28 August 2020: New treatment options for people with advanced or unresectable hepatocellular carcinoma (HCC) may now be a step closer after three research groups presented safety and efficacy data at The Digital International Liver Congress™ (DILC) 2020. After a decade in which systemic treatment for advanced HCC was limited to a single option, sorafenib,1 these results build on other developments in recent years that could significantly improve the lives of patients with this difficult-to-treat condition.
Liver cancer is the second most common cause of cancer fatalities worldwide, with HCC accounting for over 90% of primary liver cancers. Around 90% of HCCs are associated with widespread risk factors such as chronic hepatitis B and C infection, non-alcoholic fatty liver disease (NAFLD), alcohol intake and aflatoxin exposure. The prognosis for patients with HCC remains poor; in Europe for example, the 3-year survival rates for patients diagnosed with any-stage HCC while under surveillance is estimated to be 47.3%, and as low as 21.8% for those diagnosed while not under surveillance. However, an increasing number of emerging treatments in recent years have the potential to improve this outlook.
The IMbrave150 study, presented at DILC 2020 and now published in the New England Journal of Medicine, investigated the combination of atezolizumab and bevacizumab (atezo+bev) against the standard systemic therapy, sorafenib. In this randomized, open-label trial, patients with unresectable HCC who had not received prior systemic therapy were treated with either atezolizumab 1,200 mg intravenously (IV) + bevacizumab 15 mg/kg IV or sorafenib 400 mg twice daily. Improvements in overall survival and progression-free survival with the combination therapy have been previously reported in this trial. Median treatment durations were 7.4 months for atezolizumab, 6.9 months for bevacizumab and 2.8 months for sorafenib. Adverse events (AEs) of grade 3-4 were reported in 57% of patients receiving atezo+bev (n=329) and 55% of those receiving sorafenib (n=156). The most severe grade 5 AEs occurred in 5% and 6% of patients, respectively, and more patients receiving atezo+bev than sorafenib required corticosteroid treatment (12% vs 3%). The rate of immune-mediated hepatitis was comparable between treatments, while other AEs of special interest also occurred at similar rates and were mostly mild (grade 1-2).
"Atezo+bev was generally well-tolerated, and adverse events of interest in this class of therapy were manageable," said Professor Michel Ducreux of the Gustave Roussy Cancer Center in France. "Combined with previous efficacy results, these data suggest that atezo+bev should be considered as the new standard of care in patients with unresectable HCC who have not received previous systemic therapy."
A combination of the multikinase inhibitor lenvatinib and pembrolizumab, an antiprogrammed death receptor-1 monoclonal antibody, has also been investigated in a Phase 1b study in a first-line population. Patients received lenvatinib 12 mg/day (8 mg/day if weighing <60 kg) and pembrolizumab 200 mg IV every 21 days. In an initial safety phase (Part 1) with six patients, there were no dose-limiting toxicities reported. A second phase (Part 2) included 80 patients as of 31 October 2019, with a median duration of treatment of 8.5 months and a median follow-up of 11.5 months. Median overall survival was 22.0 months (95% CI 14.6-not estimable) and median progression-free survival was 8.6 months (95% CI 6.9-9.7). The objective response rate was 43.8% (95% CI 32.7-55.3), with a median time to response of 2.4 months (range: 1.2-11.8) and a median duration of response of 12.6 months (95% CI 6.5-18.7). Disease control (defined as complete response + partial response + stable disease for ?5 weeks) was achieved in 83.8% (95% CI 73.8-91.1) of patients. Treatment-related AEs occurred in 95% of patients, including 35% who experienced serious adverse events and three fatalities.
Encouraging results for patients with advanced HCC previously treated with sorafenib were also presented following a subgroup analysis of the CheckMate 040 trial. This study assessed the efficacy and safety of nivolumab + ipilimumab in three different dose combinations. In the cohort receiving ipilimumab at 3 mg/kg and nivolumab at 1 mg/kg, among 50 patients previously treated with sorafenib, the overall response rate was 32%, including 4 patients achieving complete response, and median overall survival was 22.8 months. This combination has been approved by the FDA as a second-line treatment after sorafenib. The results were further analyzed by duration of prior exposure to sorafenib (up to 6 months vs more than 6 months). Response rate (36% vs 29%), disease control rate (63% vs 46%), and median overall survival (25.5 vs 19.2 months) were numerically higher in the subgroup of patients with longer duration of prior sorafenib. However, less favorable disease characteristics at baseline in the subgroup with shorter duration of prior sorafenib may have had an impact on these outcomes. In terms of safety, treatment-related adverse events of any grade and grade 3 or higher were reported at similar rates. The same was true for liver toxicities although aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations of grade 3 or higher were more frequent among patients with a shorter duration of prior sorafenib. The low numbers of patients in subgroups mean that a cautious interpretation of these data is warranted.
"Nivolumab and ipilimumab led to clinically meaningful benefits and a manageable safety profile in patients previously treated with sorafenib," said Professor Bruno Sangro of the Clinica Universidad de Navarra, Spain. "Altogether, our results indicate that the NIVO1+IPI3 combination is a promising new treatment option for advanced HCC in the second line, independent of the duration of prior sorafenib administration."
"This clinical research will have an important impact on the current landscape of advanced HCC treatment, as it marks an evolution from one single agent to multiple options for these patients," said Professor Maria Reig of the Hospital Clinic of Barcelona, Spain, and EASL Governing Board member. "Physicians have the responsibility and challenge to select the best sequential treatment for each individual patient. In this regard, EASL is committed to supporting patient organizations and physicians in this incredible and complex clinical decision-making challenge, which is conditioned not only by treatment and patient characteristics, but also geographical factors."
About The International Liver Congress™
This annual congress is EASL's flagship event, attracting scientific and medical experts from around the world to learn about the latest in liver research and exchange clinical experience. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is being held entirely digitally due to the global health situation. The Digital International Liver Congress™ 2020 will take place from 27-29 August 2020. For more information on attendance and registration, please visit https://ilc-congress.eu/.
About The European Association for the Study of the Liver (EASL)
Since its foundation in 1966, this not-for-profit organization has grown to over 4,500 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European association with international influence, and with an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.
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Session title: Phase III Oncology
Date and time of session: Friday 28 August 2020, 15:30-15:45
Presenter: Richard Finn
Abstracts: A phase 1b study of lenvatinib plus pembrolizumab in unresectable hepatocellular carcinoma
Session title: Phase III Oncology
Date and time of session: Friday 28 August 2020, 15:45-16:00
Presenter: Michel Ducreux
Abstracts: Atezolizumab + bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma: safety results from the Phase III IMbrave150 study
Session title: Phase III Oncology
Date and time of session: Friday 28 August 2020, 16:00-16:15
Presenter: Bruno Sangro
Abstracts: Nivolumab + ipilimumab combination therapy in patients with advanced hepatocellular carcinoma: subgroup analyses from CheckMate 040
Richard Finn has received consulting or advisory fees from Pfizer, Bayer, Novartis, Bristol Myers Squibb, Merck, Eisai, Lilly, Genentech/Roche, AstraZeneca, Exelixis, and C Stone Pharma. He has received research funding (paid to his institution) from Pfizer, Bayer, Novartis, Eisai, Lilly, Merck, Bristol Myers Squibb, and Roche/Genentech. He has also provided expert testimony for Novartis and Bayer.
Michel Ducreux has received speaker fees from or participated in advisory boards for Roche, Merck Serono, Bayer, Servier, Amgen, Ipsen, Halio DX, Pierre Fabre, MSD, Keocyt, and Lilly. He has also received clinical trial funding from Roche, Merck Serono, Bayer, and Keocyt.
Bruno Sangro has received consulting, advisory role, or honoraria fees from Adaptimmune, Bayer, Bristol Myers Squibb, BTG, H3 Biomedicine, Ipsen, Lilly, Merck, Onxeo, Roche, and Sirtex Medical. His institution has also received grant fees from Bristol Myers Squibb, and Sirtex Medical.
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2. Estes C, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123-33.
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4. Singal AG, et al. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLoS Med. 2014;11(4): e1001624.
5. Finn RS, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894-905.
Journal of Hepatology