The landscape of systemic therapy for hepatocellular carcinoma (HCC) has undergone a major transformation, shifting from single-agent targeted or immunotherapies to dual immune checkpoint inhibitors and immune-targeted combination regimens. The 2025 ASCO Gastrointestinal Cancers Symposium (ASCO GI), held on January 23, 2025, highlighted two pivotal studies—CheckMate 9DW and CARES-310—focusing on dual immunotherapy strategies for previously untreated unresectable hepatocellular carcinoma (uHCC) and the impact of viral infection status on treatment outcomes.

Oncology Frontier is pleased to present a comprehensive summary of these studies and expert insights from Dr. Xiufeng Liu of the General Hospital of Eastern Theater Command.

Dr. Xiufeng Liu：

Both CheckMate 9DW and CARES-310 have already been incorporated into clinical guidelines. CheckMate 9DW aligns with HIMALAYA, while CARES-310 is comparable to LEAP-002. For a long time, optimizing first-line treatment options for unresectable hepatocellular carcinoma (uHCC) has been a challenging yet welcome dilemma in the field. Here, I will attempt to serve as a guide, leading you through ASCO GI 2025 abstracts #520 and #578, exploring the potential of dual immune checkpoint inhibitor (ICI) therapy and immune-targeted therapy.

Few would attempt a direct comparison between the control arms of CheckMate 9DW and CARES-310. In CheckMate 9DW, more than 85% of patients in the control arm received lenvatinib, while in CARES-310, all patients in the control arm received sorafenib. The median overall survival (mOS) in the control arms was 20.6 months vs. 15.2 months, median progression-free survival (mPFS) was 9.2 months vs. 3.7 months, and objective response rate (ORR) was 13% vs. 5.9%. This scenario seems to be replaying the 2017 REFLECT trial, where lenvatinib demonstrated non-inferiority to sorafenib (HR=0.92). However, back in 2017, immune checkpoint inhibitors were not yet approved for HCC, and achieving non-inferiority was a significant challenge. REFLECT reported lenvatinib vs. sorafenib data with an OS of 13.6 months vs. 12.3 months, PFS of 7.4 months vs. 3.7 months, and ORR of 24% vs. 9.2%. Examining the evolution of tyrosine kinase inhibitors (TKIs) in uHCC treatment, it is evident that TKIs have entered a new era, supported by immunotherapy, significantly improving both short-term and long-term outcomes.

Shifting perspectives, one might ask: Would surgeons prefer dual ICI therapy or immune-targeted therapy? The ORR for nivolumab + ipilimumab in CheckMate 9DW is 36% (including 7% complete response), while camrelizumab + apatinib in CARES-310 achieved 25.4% ORR, with mOS approaching two years in both studies. As uHCC treatment advances, the two-year survival benchmark will soon be surpassed, and multidisciplinary teams (MDTs) are eagerly exploring new possibilities, taking advantage of time to create treatment opportunities.

CheckMate 9DW may have answered an intriguing question. Even patients with stable disease (SD) at best overall response (BOR) achieved a median OS of 30 months, while those with complete response (CR) or partial response (PR) had an OS that was not yet reached. Could this suggest a protective effect, akin to “shielding” patients from disease progression? HIMALAYA exhibited a similar trend, raising the question of whether dual ICI therapy has a role in adjuvant treatment. This idea may seem speculative, but it warrants further investigation. On the other hand, although immune-targeted therapy has a slightly lower ORR than dual ICI therapy, its rapid onset of action and early OS separation may appeal more to surgeons, potentially influencing future conversion therapy strategies in China. Drug cost-effectiveness and accessibility will remain critical considerations.

Both CheckMate 9DW and CARES-310 also addressed an important question: Can second-generation immunotherapy strategies overcome the challenges posed by different HCC etiologies? In CheckMate 9DW, the distribution of HBV/HCV/non-viral HCC was 34%/27%/37%, while in CARES-310, it was 76.5%/8.1%/15.4%. Although subgroup OS varied based on etiology, all were significantly prolonged compared to the control groups.

Previously, meta-analyses suggested that non-viral HCC patients may not benefit from immunotherapy, a conclusion supported by Josep M. Llovet, one of the most renowned figures in liver cancer research. His insights, derived from CheckMate 459 and KEYNOTE-240, indicated that single-agent ICIs were ineffective for non-viral HCC. However, the era of ICI monotherapy is coming to an end, with CTLA-4 inhibitors, VEGFR inhibitors, TIGIT inhibitors, and local therapies such as TACE, HAIC, and SBRT emerging as complementary approaches that could reactivate the HCC immune microenvironment through multiple mechanisms. Some even propose the extreme notion that “immune resistance” is a misleading concept, an argument that continues to gain traction.

As these findings evolve, new evidence is reshaping our understanding of HCC immunotherapy, and ongoing research will likely challenge long-standing assumptions. The results of CheckMate 9DW and CARES-310 provide further justification for integrating dual ICI and immune-targeted therapies into first-line treatment strategies, paving the way for future breakthroughs in hepatocellular carcinoma management.

Xiufeng Liu , MD, PhD

Deputy Director, Department of Oncology, Qinhuai Medical District, Eastern Theater Command General Hospital

Chief Physician, Doctor of Medicine

Secretary, National Health Commission’s Committee on Oncology Capacity Building and Continuing Education

Member, National Cancer Center Liver Cancer Quality Control Expert Committee

Vice Chairman and Secretary-General, CSCO Liver Cancer Expert Committee

Vice Chairman, CSCO Biliary Tract Cancer Expert Committee

Standing Member, CSCO Gastrointestinal Stromal Tumor Expert Committee

Standing Member, Chinese Anti-Cancer Association (CACA) Liver Cancer Committee

Standing Member, China Liver Cancer Precision Therapy Alliance Expert Committee

Recipient of the 4th National Famous Doctor Award for Excellence