Authors: Song Chen, Ning Lu, Ming Zhao
Affiliation: Sun Yat-sen University Cancer Center
Editor’s Note:Since the advent of immune checkpoint inhibitors (ICI) for the treatment of malignant tumors, the exploration of their use in hepatocellular carcinoma (HCC) has been relentless. In 2017 and 2018, nivolumab and pembrolizumab were respectively granted accelerated approval by the FDA for second-line treatment of HCC following progression on sorafenib. However, both agents failed to meet primary endpoints in phase III clinical trials (CheckMate-459 for nivolumab and Keynote-240 for pembrolizumab) as first-line and second-line treatments respectively, which prevented them from securing a standalone role in HCC treatment. Conversely, a phase III trial in an Asian population (Keynote-394), which tested pembrolizumab as a second-line treatment compared to a placebo, reported positive results, and pembrolizumab continues to be conditionally used post-sorafenib progression. Subsequent extensive clinical research has continued to explore the role of ICIs across the entire spectrum of HCC treatment, including neoadjuvant and adjuvant therapies around curative resection, first-line therapy combining with TACE for intermediate-stage HCC, and first and second-line treatments for advanced-stage HCC. Professor Ming Zhao from the Sun Yat-sen University Cancer Center provides a comprehensive review of the recent applications of immunotherapy in HCC.
Neoadjuvant and Adjuvant Therapy for Curative Resection
The primary modalities for curative treatment of liver cancer include surgical resection and local ablation. However, the early recurrence rate within two years post-curative treatment exceeds 50%, mainly due to occult micro-metastases undetectable by preoperative imaging. Thus, administering neoadjuvant therapy before surgery or adjuvant therapy postoperatively can effectively kill residual tumor lesions or cells, potentially achieving true “cure.”
In 2023, the results of the IMbrave050 clinical study were published, marking the first phase III clinical study to assess immune combination therapy as adjuvant treatment post-curative surgery for HCC. Compared to active monitoring, the postoperative use of the combination of bevacizumab and atezolizumab (“T+A” scheme) significantly extended disease-free survival and reduced the risk of disease recurrence or death by 28%, with good safety profiles. However, the overall survival (OS) data from this study are still immature and await further reporting. A subsequent phase II clinical study reported that postoperative adjuvant treatment with the single-agent sindilizumab also effectively reduced recurrence rates and improved overall survival. These results indicate that adjuvant treatment based on ICIs can effectively reduce postoperative recurrence rates and further extend patient survival after curative treatment for HCC.
Given the remarkable success of neoadjuvant immunotherapy in other cancers, its application in HCC is also being explored. A phase II clinical study reported the effects of perioperative nivolumab alone or in combination with ipilimumab in 27 patients with resectable liver cancer. The nivolumab monotherapy group and the combination therapy group had adverse events of grade 3-4 in 23% and 43% of patients, respectively, with overall acceptable safety. No patients in either group had surgery delayed due to adverse events, although 7 patients did not undergo surgery due to disease progression or poor compliance. Among those who underwent surgery, 3 out of 9 patients (33%) in the monotherapy group and 3 out of 11 patients (27%) in the combination therapy group achieved major pathological responses (MPR). Additionally, cabozantinib combined with nivolumab and simipirimab as neoadjuvant therapy for liver cancer was also effective in improving pathological response, but phase III clinical studies are needed to further confirm the role of ICIs in preoperative neoadjuvant treatment for HCC.
Neoadjuvant immunotherapy not only effectively enhances the activity of anti-tumor CD8+ T cells, enhancing immune surveillance of micro-metastases or cells, thereby reducing the rate of postoperative recurrence, but also allows for subsequent analysis of biomarkers from the resected tumor tissue, which is a significant advantage.
Intermediate-Stage Liver Cancer Combined with TACE Treatment
Research has found that transarterial chemoembolization (TACE) can induce tumor necrosis and then release antigens into the bloodstream, improving the overall cytokine environment, including the regulation of levels of type I helper T cells and regulatory T cells (Treg), thus enhancing the immunotherapy effect. To further confirm, Pinato et al. in 2021 performed immunological biomarker testing on pathological specimens from
liver cancer patients post-surgery, finding that specimens from the 58 cases that had undergone preoperative TACE showed significantly lower expression of CD4+/FOXP3+ and CD8+/PD-1+ compared to those without preoperative treatment, with both markers associated with improved postoperative recurrence-free survival (RFS). Additionally, subgroup analysis of specimens with residual tumor cells that had undergone TACE preoperatively found that TACE can increase the inflammatory response within the tumor and activate the expression of tumor antigens, thereby increasing the efficacy of combined immunotherapy.
In 2024, the results of the EMERALD-1 study were published, dividing the study into three groups: TACE alone, TACE combined with defalizumab, and TACE combined with defalizumab and bevacizumab for the treatment of intermediate-stage HCC. The study met its primary endpoint. Although the PFS of the TACE combined with defalizumab group did not significantly extend compared to TACE alone (10.0 months vs. 8.2 months, HR=0.94, P=0.638), the PFS of the TACE combined with defalizumab and bevacizumab significantly extended (15.0 months vs. 8.2 months, HR=0.77, P=0.032), confirming the synergistic effect of the triple combination of immunotherapy, TACE, and targeted therapy. Currently, clinical studies of intermediate-stage liver cancer combined with immunotherapy are underway, still in the clinical trial phase, with no results published yet. Other explorations of immunotherapy combined with TACE and targeted therapy for intermediate-stage liver cancer, such as LEAP 012, TALENTACE, and EMERALD-3, are ongoing and await further verification of the triple therapy’s efficacy and safety.
Advanced-Stage Liver Cancer First and Second-Line Treatment
First-Line Treatment
For over a decade, tyrosine kinase inhibitors (TKI) including sorafenib and lenvatinib have been the standard first-line treatment for advanced-stage HCC. In 2019, the success of the IMbrave150 study established the position of ICIs combined with anti-angiogenic drugs as the first-line treatment for advanced HCC, significantly improving tumor response rates and survival outcomes compared to sorafenib. Subsequent studies reported that sindilizumab combined with a bevacizumab analog (“double-hit” scheme) similarly achieved clinical efficacy superior to sorafenib, further confirming the clinical efficacy of ICIs combined with anti-angiogenic drugs in the treatment of advanced HCC.
The LEAP 002 study was the first phase III clinical study of TKI combined with ICI as a first-line treatment for advanced HCC, but it ended in failure, prompting a reevaluation of the clinical efficacy of TKI combined with ICI treatment for advanced HCC. However, the recent CARES-310 study (“double A” scheme) achieved positive results. Compared to sorafenib, the “double A” scheme significantly improved OS (22.1 months vs. 15.2 months, HR=0.62, P<0.0001) and PFS (5.6 months vs. 3.7 months, HR=0.52, P<0.0001), thereby establishing the position of TKI combined with ICI in the first-line treatment of advanced HCC.
The HIMALAYA study established the position of dual immunotherapy as the first-line treatment for advanced HCC. The study compared three different treatment schemes: defalizumab monotherapy, defalizumab combined with ticilimumab, and sorafenib. Results showed that the median OS in the defalizumab combined with ticilimumab group was 16.4 months, compared to 13.8 months for the sorafenib group (HR=0.78, P=0.0035), and 16.6 months for the defalizumab monotherapy group, with the median OS of defalizumab monotherapy not inferior to sorafenib (HR=0.86, non-inferiority margin 1.08).
Additionally, the RATIONALE-301 study found that tislelizumab, compared to sorafenib, achieved the predefined primary study endpoint, with a non-inferior OS. The median OS in the tislelizumab group was 15.9 months, compared to 14.1 months in the sorafenib group (HR=0.85), reducing the risk of death by 15%, and extending the median OS by 1.8 months, indicating a trend of survival benefit. From the study’s survival curves, as treatment duration extended, the OS curves for the tislelizumab group and the sorafenib group gradually separated, showing an increasingly significant difference and a growing trend of survival benefit, highlighting the tail effect of immunotherapy, confirming the effectiveness of single-agent ICI in the treatment of advanced HCC.
Second-Line Treatment
The KEYNOTE-240 study included 413 patients with advanced HCC previously treated with sorafenib, randomly assigned in a 2:1 ratio to receive pembrolizumab or placebo. The median OS in the pembrolizumab group was 13.9 months, better than 10.6 months in the placebo group, but the difference was not statistically significant (HR=0.78, P=0.024). The Keynote-394 study, similar in design to Keynote-240 but involving primarily an Asian population, showed significant improvement in OS for patients receiving pembrolizumab compared to placebo. The CheckMate 040 study assessed the efficacy of CTLA-4 antibody combined with PD-1 antibody as a second-line treatment post-sorafenib, with 148 patients receiving three different dosing regimens of nivolumab combined with ipilimumab. At a median follow-up of 30.7 months, the best ORR was 32%, and the median duration of response was not reached. Based on these results, the FDA accelerated approval of this regimen for second-line treatment of advanced HCC in March 2020.
