Editor’s Note:
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Most patients are unable to undergo surgical resection at the time of diagnosis, making systemic therapy an important treatment approach for this group. The combination immunotherapy of Atezolizumab plus Bevacizumab (“T+A”) has become the new first-line standard treatment for unresectable HCC patients due to its significant improvement in overall survival (OS) compared to sorafenib. However, its effectiveness in different populations, including HCC patients with different etiologies, Child-Pugh B grade HCC, and intermediate-stage HCC beyond the up-to-seven criteria, remains unclear. The journal “Hepatology Digest” has reviewed recent studies on this topic for the benefit of readers.
1. “T+A” Therapy is Effective for HCC of Different Etiologies
Previous research suggests that the biological characteristics of HCC may be influenced by various liver disease etiologies such as viral infections, alcohol-related damage, and metabolism, which in turn could affect the efficacy of immune checkpoint inhibitors (ICIs) in HCC. Non-alcoholic fatty liver disease (NAFLD) is particularly thought to exhibit resistance to ICIs.
A recent post-analysis study of the IMbrave150 trial [1] selected 279 patients from the intended treatment population who received “T+A” therapy and had available clinical data. These patients were divided into four groups based on different HCC etiologies: NAFLD (n=47), hepatitis C (HCV, n=70), hepatitis B (HBV, n=108), and alcoholic liver disease (ALD, n=51). The study compared whether there were differences in the efficacy of “T+A” therapy among these groups.
The results showed that based on RECIST 1.1 criteria, the objective response rates (ORR) for the NAFLD, HCV, HBV, and ALD groups were 33.3%, 28.8%, 34.0%, and 23.5%, respectively, with no significant differences between the groups (P=0.64). The median progression-free survival (PFS) for the four groups was 9.5, 8.4, 6.7, and 7.0 months, respectively, also with no significant differences (P=0.97). The median overall survival (OS) for the groups was 19.2, 24.6, 19.1, and 16.9 months, respectively, again with no significant differences (P=0.41), as detailed in Figure 1.
Figure 1. ORR, PFS, and OS in Different Etiology Groups [1]
Further multivariate Cox regression analysis and sensitivity analysis also confirmed that there were no statistically significant differences in PFS and OS between the NAFLD group and other etiology groups. Among the NAFLD cohort, the 38 patients with non-alcoholic liver injury showed no statistically significant differences in ORR, PFS, and OS in multiple comparisons. When using mRECIST or imRECIST criteria, there were still no statistically significant differences in PFS and ORR between different etiology groups. Additionally, when assessing PD-L1 expression levels using Tumor Proportion Score (TPS) or Combined Positive Score (CPS), there were no statistically significant differences among the different etiology groups.
Therefore, this study indicates that the “T+A” therapy is effective for HCC of different etiologies, notably including NAFLD and non-alcoholic steatohepatitis (NASH) patients, showing no significant difference in efficacy compared to other etiology HCC patients.
2. “T+A” Therapy Shows Efficacy in Late-Stage Child-Pugh B HCC
Previous observational studies show that the median OS for untreated Child-Pugh B grade HCC patients is only 2-5 months. The systemic treatment options for Child-Pugh B grade HCC patients are limited, as these patients are often excluded from prospective clinical trials due to impaired liver function. Sorafenib has been the most commonly used drug in previous studies for Child-Pugh B grade HCC patients, but the OS after treatment is only about 2.5-5.2 months.
A recent multicenter, retrospective study [2] explored the efficacy of “T+A” therapy in late-stage Child-Pugh B HCC patients. The study included 36 unresectable Child-Pugh B grade HCC patients and compared them with an independent cohort of Child-Pugh A grade HCC patients (n=133).
Baseline data for the Child-Pugh B group: median age was 61 years, 83.3% were male, and HBV infection was the most common etiology (n=21, 58.3%). The proportions of patients with Child-Pugh scores of B7, B8, and B9 were 66.7% (n=24), 25.0% (n=9), and 8.3% (n=3), respectively. A total of 25 patients (69.4%) had extrahepatic metastases, with the most common sites being the lungs (n=15, 41.7%), followed by lymph nodes (n=10, 27.8%) and bones (n=4, 11.1%). Twenty-one patients (58.3%) had major vascular invasion, and baseline serum alpha-fetoprotein (AFP) levels were above 400 ng/ml in 21 patients (58.3%).
Efficacy comparison results showed that among Child-Pugh B grade patients, 4 (11.1%) achieved partial response (PR), 17 (47.2%) had stable disease (SD), and the ORR and disease control rate (DCR) were 11.1% and 58.3%, respectively. The median follow-up time was 5.2 months (95% CI: 1.9–8.4). The median PFS and OS for Child-Pugh B grade patients were 3.0 months (95% CI: 1.7–4.3) and 7.7 months (95% CI: 4.8–10.6), respectively; the ORR and DCR for the Child-Pugh A grade group were 34.1% and 76.7%, with median PFS and OS of 9.6 months and not yet reached, respectively (Figure 2).
Figure 2. PFS and OS in Child-Pugh A and B Grade Patients [2]
Therefore, this study indicates that the “T+A” therapy has certain efficacy in late-stage Child-Pugh B HCC patients, necessitating further prospective studies to identify subgroups that may benefit.
3. TACE Combined with “T+A” Shows Preliminary Efficacy in Intermediate-Stage HCC Patients Exceeding up-to-seven Criteria
Intermediate-stage HCC patients (BCLC B stage) account for 20%-30% of all HCC cases. These patients have a poor prognosis, especially those exceeding the up-to-seven criteria in intermediate-stage HCC, where treatment remains challenging. In the IMbrave 150 study, the ORR for intermediate-stage HCC patients receiving “T+A” therapy was 44%, but only 17.7% at 6 weeks for those exceeding the up-to-seven criteria.
Transarterial chemoembolization (TACE) combined with immunotherapy can trigger a synergistic anticancer effect. A multicenter, single-arm, retrospective study in China explored the efficacy and safety of TACE combined with “T+A” in intermediate-stage HCC patients exceeding the up-to-seven criteria [3].
The study included 21 intermediate-stage HCC patients who received TACE combined with “T+A” as first-line treatment. The median age was 56 years, with 19 male patients. 20 patients (95.2%) had Child-Pugh A grade liver function, and 19 patients (90.5%) were classified as mALBI grade 1/2a. The median follow-up period was 11.7 months (range: 7.5–15.0 months).
According to RECIST 1.1 criteria, the ORR was 42.9%, and the DCR was 100%; according to mRECIST criteria, the ORR was 61.9%, and the DCR was 100% (Table 1). The PFS and OS had not yet been reached, with a 1-year PFS rate of 76.2% and a 1-year OS rate of 90.5% (Figure 3). The proportion of patients with a durable response rate (DRR) ≥3 months was 57.1%, and DRR ≥6 months was 47.6%. The most common treatment-related adverse event (TRAE) for the combined therapy was fever (71.4%), with the most common grade 3/4 TRAE being hypertension (14.3%).
Table 1. Efficacy of TACE Combined with “T+A” in Intermediate-Stage HCC Patients Exceeding up-to-seven Criteria [3]
Figure 3. PFS and OS After Treatment in Intermediate-Stage HCC Patients Exceeding up-to-seven Criteria [3]
Summary
Based on the groundbreaking progress of the IMbrave 150 study, the “T+A” immunotherapy combination has become the first-line standard treatment for late-stage unresectable HCC. Clinical data in different populations in the real world are increasingly abundant. The three studies mentioned above have confirmed the efficacy of “T+A” therapy in HCC of different etiologies, explored the application of “T+A” therapy in Child-Pugh B grade HCC patients, and provided a basis for the combination of “T+A” with TACE in intermediate-stage HCC patients exceeding up-to-seven criteria. These findings reveal the significant potential of “T+A” therapy in the treatment of HCC. In the future, more research is anticipated to bring better survival benefits to HCC patients.
References:
[1] Espinoza M, Muquith M, Lim M, Zhu H, Singal AG, Hsiehchen D. Disease Etiology and Outcomes After Atezolizumab Plus Bevacizumab in Hepatocellular Carcinoma: Post-Hoc Analysis of IMbrave150. Gastroenterology. 2023 Jul;165(1):286-288.e4. doi: 10.1053/j.gastro.2023.02.042.
[2] Cheon J, Kim H, Kim HS, Kim CG, Kim I, Kang B, Kim C, Jung S, Ha Y, Chon HJ. Atezolizumab plus bevacizumab in patients with Child-Pugh B advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2023 Jan 12;15:17588359221148541.
[3] Wang K, Zhu H, Yu H, Cheng Y, Xiang Y, Cheng Z, Li Y, Li T, Wang D, Zhu Z, Cheng S. Early Experience of TACE Combined with Atezolizumab plus Bevacizumab for Patients with Intermediate-Stage Hepatocellular Carcinoma beyond Up-to-Seven Criteria: A Multicenter, Single-Arm Study. J Oncol. 2023 Apr 15;2023:6353047.
