On April 22, the CLEAP004 study: analysis of progression patterns after first-line immunotherapy for advanced liver cancer, initiated by the CLEAP China Young and Middle-aged Liver Cancer Research Group, was published online in Frontiers in Immunology.
Professor Liu Xiufeng from the Qinhuai Medical District of the Eastern Theater General Hospital and Professor Sun Huichuan from Zhongshan Hospital Affiliated to Fudan University are the corresponding authors of this study, and Professor Yang Zhaoxu from the Qinhuai Medical District of the Eastern Theater General Hospital is the first author of this study. Dr. Pan Yangxun from Sun Yat-sen University Cancer Center is the co-first author.
Introduction to the content of the study
Background:
In recent years, the stratification standards for first-line clinical research have been highly unified. However, the pattern of disease progression after progression of immune checkpoint inhibitors (ICIs)-based systemic therapy in patients with advanced hepatocellular carcinoma (HCC) who are not candidates for surgical intervention is still unclear, which also poses challenges to the judgment of follow-up treatment and prognosis.
Methods:
This is a retrospective study that enrolled inoperable CNLC stage IIIa and CNLC stage IIIb patients admitted to eight centers between January 2017 and October 2022. All patients received at least two cycles of first-line therapy containing immune checkpoint inhibitors. Pattern of disease progression was assessed using RECIST criteria 1.1. According to the characteristics of imaging progression, different progression modes were classified.
The final number of patients enrolled was 129 (Figure 1). A retrospective analysis of the clinical records of cohorts first recruited in ICIs treatment was performed. The patient's hepatocellular carcinoma (HCC) was confirmed using histological confirmation or non-invasive imaging criteria, and clinical data during the treatment period were collected, and all clinical data were collected with the consent of the patient and reported to the clinical research ethics committee of the hospital for approval.
The primary endpoints of the study are post-progression survival (PPS) and overall survival (OS). Subgroup analyses were used to compare the efficacy of different immunotherapy combinations. The efficacy of patients with alpha-fetoprotein (AFP) levels ≥ 400 ng/mL was compared with those with AFP levels < 400 ng/mL.
Figure 1
Table 1
Progression Mode Definition:
Based on the initial stage of the disease and the mode of disease progression, and taking into account the unique national conditions of China, the investigators refined and improved the classification of the progression pattern originally developed by Jordi Bruix in 2019 (16). Specifically, the progression patterns are divided into four distinct groups, as shown in Figure 2.
(1) Post-progression stage IIb (p-IIb) is characterized by an expansion of more than 20% in the size of the target liver lesion and/or the appearance of a new lesion in the liver without any intrahepatic vascular invasion.
(2) Compared with the baseline stage, the liver has new lesions or an increase of more than 20% in the original lesions, and at the same time there are new intrahepatic vascular infiltrates or stable liver lesions, and new intrahepatic vascular infiltrates appear. (Designated as post-progression stage IIIa, p-IIIa).
(3) Extrahepatic lesion progression, intrahepatic lesion remains unchanged, commonly referred to as stage IIIb progression (p-IIIb).
(4) The simultaneous occurrence of two or more of the two progressions described in points (1), (2), and (3) is called extensive progression of intrahepatic and extrahepatic lesions (called post-progression stage IIIc, p-IIIc stage).
Figure 2
A total of 129 patients who met the inclusion criteria were included in the study after being collected and screened from the CLEAP database. These patients were on at least two cycles of immunotherapy (PD-1/PD-L1) with or without a small molecule tyrosine-targeted agent (TKI), or in combination with bevacizumab or becarizumab biosimilars. Disease development pattern was assessed using immune RECIST 1.1 criteria. The most recent initial treatment date recorded in this database is August 2022. The study classifies the pattern of disease progression and continuously monitors all participants in the study until they die.
Statistical analysis:
The time interval was calculated using the Kaplan-Meier technique, followed by a log-rank test for comparison between the groups. To better understand the differences in OS and PPS in patients, the investigators conducted subgroup analyses comparing the administration of immune checkpoint inhibitor (ICI) monotherapy or combination therapy, as well as differences in patients with different AFP levels. Statistical software used includes SPSS 26.0 and Graph Pad Prism 9 as well as Rsoftware version 4.3.3(http://www.r-project.org/). A P-value of <0.05 is considered statistically significant.
Findings:
Figure 3A, B shows PPS and overall survival (OS) for all eligible patients (N = 129). Based on the different modes of progression, the investigators summarized four different modes of disease progression: p-IIb, p-IIIa, p-IIIb, and p-IIIc. These patterns highlight the heterogeneity of HCC in response to immunotherapy and its impact on patient outcomes, particularly post-progression survival (PPS) and overall survival (OS) (Figure 3C,D).
Figure 3
The study identified four different modes of progression: p-IIb, p-IIIa, p-IIIb, and p-IIIc. There were significant differences in PPS and OS in different modes of progression. PPS and OS were the longest in the p-IIb group, with PPS at 12.7 months (95% CI: 9.3-16.1) and OS at 19.6 months (95% CI: 15.6-23.5), followed ;p by PPS at 10.5 months (95% CI: 7.9-13.1) and OS at 19.2 months (95% CI 15.1-23.3) in the p-IIb group, respectively, followed by PPS at 5.7 months (95% CI 15.1-23.3), and second from the bottom in the p-IIIc group: PPS at 5.7 months (95% CI: 4.2-7.2) and OS 11.0 months (95% CI 9.0-12.9) were shortest in the ;p-IIIa group: PPS 3.4 months (95% CI: 2.7-4.1) and OS 8.2 months (95% CI 6.8-9.5).
Further stratified analysis showed no difference in OS (HR=0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR=0.88, 95%CI: 0.57-1.36, P=0.54) with immunotherapy alone or in combination; For patients with AFP levels ≥400 ng/mL, PPS (HR = 0.79, 95% CI: 0.55-1.12, P = 0.15) and OS (HR = 0.86, 95% CI: 0.61-1.24, P = 0.39) also did not show a statistically significant difference. However, a trend towards shorter median time to progression of PPS after immunotherapy was observed in patients with AFP levels above 400ng/mL (8.0 versus 5.0 months)
Conclusion:
In this study of advanced hepatocellular carcinoma in Chinese patients treated with immune checkpoint inhibitors, the investigators identified four different progression patterns (p-IIb, p-IIIa, p-IIIb, and p-IIIc) based on different progression characteristics of imaging, which showed significant differences in PPS and OS, demonstrating the heterogeneity of disease progression and prognosis after immunotherapy failure, and providing a reference for the prognosis of patients. However, this is a small retrospective study analysis that needs to be further validated in large cohorts to develop prognostic models that integrate different modes of progression, which is also necessary to guide subsequent treatment decisions. In addition, the progression of immunotherapy in patients with AFP level ≥400ng/mL also needs to be further observed and confirmed in clinical practice. Taken together, the findings of this paper provide valuable insights into future personalized treatment decisions.
Prof. Xiufeng Liu
Qinhuai Medical Area, General Hospital of the Eastern Theater of Operations
Deputy Director/Chief Physician of the Department of Medical Oncology Doctor of Medicine
Deputy Director of the Office of Clinical Research Institutions of the Eastern Theater General Hospital
Secretary of the Oncology Committee on Capacity Building and Continuing Education of the National Health Commission
Member of the Liver Cancer Quality Control Expert Committee of the National Cancer Center
The 4th National Famous Doctor, Excellent Style
Member of the 4th Council of the Chinese Society of Clinical Oncology (CSCO).
Vice Chairman and Secretary General of CSCO Liver Cancer Expert Committee
Vice Chairman of CSCO Biliary Tract Tumor Expert Committee
Member of the Standing Committee of CSCO Gastrointestinal Stromal Tumor Expert Committee
He is a member of the Standing Committee of the Liver Cancer Committee of the Chinese Anti-Cancer Association
He is a member of the Standing Committee of the Expert Committee of the China Alliance for Precision Treatment of Liver Cancer
He is a member of the Standing Committee of the Digestive Surgery Committee of the Chinese Association of Research Hospitals
Vice Chairman of the Tumor Targeted Therapy Professional Committee of Jiangsu Anti-Cancer Association
Copywriting source: CLEAP
Original: CLEAP
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