Immunotherapy for Liver Cancer: Iterating Amid Challenges and Opportunities
Since immunotherapy has become an important approach in cancer treatment, the application of immune checkpoint inhibitors (ICIs) in the clinical management of advanced hepatocellular carcinoma (HCC) has achieved remarkable results, reshaping the landscape of systemic therapy for HCC. ICI-based combination therapies are progressively being explored, and positive outcomes from clinical trials along with accelerated FDA approvals suggest that immunotherapy combinations may become the mainstream treatment for HCC in the future.
However, careful consideration is essential. During ongoing clinical practice, in-depth discussions on topics such as selection of immunotherapy regimens, biomarker research, and integration with other treatment modalities will provide new perspectives for HCC immunotherapy and combination strategies.
On November 18, NEJM Medical Frontiers, jointly organized by the New England Journal of Medicine (NEJM) and Jiahui Medical Research and Education Group (JMRE), together with NEJM oncology editor Professor Dan L. Longo, collaborated with multiple experts from the Chinese Society of Clinical Oncology (CSCO) to conduct the CSCO-NEJM Medical Frontiers—JMRE Symposium. The event thoroughly reviewed and discussed landmark clinical studies on cancer immunotherapy over the past decade. In this online academic exchange, Professor Andrew X. Zhu (Zhuxiuxuan), Director of Jiahui International Cancer Center and Harvard Medical School faculty, highlighted the opportunities and challenges of immunotherapy in the era of combination therapy for advanced HCC. Here, we summarize Professor Zhu’s academic insights for our readers.
Development of HCC Treatment and Future Challenges
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and ranks among the leading causes of cancer-related deaths. Most patients are diagnosed at advanced stages, and even those eligible for early-stage surgical treatment face high postoperative recurrence and metastasis rates.
The treatment of HCC still faces numerous unresolved issues and challenges. For such an aggressive disease, it is necessary to: Explore more effective systemic therapies; Optimize the sequence of existing drug treatments for better efficacy; Design and promote biomarker-based clinical studies; Develop other ICIs and cell-based therapies (e.g., CAR-T cell therapy) to enhance immunotherapy effectiveness; Consider immunotherapy in adjuvant or earlier neoadjuvant settings based on current outcomes; Integrate existing drug regimens with local HCC treatments, including transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), selective internal radiation therapy (SIRT), and radiotherapy.
Looking back at the development of HCC treatment, sorafenib opened the era of molecular targeted therapy in first-line treatment for advanced HCC, maintaining its dominant position for a decade. The REFLECT study demonstrated that lenvatinib achieved non-inferior outcomes compared with sorafenib and together they now represent the first-line standard for targeted therapy in HCC. With the approval of atezolizumab plus bevacizumab, immunotherapy has entered first-line treatment, enriching the therapeutic options for advanced HCC. Drugs including regorafenib, ramucirumab, cabozantinib, nivolumab, and pembrolizumab have become effective second-line options. HCC treatment has evolved from chemotherapy to targeted therapy, immunotherapy, and now to combination therapy.
Fisogatinib (BLU-554) is a potent, highly selective, irreversible small-molecule inhibitor of FGFR4. Studies by Kim et al. showed that BLU-554 demonstrated good efficacy and tolerability in FGF19 immunohistochemistry-positive (IHC+) advanced HCC patients. The objective response rate (ORR) in FGF19-positive HCC patients reached 17% (11/66), highlighting the oncogenic role of the FGF19-FGFR4 signaling pathway and the predictive value of FGF19 for FGFR4 inhibitors.
The REACH and REACH-2 studies evaluated ramucirumab in HCC patients with disease progression after sorafenib or who could not tolerate its toxicity. REACH did not meet its primary endpoint; however, subgroup analysis of patients with baseline AFP ≥400 ng/mL showed a median overall survival (mOS) of 7.8 months with ramucirumab versus 4.2 months with placebo. REACH-2 enrolled only AFP ≥400 ng/mL patients and confirmed the clinical efficacy of ramucirumab. The FDA has approved ramucirumab as second-line monotherapy for HCC patients with AFP ≥400 ng/mL previously treated with sorafenib—marking the first study to demonstrate the clinical significance of biomarker-guided HCC therapy.
New Opportunities Brought by Immunotherapy
Tumor cells can evade and suppress the host immune system through highly complex mechanisms. HCC, as a typical inflammation-associated malignancy, has a complex immune microenvironment. Immunotherapy enhances immune responses, triggers tumor-specific immunity, breaks immune tolerance, and reactivates immune cells to recognize and kill tumor cells, thereby slowing tumor progression.
The CheckMate 040 and KEYNOTE-224 studies established the role of nivolumab and pembrolizumab monotherapy in second-line HCC treatment, with mOS extended to 15.1 and 12.9 months, respectively.
Optimal strategies and timing for HCC immunotherapy may focus on: Exploring combination regimens to improve ICI efficacy, such as ICI plus anti-VEGF(R) antibodies, ICI plus multi-target tyrosine kinase inhibitors (TKIs), or combinations of different ICIs; Determining the best timing for immunotherapy in HCC, including comparisons between first-line and second-line treatments, adjuvant therapy, and integration with local treatments like ablation or radiotherapy.
The IMbrave 150 study is a milestone in HCC treatment. It showed that atezolizumab (PD-L1 inhibitor) plus bevacizumab (anti-VEGF monoclonal antibody) as first-line therapy for advanced HCC significantly prolonged median OS, reduced the risk of death by 42%, extended median progression-free survival (PFS) by 2.5 months (6.8 vs. 4.3 months), and increased ORR by 15.4% (27.3% vs. 11.9%). Notably, 18 patients achieved complete response, and the combination also improved patient quality of life.
Another phase 1b study evaluated lenvatinib (multi-target TKI) plus pembrolizumab (PD-1 inhibitor) as first-line therapy in unresectable HCC. The study reported mOS of 22.9 months, mPFS of 8.6 months, and ORR of 46% (mRECIST; 36% by RECIST v1.1). Adverse events were predictable and manageable, with grade ≥3 treatment-related events mainly including hypertension, diarrhea, and fatigue, which could be addressed to maintain treatment continuity. A phase 3 trial comparing this combination to lenvatinib monotherapy is ongoing.
Summary
Through well-conducted clinical trials, significant progress has been made in the treatment of advanced HCC. Atezolizumab plus bevacizumab has become the new first-line standard for advanced HCC. Combination therapy has shown preliminary success and is being actively explored in first-line and adjuvant settings, as well as in combination with traditional local treatments. Future directions include exploring other ICIs and cell-based therapies (e.g., CAR-T) to further improve immunotherapy efficacy, and conducting clinical trials based on biomarkers and molecular characteristics to guide HCC therapy.
