Editor’s Note:
At the recently concluded international annual flagship event in the field of hepatology – the American Association for the Study of Liver Diseases Annual Meeting (AASLD 2023), Professor Mark Yarchoan from the Johns Hopkins University School of Medicine was invited to speak on “The Role of Systemic Therapy from Early to Advanced Stages of HCC”. In his talk, he presented recent advances in neoadjuvant and adjuvant therapies for hepatocellular carcinoma (HCC). Following the conference, Professor Yarchoan further discussed, in an exclusive interview with “Hepatology Digest”, various aspects of HCC treatment, including the combination of local and systemic therapies, personalized treatment approaches, precision medicine strategies, and the application and prospects of innovative therapies in the management of intermediate and advanced HCC. The video of the interview and the transcript in both English and Chinese are shared below.
Systemic Combination Therapies Bring Survival Breakthroughs, but Overall Response Rates Need Improvement
“Hepatology Digest”: What are the current treatment strategies for intermediate and advanced HCC and their efficacy? What challenges and limitations do they face?
Professor Mark Yarchoan: In the past few years, several new treatment methods have shown improved outcomes for patients with intermediate and advanced HCC. These therapies include the combination of bevacizumab and PD-L1 therapy (Atezolizumab), tyrosine kinase inhibitors (Apatinib) combined with PD-1 therapy (Camrelizumab), and the concurrent use of dual checkpoint inhibitors (Durvalumab + Tremelimumab).
I believe that these new therapies, compared to the old standard of sorafenib treatment, have improved patient survival. Clinical trials in phase III show that both overall survival (OS) and progression-free survival (PFS) have been extended for patients.
Although these combined therapies have indeed brought breakthroughs in the treatment of HCC, the response rates to these treatments are still only about 20% to 30%, with only 10% of patients achieving long-term survival. Therefore, even though we have made significant progress, doubling survival rates, there is still much work to be done in the future.
Combination of Local and Systemic Therapy: A Potential New Standard for Intermediate-Stage HCC
“Hepatology Digest”: How does the combination of local and systemic therapy improve prognosis and survival rates in the treatment of intermediate-stage HCC? What is the synergy between them?
Professor Mark Yarchoan: I believe that intermediate-stage HCC is a highly heterogeneous tumor. Some tumors should be treated with local therapies, some with systemic therapies, and others may benefit from a combination of both. Generally, the more tumors there are, the more there is a need for systemic treatment, possibly requiring a combination of multiple criteria to assess disease burden and decide on the use of systemic therapy.
A recent report showed that adding bevacizumab and durvalumab to local therapy could prolong PFS in patients with intermediate-stage HCC. This could represent a new treatment standard, but more data are needed to confirm this. Overall, I think we are moving towards a model that combines local and systemic therapies. Additionally, recent studies suggest that even in advanced liver cancer, local treatment could be considered. So, I think this is an evolving field.
In terms of synergy, there is a view that local therapy can induce immunogenic cell death, making the tumor more detectable by the immune system, similar to what is seen with SARS-CoV-2 vaccines. I am not sure if this is truly effective, but clinically there appears to be a synergistic effect. Local therapy can reduce the disease burden in the most urgent areas, while systemic therapy works throughout the body. So, I think this is an evolving paradigm.
Genetic Sequencing and New Technologies: Ushering in an Era of Personalized, Precision Medicine
“Hepatology Digest”: What role do personalized treatment strategies and precision medicine play in the current and future treatment of intermediate and advanced HCC? How can individualized treatment plans be devised based on patients’ genetic characteristics and the tumor microenvironment?
Professor Mark Yarchoan: Currently, our approach to treating liver cancer is somewhat ‘one-size-fits-all’. The choice of systemic therapy is often made to avoid side effects rather than for other reasons, such as patients with a risk of bleeding tending to avoid bevacizumab.
Clearly, many of us are awaiting a new era where we can tailor treatments based on biomarkers in the tumor microenvironment. However, the application of these biomarkers is still not mature. Today, biomarkers like PD-L1 expression levels and the extent of tumor mutations are not very helpful in choosing systemic therapy.
I do believe that in the future, there will be therapies targeted at specific genomic subgroups of HCC, such as KRAS inhibitors, IDH-1 inhibitors. We occasionally find these genotypes in HCC. Most excitingly, therapies based on Wnt/β-catenin inhibitors are on the horizon. So, the era of rational treatment based on genetic information obtained from tumor sequencing may not be too far off.
Systemic Therapy: A Potential Key to Curing HCC
“Hepatology Digest”: What are the significant breakthroughs and advancements in innovative therapies for intermediate and advanced HCC in recent years? How do these innovative therapies change the current treatment landscape?
Professor Mark Yarchoan: I think a clear trend is the increasingly earlier use of systemic therapy. The progression of the disease from early to intermediate and then to advanced stages previously relegated systemic therapy as a palliative approach for late-stage disease. However, in the past few years, we have more and more data showing that systemic therapies, including adjuvant and even neoadjuvant chemotherapy, can be effective in the intermediate stages of the disease. For example, preoperative systemic therapy can alleviate the patient’s condition and eliminate micrometastases. Therefore, I would say that this represents a breakthrough for systemic therapies, not just for treating patients in the advanced stages, but also with the potential to achieve a curative goal.
