Phase III drugs under development in the US, EU, China and Japan. With such a medical need, improved mitigation of drug resistance would be a salient competitive advantage for novel agents entering the advanced HCC market.
Another challenge is the demand for more effective agents with a more economical price tag. The latest first-line immune checkpoint inhibitor (ICI) combination of AstraZeneca’s Imfinzi (durvalumab) with Imjudo (tremelimumab) showed a median overall survival (OS) of 16.4 months, reducing the risk of death by 22% versus Nexavar (13.8 months) in its Phase III HIMALAYA trial. Despite the improved efficacy provided by immunotherapies over targeted therapies, their steeper pricing undoubtedly adds further financial burden to payers and patients. One potential solution to this problem is the development of Chinese PD-1 inhibitors, driven by the world’s highest HCC incidence in China and Chinese biopharmaceuticals pursuing commercial opportunities from global registrations.
Chinese biopharmaceuticals are likely to have more flexibility in offering significant discounts on their biologics’ price tags, as observed in their price-cutting effort to get on the Chinese National Reimbursement Drug List (NRDL). This could create a pricing advantage that would disrupt Western competitors. Still, Chinese biologics had a rocky start when Innovent Biologics’ and Lilly’s Tyvyt (sintilimab) received an FDA rejection on its application in the first-line setting for non-squamous non-small cell lung cancer. Regulatory challenges exist for Chinese ICIs on the pathway to FDA approvals, notably in establishing patient diversity and adopting a contemporary and relevant comparator in their pivotal trials.
Chinese ICI players in the HCC pipeline, such as Hengrui’s Airuika (camrelizumab, NCT03764293), Junshi Biosciences’ Tuoyi (toripalimab, NCT04523493), and CStone Pharmaceuticals’ nofazinlimab (NCT04194775), are more well-geared towards overcoming such regulatory challenges with their global trial setup and adopting Nexavar or Lenvima as the comparator. Although changes to the advanced HCC treatment landscape are underway, further clinical development and innovations are needed to bring greater benefits to HCC patients around the world.