Editor’s note:
Hepatocellular carcinoma (HCC) is a prevalent malignant tumor posing a significant threat to human health with considerable heterogeneity. Specifically, intermediate-stage HCC spans a range from liver function reserve ChHepatology Digest-Pugh A grade (5 points) to B grade (9 points), tumor sizes from 5 cm to >10 cm, and the number of nodules from 4 to >10. There is an urgent need for refined clinical treatments. Significant advancements in systemic treatments have recently improved the survival of advanced-stage HCC patients. Systemic treatments for intermediate-stage HCC have become a major focal point in the field. At the recently concluded 17th International Liver Cancer Association (ILCA) Annual Meeting, Dr. Masatoshi Kudo from Kindai University, Japan, presented an oral report on a clinical study (REPLACEMENT study, Abstract No. O-15) of atezolizumab combined with bevacizumab (referred to as “T+A”) for patients with intermediate-stage HCC unsuitable for TACE treatment. We had the privilege to interview Dr. Kudo for insights into this research and its findings.
Hepatology Digest: The application of systemic treatments for intermediate-stage HCC is still being explored. Could you introduce the background and primary objectives of the REPLACEMENT study you presented at this ILCA meeting?
Dr. Kudo: As many know, based on the IMbrave150 clinical trial results, “T+A” is now a recommended first-line treatment for advanced-stage HCC. In the intermediate-stage HCC patient subgroup analysis of the IMbrave150 trial, “T+A” also showed a promising efficacy trend, with a median PFS (progression-free survival) of 12.6 months and a response rate of 50% (as per mRECIST criteria).
On the other hand, TACE has always been the standard treatment recommended for intermediate-stage HCC. However, given the significant heterogeneity in tumor size, number, and liver function in HCC, many intermediate-stage HCC patients are not suitable for TACE, like those exceeding the “up-to-seven” criteria or with a significant tumor burden. Hence, our REPLACEMENT study aimed to explore the efficacy and safety of “T+A” in such patients.
Hepatology Digest: Based on your research data, how would you evaluate the efficacy and safety of “T+A” in intermediate-stage HCC patients who are unsuitable for TACE?
Dr. Kudo: In this multi-center, phase II study, we included intermediate-stage HCC patients treated from December 2020 to September 2021 with atezo 1200 mg + bev 15 mg/kg q3w, continuing until disease progression, adverse events, or other reasons prompted discontinuation. The inclusion criteria were: no prior systemic or TACE treatment, liver function ChHepatology Digest-Pugh A grade, an ECOG score of 0 or 1, and adequate hematological/organ function. The primary endpoint was mRECIST-based PFS evaluated by researchers. Secondary endpoints included objective response rate (ORR), RECIST 1.1 version PFS assessed by researchers, overall survival rate (OS), and safety.
Results indicated a median PFS of 9.1 months based on mRECIST after an average 2.5 years follow-up. The 12-month OS rate evaluated was 84.6%. ORR stood at 44.6%, with a complete remission (CR) rate of 17.6%, and a very low disease progression (PD) rate of 6.8%. The disease control rate was 19.5%. These promising results suggest that “T+A” treatment can provide a lasting therapeutic response in intermediate-stage HCC patients unsuitable for TACE. In a further subgroup analysis comparing different etiologies (virus-associated HCC vs. non-virus-associated HCC) and tumor numbers (≥11 or ＜11), similar PFS was observed among different groups.
Regarding safety, no new treatment-related adverse events (AE) were observed. The most common AEs (affecting ≥10% of patients) were hypertension (71.6%), proteinuria (50.0%), discomfort (27.0%), anorexia (18.9%), edema (16.2%), pruritus (16.2%), and diarrhea (13.5%). Grade 3 AEs with >5% occurrence were hypertension (17.6%) and proteinuria (9.5%). Hence, these are very promising efficacy results.
Hepatology Digest: Your report also touched upon an exploratory analysis comparing with TACE treatment. What were the outcomes?
Dr. Kudo: Besides assessing the efficacy and safety of “T+A,” we retrospectively collected data from patients treated with TACE from January 2017 to December 2017. A propensity score matching (PSM) analysis was conducted to compare the efficacy of “T+A” and TACE. The analysis indicated that “T+A” had better OS and PFS rates compared to TACE, with hazard ratios (HR) of 0.59 and 0.54, respectively. These findings underscore the promising prospects of the study, revealing the considerable success of “T+A” in patients unsuitable for TACE, with significant survival improvement.
Hepatology Digest: Could you summarize the achievements of this research and its clinical implications for us?
Dr. Kudo: Previous research has indicated that TACE is unsuitable for intermediate-stage HCC patients with high tumor burdens exceeding the “up-to-seven” criteria. Our REPLACEMENT study found that the “T+A” immunotherapy combination offers a high tumor response and good safety profile for these patients, presenting an excellent treatment choice from both efficacy and safety perspectives. We hope this study will pave the way for reconsideration of current treatment options, especially in light of the promising results and the wider applicability of this treatment approach. We anticipate that “T+A” may be established as a standard treatment for intermediate-stage HCC patients unsuitable for TACE in the future.
TAG: ILCA 2023, Interview, HCC, T+A
