Editor's Note: The release of studies like HIMALAYA has marked the beginning of the dual immunotherapy era in advanced liver cancer treatment. As the majority of Chinese liver cancer patients are diagnosed at an advanced stage, finding the optimal systemic therapy, including durvalumab, in combination with local therapies to further improve patient outcomes has become a research focus. At the 2024 European Society for Medical Oncology (ESMO) Annual Meeting, held from September 13 to 17 in Barcelona, Spain, Dr. Rongping Guo's team from Sun Yat-sen University Cancer Center presented the results of their HILL study (982P) in a poster session. The study demonstrated that the combination of durvalumab, lenvatinib, and hepatic arterial infusion chemotherapy (HAIC) achieved a 2-year overall survival (OS) rate of 94%, with manageable side effects, contributing valuable insights from China for the treatment of advanced liver cancer. Oncology Frontier invited Dr. Rongping Guo for an in-depth interview to discuss the study.

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Oncology Frontier: The 2024 ESMO conference is in full swing, and congratulations to your team on the success of the HILL study being selected for a poster presentation. Could you share the design of this study and the rationale behind it?

Dr. Rongping Guo: It’s an honor to participate in this prestigious annual oncology event here in Barcelona. Each year, ESMO presents significant research advances, some of which shape clinical guidelines in oncology. In the field of liver cancer, this year’s HIMALAYA study revealed long-term survival data, showing a 4-year survival rate of 25% and a 5-year survival rate approaching 20%, offering new hope for patients.

For Chinese liver cancer patients, most are diagnosed at an advanced stage. In clinical practice, we observe that about 75% of patients are in the middle or late stages when diagnosed. Unlike Western approaches, Chinese doctors place greater emphasis on local treatments, as local control is critical for liver function recovery and the ability to undergo further treatments.

Traditionally, transarterial chemoembolization (TACE) has been the mainstay of local treatment for liver cancer. However, in recent years, we have been exploring the role of hepatic arterial infusion chemotherapy (HAIC) in local treatment, as studies suggest that liver cancer remains sensitive to chemotherapy. Systemic treatments may not achieve optimal concentrations of oxaliplatin, and we also considered liver function and the toxicity of the drugs. Through HAIC, chemotherapy can be delivered directly into the tumor’s blood supply via femoral artery catheterization using the FOLFOX regimen. Recent exploratory studies have shown that HAIC offers superior efficacy over traditional TACE, especially in patients with high tumor burdens or vascular invasion.

For most advanced liver cancer patients, first-line treatment strategies typically include targeted therapies like sorafenib and lenvatinib, as well as immunotherapies, which have increasingly played a key role over the past five years. Given the prevalence of advanced liver cancer in clinical practice, we explored the combination of local treatments with HAIC, PD-1 antibodies, and lenvatinib with PD-1 antibodies to further improve patient outcomes.

With the advent of the PD-L1 antibody durvalumab, we hoped it could play a larger role in combination therapies for liver cancer. Studies have shown that PD-L1 antibodies have lower toxicity compared to PD-1 antibodies, making them a safer option. This sparked the initial design of the HILL clinical trial. Our retrospective data showed that combining durvalumab with local treatments led to improved OS and tumor control rates compared to PD-1 antibodies, giving us the confidence to move forward with the HILL study.

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Oncology Frontier: Could you share the efficacy and safety of the combination of durvalumab and the FOLFOX regimen in the HILL study?

Dr. Rongping Guo: Our retrospective study indicated that the combination of durvalumab with local treatments was safe. The results of the HILL study further confirmed these findings. In the HILL study, 40 patients were enrolled to explore the efficacy of durvalumab combined with lenvatinib and HAIC. The results showed that although the median OS had not yet been reached after nearly 3 years of follow-up, over 90% of the patients were still alive at the 2-year mark, with minimal clinical side effects.

Adverse events (AEs) were reported in 85% of the 40 patients, though most were grade 0-2, with only two patients experiencing grade 3 AEs. These were managed by clinicians, allowing the patients to continue treatment. The most common AEs were liver function abnormalities and thrombocytopenia.

The study also demonstrated good tumor shrinkage rates. The objective response rate (ORR) was 75%, with 9 patients achieving radiological or pathological complete response (CR). Of the 40 patients, 38 had portal vein invasion or extrahepatic metastasis, with only 2 patients in the intermediate stage of liver cancer and high tumor burden. These results suggest that the combination of durvalumab, lenvatinib, and HAIC is highly effective. Furthermore, 7 patients were able to undergo surgical resection following treatment, with 3 of them achieving pathologic CR.

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Oncology Frontier: How do you think the HILL study will impact future clinical practice for liver cancer?

Dr. Rongping Guo: For patients with advanced liver cancer, we are still analyzing the optimal treatment model. Currently, the main strategy involves combining local treatments with systemic therapies. However, it remains to be determined whether TACE or HAIC should be performed first, or if another local control method would yield better results.

There are now several systemic therapy options based on immunotherapy, such as TKI combined with PD-1 antibodies, anti-angiogenic drugs combined with PD-1 or PD-L1 antibodies, and dual immunotherapy combinations. Studies have shown that when systemic treatments are combined, PD-L1 antibodies like durvalumab offer a higher safety profile while maintaining good tumor control efficacy.

In the future, we plan to conduct more large-scale clinical studies to further investigate these findings. Our exploratory analysis in the HILL study found that HAIC can alter the immune microenvironment, including increased PD-1 expression and greater immune cell infiltration. Moving forward, more research is needed to determine whether immunotherapies should include PD-1 antibodies, PD-L1 antibodies, dual immunotherapies, or CTLA-4 antibodies. The HILL study is only the beginning; future studies on durvalumab and other immunotherapy drugs will help us better understand these mechanisms.

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Oncology Frontier: This study provides a new treatment option for liver cancer patients. What do you think are the hot research topics in systemic treatment for liver cancer in the future, and what studies is your team conducting or planning to improve patient outcomes?

Dr. Rongping Guo: In recent years, numerous studies have focused on systemic treatment for liver cancer, particularly on long-term survival. For example, the O+Y regimen (nivolumab combined with ipilimumab) was presented at the ASCO conference, while the STRIDE regimen (durvalumab combined with tremelimumab) was shared at the ESMO conference, offering valuable insights into long-term survival.

Assessing the impact and benefits of immunotherapy on long-term survival will likely be a critical area of future research. Given the growing clinical use of immunotherapies and dual immune combinations, there is room for further exploration, such as investigating durvalumab in front-line treatment or in perioperative and neoadjuvant settings. For Chinese patients, many of whom have cirrhosis and high tumor burdens, there is potential to explore combining durvalumab with dual immunotherapy regimens and local treatments.

To date, TKIs remain vital in liver cancer treatment and are widely used. Could we combine TKIs with durvalumab, tremelimumab, and local treatments in a four-pronged approach? How can we balance AEs while achieving optimal outcomes? These are questions that warrant further exploration in future studies.

Dr. Rongping Guo

Chief Physician and Doctoral Supervisor

Deputy Director of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center

Principal Investigator of Liver Cancer Comprehensive Treatment Clinical Trials

Standing Member of the Chinese Anti-Cancer Association’s Liver Cancer Committee

Former Chairman of the Guangdong Liver Cancer Committee

Vice Chairman of the Guangdong Medical Association Hepatobiliary Surgery Branch

Board Member of the Southern Tumor Clinical Research Association (CSWOG)

Honorary Titles: “Lingnan Famous Doctor,” “Guangzhou Good Doctor”