Over the past 5 years, the number of standard treatments for unresectable hepatocellular carcinoma (HCC) has increased with combinations including atezolizumab (Tecentriq) plus bevacizumab (Avastin) as first-line therapy, and regorafenib (Stivarga) , camrelizumab (AiRuiK), or nivolumab (Opdivo), ipilimumab (Yervoy) and ramucirumab (Cyramza) in the second line.
A number of FDA-approved tyrosine kinase inhibitors have also come to the fore, including sorafenib (Nexavar) and lenvatinib (Lenvima). Clinical trial data has shown that these agents demonstrate efficacy and safety, leading to their potential therapeutic use in this patient population.
“We have upcoming agents that include immune checkpoint inhibitors either in combination or separately, and we are waiting to see if the landscape of first-line therapy will expand forever with the addition of these agents,” said Pierre Gholam, MD, in an interview with Targeted OncologyMT.
Several trials and research examining treatment options for HCC patients are ongoing, some of which were presented at the European Society for Medical Oncology (ESMO) Congress 2022.
Three trials showed both expected and surprising data in the HCC space. These trials included the Phase 3 study RATIONALE-301 (NCT03412773) of first-line tislelizumab versus sorafenib, a Phase 3 study (NCT03764293) of the combined use of the PD-1 inhibitor camrelizumab and rivoceranib, and the phase 3 LEAP-002 study (NCT03713593) of lenvatinib and pembrolizumab (Keytruda).
In the interview, Gholam, a professor at Case Western Reserve University School of Medicine in Cleveland, Ohio, discussed several studies currently influencing the HCC treatment landscape.
Targeted oncology: what is the current reference therapy in HCC?
Golam: The reference treatment for unresectable HCC has developed considerably over the last 5 years. On the front line, we have standard treatment options that include the combination of atezolizumab and bevacizumab. We also have FDA cleared multikinase inhibitors including sorafenib and lenvatinib. These agents have demonstrated their efficacy and safety in large clinical trials and can be used to treat patients, depending on their specific clinical characteristics.
In the second line, there are additional options that include regorafenib, camrelizumab, the combination of nivolumab and ipilimumab and ramucirumab in the setting of patients who have AFP [alpha-fetoprotein tumor] greater than 400. These are available options for many patients. Some patients have been successful in obtaining third line for some of these options. Prominently, cabozantinib was used.
What stood out to you this year at ESMO Congress 2022?
Data expected from the LEAP-002 trial, which was a trial of a combination of pembrolizumab and lenvatinib compared to lenvatinib alone in unresectable first-line HCC. There had previously been an announcement that the study had not reached its overall survival endpoint, but the additional details presented provide more clarity on this.
In particular, what they show is that the combination of pembrolizumab and lenvatinib provided a median overall survival of 22.1 months versus 19 months for lenvatinib alone. These results are remarkable, both for the treatment arm and for the comparator arm, by the robustness of the overall survival.. Either way, some of the best or best results of any frontline study.
Other analyzes were reported, including the duration of response which was 16.6 months for the combination and 10.4 months for lenvatinib alone. The objective response rate was 26% for the combo and 17% for lenvatinib alone. The safety profile was also associated with an adverse event profile, which more or less reflected the expected adverse events associated with both immune checkpoint inhibitor therapy and TKI. [tyrosine kinase inhibitors].
This is a very interesting twist in the front line HCC landscape as it accounts for 2 therapies previously studied individually and now in combination which yield quite high median overall survivals in the first line setting.
What do you think of the phase 2 trial evaluating camrelizumab and rivoceranib vs sorafenib in first line for unresectable HCC?
This was a study conducted mainly in China where these 2 agents are compared to sorafenib. In the setting, the combination achieved median overall survival of 22.1 months versus 15.2 months for sorafenib. I think it is remarkable that the baseline patient characteristics included a very strong focus on patients whose liver disease was due to hepatitis B. About 76% of the patients had hepatitis B.
Other than that, the overall characteristics of the patients were quite similar to what one would expect in a first study. The objective response rate for the combination was 25.4 months and for sorafenib alone it was 5.9 months.
What safety results have been concluded with this research?
The adverse events that were reported were quite comparable to what one would expect from a combination of an immune checkpoint inhibitor and a TKI. I think the conclusion from all the data we reported in this study is that this may be a viable combination, certainly in the subset of patients with disease caused by hepatitis B. We’ll see if this combination is following the regulatory process for possible approval in the [United States] and Northern Europe.
Can you tell us about the context of the RATIONALE-301 phase 3 trial?
This third notable study was the comparison of first-line tislelizumab, which is another IgG for the anti-PD-1 monoclonal antibody, to sorafenib. The front-line study aimed to see if this new agent was non-inferior to sorafenib with the possibility of testing the superiority of the data.
What were some of the conclusions of the final analysis of RATIONALE-301?
This study ultimately showed that tislelizumab achieved median overall survival of 15.9 months in the first line versus 14.1 months in the sorafenib arm. Some subset analyzes have suggested that tislelizumab may have differential efficacy in patients older than 65 years, potentially patients with more advanced disease in terms of tumor spread, possibly infected patients by hepatitis C and women. There was also not much difference in terms of the adverse event profile between the 2 arms.
Notably, progression-free survival was oddly longer for sorafenib at 3.6 months than for tislelizumab at 2.2 months, a somewhat peculiar finding that I believe has yet to be explained. Overall, there were fewer discontinuations and changes with tislelizumab than with sorafenib. If we looked at the adverse events leading to death, they were comparable between the 2 arms.
What do these trials mean for the future of the HCC space?
To sum up, we have new information. We are familiar with pembrolizumab and lenvatinib, both in combination and separately. We have upcoming agents that include immune checkpoint inhibitors, either in combination or separately, and we are waiting to see if the frontline therapy landscape will expand forever with the addition of these agents. .
What recommendations might you have for community oncologists who want to learn more about this space?
The resources available to community oncologists today have expanded significantly. Ten years ago, if I had said that Twitter was a valuable resource for researching information and debating, people would have said, ridiculous. But today, I think you can find credible sources of medical information and therapy updates, including HCC therapy, on Twitter.
The Targeted Oncology Platform provides updates so physicians can receive emails or summaries you can use. There are a variety of other resources, including ESMO’s societal resources [European Society of Oncology Annual Congress] and other national societies to which one can connect. There is a lot of real time information that you can get from social media and also in documents that you can get through literature and websites.
What unmet needs still exist in the HCC space?
The unmet need for first-line treatment of unresectable HCC revolves primarily around the sickest patient. A patient who has a higher risk of bleeding, a patient who has more advanced liver disease, infantile Pugh’s cirrhosis or worse. A patient who may have very significant vascular involvement, including portal vein occlusion of the main portal vein. In these patients, options are available, but somewhat limited by the lack of evidence.
In the future, we hope to have more data that would support expanding the use of some of the agents we currently have, or potentially new agents that could be tailored to the needs of these specific patients.