Disease Analysis: Hepatocellular Carcinoma (HCC)

Disease Overview

Latest key takeaways

• Datamonitor Healthcare estimates that in 2018, there were 682,000 incident cases of hepatocellular carcinoma (HCC) worldwide in those aged 40 years and older, and forecasts that number to increase to 812,000 cases by 2027. The majority of HCC diagnoses (70.7%) worldwide are in males, ranging from 56.0% to 72.4% across regions.
• Nexavar has been firmly established as the standard of care in advanced HCC since gaining approval in the US in 2007. However, Nexavar is forecast to steadily lose market share after the introduction of generics in 2020 (US), 2021 (EU), and 2022 (Japan). Additionally, Nexavar will face strong competition from the combination of Tecentriq + bevacizumab, which was the first regimen to demonstrate both superior overall survival (OS) and progression-free survival (PFS) over Nexavar, in the Phase III IMbrave150 study.
• Datamonitor Healthcare forecasts significant growth in the US, Japan, and five major European markets (France, Germany, Italy, Spain, and the UK) over the next decade. Numerous PD-1/PD-L1 therapies are expected to be approved as monotherapies or as part of combination regimens for the first-line treatment of advanced HCC and are expected to see significant uptake in this setting. Furthermore, the approvals of expensive combination therapies in HCC will continue to drive market growth despite the generic erosion of key brands such as Nexavar.
• After demonstrating a PFS benefit and non-inferior OS to Nexavar in the Phase III REFLECT study, Lenvima became the second systemic therapy approved as a first-line treatment for HCC, in 2018. However, Lenvima is also expected to face significant competition from both the combination of Tecentriq + bevacizumab and from other immunotherapy regimens in development for the first-line setting. The loss of revenue to these therapies could be mitigated by approval of a Lenvima + Keytruda combination, which is currently being tested in the Phase III LEAP-002 trial.
• Following positive results from the Phase III RESORCE trial, Stivarga was the first therapy to be approved for HCC patients previously treated with Nexavar, in 2017. However, Stivarga now faces strong competition for these previously treated patients from targeted therapies Cabometyx and Cyramza, and immune checkpoint inhibitor therapies Yervoy and Keytruda.
• Although Cyramza failed to meet its primary endpoint in the Phase III REACH trial, the subsequent Phase III REACH-2 trial confirmed the drug’s efficacy in the subgroup of patients with high levels of alpha-fetoprotein (AFP), and supported a US approval for HCC patients who have been previously treated with Nexavar and have AFP levels ≥400ng/mL. Cyramza faces competition from Cabometyx and Stivarga, which are also approved for patients who have progressed on Nexavar, and from immunotherapies.
• Cabometyx is approved for HCC patients who have progressed on Nexavar, where it faces competition from Stivarga, Cyramza, and the immunotherapies. Exelixis is also pursuing the combination of Cabometyx + Tecentriq in the first-line Phase III COSMIC-312 study. However, first results were modest, and the combination has currently failed to demonstrate a significant improvement in OS over Nexavar.
• Imfinzi + tremelimumab, a PD-L1 inhibitor + CTLA-4 inhibitor combination, is being investigated for the first-line treatment of advanced HCC in the Phase III HIMALAYA trial. Additionally, AstraZeneca is investigating Imfinzi for the treatment of patients with locoregional HCC in the Phase III EMERALD-1 study and for the adjuvant treatment of patients with HCC who are at high risk of recurrence after hepatic resection or ablation in the Phase III EMERALD-2 study. Approval in these settings would help to differentiate Imfinzi from other PD-1/PD-L1 inhibitors in HCC.
• In 2017, Opdivo became the first drug in the PD-1/PD-L1 inhibitor class approved in the US for the treatment of advanced HCC patients who have progressed on Nexavar. Additionally, the combination of Opdivo + Yervoy received an accelerated approval in March 2020 for the same treatment setting, becoming the first regimen containing a drug in the PD-1/PD-L1 inhibitor class combined with a CTLA-4 inhibitor approved for HCC in the US. However, after the confirmatory first-line Phase III CheckMate 459 trial failed to show a statistically significant OS benefit in comparison to Nexavar, the FDA’s Oncologic Drugs Advisory Committee voted to withdraw Opdivo’s accelerated approval as a monotherapy in the second-line setting.
• Keytruda was approved shortly after Opdivo, in 2018, for patients who have progressed on Nexavar. Both therapies were approved under accelerated pathways based on Phase II data. Although the confirmatory Phase III KEYNOTE-240 trial of Keytruda failed to meet its primary endpoint due to the statistical plan chosen for the study and the impact of post-study treatment on survival results, the FDA’s Oncologic Drugs Advisory Committee voted unanimously to maintain Keytruda’s accelerated approval. Keytruda’s position as a monotherapy is conditional on the pending results from the KEYNOTE-394 study.
• Following the failure of Opdivo’s CheckMate 459 trial, tislelizumab is the only PD-1/PD-L1 inhibitor being developed as a monotherapy for previously untreated HCC patients. Tislelizumab has demonstrated promising first results in previously treated patients in the Phase II RATIONALE-208 study. Given the expected competition in the first-line setting, tislelizumab’s commercial potential will be determined by its cost-benefit ratio compared to the combination regimens, as well as its efficacy in patients who are unable to tolerate combination therapy.
• Key recent regulatory events include the topline results from the Phase III COSMIC-312 study investigating Cabometyx and Tecentriq in the first-line treatment setting, and the FDA advisory panel meetings to revise the accelerated approvals of both Opdivo and Keytruda in the second-line setting.
• Key upcoming catalysts include a BLA filing for tislelizumab, as well as topline results from the Phase III HIMALAYA study of Imfinzi + tremelimumab, and from the KEYNOTE-394 study investigating Keytruda.
• The overall likelihood of approval of a Phase I HCC asset is 7.9%, and the average probability a drug advances from Phase III is 43.5%. HCC drugs, on average, take 10.6 years from Phase I to approval, compared to 9.6 years in the overall oncology space.