Treatment Approaches for Advanced Hepatocellular Carcinoma: Observations From EMSO Congress 2022

During the European Society for Medical Oncology (ESMO) Congress, held in Paris from September 9 to 13, 2022, oncologists gathered virtually and in person to discuss ground-breaking science, including basic and clinical research, integrative genomic analysis, immunogenomics, and novel prognostic biomarkers. This year’s conference included a compelling program focused on hepatocellular carcinoma (HCC).
 
Josep M Llovet, MD, PhD, FAASLD, professor of medicine and director of the Liver Cancer Program at Icahn School of Medicine at Mount Sinai, New York, provided insight into, and key takeaways from, research on HCC presented at the meeting.

There were several sessions and poster presentations on HCC at this year’s meeting. What research has the potential to affect clinical practice?

Results of 3 key trials were reported. The first one of interest is an international, randomized, open-label, phase 3 study comparing patients with unresectable HCC treated with camrelizumab plus rivoceranib vs sorafenib (ClinicalTrials.gov Identifier: NCT03764293).¹ This trial has shown that combination therapy with camrelizumab plus rivoceranib was superior to sorafenib in terms of the primary endpoint of overall survival (OS).
 
I would like to point out, however, that grade 3 and 4 treatment-related adverse events (TEAEs), such as dysfunction, thrombocytopenia, and hand-foot syndrome, occurred in 80% of trial participants. Approval of the camrelizumab plus rivoceranib combination by the US Food and Drug Administration (FDA) would have important clinical implications. It is not clear if the therapy will be approved by the FDA and the European Medicines Agency (EMA) given that more than 80% of enrollees in this trial were recruited in Asia, hence Western populations were not well represented.
 
The second trial of interest was a randomized phase 3 study of the immune checkpoint inhibitor (ICI) tislelizumab vs sorafenib as first-line treatment for unresectable HCC (ClinicalTrials.gov Identifier: NCT03412773).² The study met the primary endpoint; results indicated that tislelizumab provided a clinically meaningful OS benefit that was noninferior to sorafenib. Median survival for patients treated with tislelizumab was 15.9 months compared with 14.1 months for patients treated with sorafenib.
 
Again, it is not clear if the FDA and EMA will approve tislelizumab. I say that because of findings from the recently-completed phase 3 randomized, open-label, multicenter HIMALAYA study (ClinicalTrials.gov Identifier: NCT03298451) of tremelimumab and durvalumab as first-line therapy in patients with unresectable HCC.³ The results demonstrate that durvalumab is not inferior to sorafenib, so tislelizumab is not adding much clinical value in the field.
 
Finally, the global randomized, double-blind, phase 3 LEAP-002 study (ClinicalTrials.gov Identifier: NCT03713593) evaluated the efficacy and safety of lenvatinib plus pembrolizumab vs lenvatinib plus placebo as first-line therapy for advanced HCC.⁴ Notably, this trial showed survival beyond 21 months for patients treated with lenvatinib plus pembrolizumab and 19 months for patients treated with lenvatinib alone. The results did not meet the primary endpoint of OS, so the implications for HCC may be important in terms of the response to lenvatinib monotherapy; this represents a breakthrough for use of a single-agent tyrosine kinase inhibitor (TKI) as front-line therapy for HCC.
 
We need to consider that the first 2 studies used sorafenib as the comparator drug, with a median survival ceiling of approximately 15 months. As a result, this will have clinical impact on the management of patients with HCC getting front-line therapy, particularly those with contraindications for ICIs.

In a multicenter study, De Souza and colleagues determined the indirect impact of COVID-19 health service utilization on HCC outcomes.⁵ Significant delays across all treatments for patients with HCC were observed, especially for patients undergoing curative therapies. Is this still an indirect effect of the pandemic and if so, how could the situation be resolved?

The median delay in implementing therapies at the early stages of HCC was approximately 50 days, but so far this study did not identify any impact on OS. I certainly agree that in cases of advanced HCC, a 50-day delay in implementation of therapy may have important clinical implications. Extensive studies are needed to assess the impact of the COVID-19 pandemic on health service utilization in patients with HCC.

Yuan and colleagues conducted a large, multicenter, real-world study of 582 patients to assess transarterial chemoembolization (TACE)-based systemic therapy in patients with HCC.⁶ Patients received TACE monotherapy, TACE plus TKIs, TACE plus ICIs, or TACE plus TKIs plus ICIs. The investigators observed that the group treated with TACE plus TKIs plus ICIs achieved the longest median progression-free survival (PFS) and OS compared with the other 3 study groups. What are your views on TACE, and does this study provide compelling evidence of its efficacy for treatment of HCC?

This study is an uncontrolled investigation that provides some interesting data, but I do not anticipate it having any impact on the management of patients with HCC. Several phase 3 trials being conducted for regulatory approval are comparing TACE monotherapy vs TACE-based combination therapies with durvalumab plus bevacizumab, atezolizumab plus bevacizumab, and lenvatinib plus pembrolizumab. I expect that these trials will change current clinical practices for HCC because systemic therapies are likely to be used in combination with locoregional therapies in intermediate stage HCC.

Cuproptosis, a newly discovered cell death process triggered by targeted accumulation of copper in mitochondria, was assessed by Wang and colleagues as part of an HCC risk model.⁷ These researchers applied it to develop a prognosis model and drug candidate selection method for HCC. They found that IC₅₀ values of doxorubicin, vinorelbine, and cisplatin were lower for patients in the high-cuproptosis-risk-score group, while chemotherapy drugs such as elesclomol, gefitinib, and imatinib had lower IC₅₀ values when used for patients with low cuproptosis risk scores. The authors suggest that a cuproptosis risk model may facilitate selection of anticancer drugs for patients with HCC. Do you think this work will provide new insight into the prognostication of HCC? Might this research have other applications in healthcare?

In their communication, which includes assessment of 530 patients, the researchers provide evidence of certain correlations in terms of cell subtypes found in the tumor microenvironment and how these link to the potential effectiveness of systemic therapies. The data are preliminary, and the research is very new and far from clinical implementation.

The question of whether programmed death ligand-1 (PD-L1) is a good predictive biomarker for use of anti-PD-1 therapy in esophagogastric cancer was debated in detail during a Controversy Session at ESMO this year. Several abstract presentations^1,2,4 showed encouraging efficacy data from phase 3 trials of first-line treatment with an anti-PD-1 antibody with or without a kinase inhibitor in patients with advanced HCC. Can you share some key learning points from this research and your opinion on the use of PD-L1-related therapies for patients with advanced HCC?

I think these drugs are currently the backbone of any drug combination used as front-line treatment for HCC. At this point, the most recent trials show that frontline therapy with atezolizumab plus bevacizumab⁸ or durvalumab plus tremelimumab³ is superior to sorafenib in the treatment of HCC.
 
It is important to bear in mind that there are substantial differences between the current trials in terms of patient populations. Consider, for instance, IMbrave 150 (ClinicalTrials.gov Identifier: NCT03434379), a global, randomized, open-label, phase 3 study of atezolizumab plus bevacizumab vs sorafenib in patients with unresectable HCC; this trial includes more patients with advanced diseases, including main portal vein invasion up to 14% and aggressive tumors.⁸ According to guidelines, atezolizumab-bevacizumab is considered the mainstay of treatment, whereas durvalumab-tremelimumab is mostly considered for patients with a potential risk of variceal bleeding who have contraindications for bevacizumab.
 
Regarding findings from the LEAP-002 trial,⁴ the combination of lenvatinib-pembrolizumab is the most promising result at this point, with an overall response of 26.1% with modified RECIST [Response Evaluation Criteria in Solid Tumors] and leading to the previously mentioned median survival rate beyond 21 months in the treatment arm. That outcome is unprecedented in this type of trial.

Do you have any final thoughts about ESMO Congress 2022? Are there any other studies for which there should be further follow-up or research?

While there are no other results presented at ESMO 2022 that I believe might change clinical practice for patients with HCC, the ESMO Congress was very successful. I was pleased to learn that there were approximately 2,000 attendees, and it was good to meet many of my colleagues there. The meeting presents an excellent opportunity to share and evaluate data that could shape the future care of patients with HCC.