Research Explores New Treatments and Combinations for Hepatocellular Carcinoma

Pierre Gholam, MD

Over the past 5 years, the number of standard-of-care therapies for unresectable hepatocellular carcinoma (HCC) has increased with combinations including, atezolizumab (Tecentriq) plus bevacizumab (Avastin) in the first-line setting, 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 forefront, including sorafenib (Nexavar), and lenvatinib (Lenvima). Data from clinical trials have shown these agents to demonstrate efficacy and safety, resulting in their potential treatment use in this patient population.

“We have agents coming down the pipeline, which include the immune checkpoint inhibitors, either in combination or separately, and we await to see whether the landscape of first-line therapy will expand forever with the addition of these agents,” said Pierre Gholam, MD, in an interview with Targeted Oncology^TM.

Multiple trials and research examining treatment options for patients with HCC are ongoing with some presented at the European Society for Medical Oncology (ESMO) Congress 2022.

Three trials have shown both expected and surprising data in the HCC space. These trials included the phase 3 RATIONALE-301 (NCT03412773) study of frontline tislelizumab vs sorafenib, a phase 3 study (NCT03764293) of the combination 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, professor at Case Western Reserve University School of Medicine in Cleveland, Ohio, discussed multiple studies currently influencing the HCC treatment landscape.

Targeted Oncology: What is the current standard-of-care therapy in HCC?

Gholam: The standard-of-care therapy for unresectable HCC has expanded considerably over the past 5 years. In the first-line, we have standard of care options which include the combination of atezolizumab and bevacizumab. We also have FDA approved multikinase inhibitors, which include sorafenib, and lenvatinib. These agents have demonstrated efficacy and safety in large clinical trials and can be used to treat patients, depending on their specific clinical characteristics.

In second-line, there are additional options which include regorafenib, camrelizumab, the combination of nivolumab and ipilimumab and ramucirumab in the setting of patients who have an AFP [alpha-fetoprotein tumor] greater than 400. These are available options for many patients. Some patients have managed to get the third-line for some of these options. Prominently, cabozantinib has been used.

What stood out to you this year at the ESMO 2022 Congress?

The anticipated data from the LEAP-002 trial, which was a trial of a combination of pembrolizumab and lenvatinib compared with lenvatinib alone in the setting of unresectable HCC in the first-line. There had previously been an announcement that the study did not meet its overall survival end point, but the additional details presented provide some more clarity regarding this.

In particular, what they show is that the combination of pembrolizumab and lenvatinib offered a 22.1-month median overall survival vs 19 months for lenvatinib alone. These results are notable, for both the treatment arm and the comparator arm, for the robustness of overall survival. In both cases, some of the best or better results from any first line study.

There were some other analyses which were reported including duration of response which was 16.6 months from the combination and 10.4 month for lenvatinib alone. Objective response rate was 26% for the combo and 17% for lenvatinib alone. The safety profile was also coupled with an adverse event background profile, which more or less reflected the expected adverse events associated with both immune checkpoint inhibitor therapy and the TKI [tyrosine kinase inhibitors].

That is a very interesting twist on the landscape of HCC in the first-line because it reports on 2 therapies previously studied individually and now in combination which yield median overall survivals that were quite high in the setting of first-line.

What are your thoughts on the phase 2 trial evaluating camrelizumab and rivoceranib vs sorafenib in the first-line for unresectable HCC?

This was a study primarily from China where these 2 agents are compared to sorafenib. In the setting, the combination achieved the median overall survival of 22.1 months vs 15.2 months for sorafenib. I think it's notable that the baseline characteristics of the patients included a very strong emphasis on patients whose liver disease was driven by hepatitis B. About roughly 76% of the patients had hepatitis B.

Aside from that, the overall characteristics of the patients were fairly similar to what one would expect in a first-time study. The objective response rate for the combination was 25.4 months and for sorafenib alone, it was 5.9 months.

What safety findings were concluded with this research?

The adverse events that were reported were fairly on par with what one would expect in the setting of a combination of an immune checkpoint inhibitor and TKI. I think that the conclusion from all the data that we reported in this study is that this may be a viable combination, certainly in the subset of patients with hepatitis B driven disease. We'll see whether this combination takes its way through the regulatory process towards potential approval in the [United States] and Northern Europe.

Can you discuss the background of the phase 3 RATIONALE-301 trial?

This third study of note was the comparison of frontline tislelizumab, which is another IgG for anti-PD-1 monoclonal antibody, to sorafenib. The first-line study aimed to see whether this new agent was non-inferior to sorafenib with the possibility of testing for superiority of the data.

What were some of the findings from the final analysis of RATIONALE-301?

This study ultimately showed that tislelizumab achieved the 15.9-month median overall survival in the first-line compared with 14.1 months in the sorafenib arm. There were some subset analyses which suggested that tislelizumab may have some differential efficacy in patients older than 65 years, potentially patients with more advanced disease in terms of tumor spread, perhaps patients with hepatitis C infection, and female patients. There was otherwise not a lot of difference in terms of adverse event profile between the 2 arms.

Notably, the progression-free survival was oddly longer for sorafenib at 3.6 months than for a tislelizumab at 2.2 months, a somewhat peculiar finding that I think has yet to be explained. Overall, there were fewer discontinuations and those modifications with tislelizumab as compared to sorafenib. If one looked at 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 agents coming down the pipeline, which include the immune checkpoint inhibitors, either in combination or separately, and we await to see whether the landscape of first-line therapy will expand forever with the addition of these agents.

What recommendations may you have for community oncologists who want to learn more about this space?

The resources available to the community oncologists today have expanded considerably. Ten years ago, if I said that Twitter was a valuable resource to look up information and debate, people would have said, ridiculous. But today, I think you can find credible sources of medical information and updates on therapies including HCC therapy on Twitter.

The Targeted Oncology platform provides updates so physicians can receive emails or summaries that you can use. There's a variety of other resources, including the societal resources from ESMO [European Society of Oncology Annual Congress] and other national societies that one can tune into. There is plenty of real time information you can get from social media and also more in documents you can get through literature and websites.

What unmet needs still exist in the HCC space?

The unmet needs for the first-line therapy of unresectable HCC primarily revolves around the sicker patient. A patient who has a higher risk for bleeding, a patient who has more advanced liver disease, child Pugh cirrhosis, or worse. A patient who may have very significant vascular involvement, including occlusion of the portal vein of the main portal vein. In those patients, options are available, but somewhat restricted 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 might be tailored to the needs of those specific patients.