Portal vein tumor thrombus (PVTT) is a frequent complication in hepatocellular carcinoma (HCC). HCC patients with PVTT have the characteristics of less treatment tolerance and poor prognosis. Immunotherapy, especially combined immunotherapy, has been successfully used in advanced HCC. However, there are no recognized universally indicators that can predict response or resistance to immunotherapy for HCC. Herein, we reported a 58-year-old HCC patient with PVTT, cirrhosis and chronic viral hepatitis, who achieved complete response (CR) after combined immunotherapy (camrelizumab combined with sorafenib or regorafenib), according to his high enrichment of tumor-infiltrating immune cells and tertiary lymphoid structure (TLS). In this case, we revealed the characteristics of the baseline tumor immune microenvironment (TIME) in a HCC patient who responded well to combined immunotherapy, suggesting that TIME can be used to assist in clinical decision making of immunotherapy for HCC.

Background: Postoperative minimal residual diseases (MRD) are one of the main causes of postoperative short-term recurrence, which were difficult to be detected by conventional imaging examinations. Circulating tumor DNA (ctDNA) provides a novel approach for detecting the existence of MRD and predicting clinical outcomes of hepatocellular carcinoma (HCC). Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. Herein, we evaluated a plasma-only ctDNA assay integrating genomic signatures to enable tumor-uninformed MRD detection. Methods: 20 patients with hepatocellular carcinoma who underwent radical surgical resection were involved from July 2019 to October 2020. Blood samples were collected for next generation sequencing (NGS) within 7 days after surgery, and 10 of them had preoperatively matched plasma ctDNA results. NGS (381 genes panel) was performed on plasma samples to capture tumor somatic single-nucleotide variants (SNVs) and copy number variants (CNVs). Clinical information was obtained to evaluate the prognostic performance of ctDNA comparing with traditional clinical biomarkers. Plasma and peripheral blood cell samples were sequenced to a mean depth of 7396 and ctDNA results correlated with recurrence-free survival (RFS). Results: Characteristics of the 20 HCC patients were as follows: 85% age≥50 years, 70% HBV positive, 75% largest tumor diameter≥5cm, 55% liver cirrhosis, 85% AFP > 400ng/ml, 60% MVI, 55% PVTT, 50% BCLC C, 70% CNLC III. After a median follow-up of 13.60 months, 10 recurrence events were recorded. In order to evaluate the presence of MRD after radical surgery, at least one low frequency SNV detected was considered ctDNA-positive. Using stringent quality criteria 8/20 (20%) were ctDNA positive after resection. The median RFS for ctDNA-positive patients was 6.98 months versus 27.57 months for ctDNA-negative patients (HR 3.727, 95% CI 0.9461-14.65; p=0.0247). Combining postoperative ctDNA SNV and preoperatively ctDNA CNV features could increase the sensitivity for predicting prognosis. To further confirm the effect of MRD on the RFS of HCC patients, multiple Cox regression was used to assess the effect of multiple factors, including MRD, alpha-fetoprotein (AFP), HBV, Liver cirrhosis, macrovascular invasion, PVTT, Child-Pugh score and CNLC stage, on the RFS. The forest plot results showed that the postoperative ctDNA was an independent factor for predicting the RFS of patients with HCC (MRD: HR=14.02, p=0.018). Conclusion: These preliminary results suggest that ultra-deep sequencing of ctDNA analyses can detect somatic mutations to reflect postoperative MRD state and predict recurrence of HCC. Plasma-only MRD detection may be an effective and convenient approach for clinical prediction of HCC postoperative recurrence risk. Citation Format: Mingxin Pan, Jianpeng Cai, Yuyan Xu, Kaihang Zhong, Tingting Chen. Postoperative minimal residual disease to predict the risk of hepatocellular carcinoma (HCC) recurrence using plasma-only circulating tumor DNA assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5118.

e16135 Background: Given its clear efficacy and high safety demonstrated in the phase 3 ZGDH3 study, donafenib has been recommended by the Chinese guidelines for the first-line treatment of unresectable hepatocellular carcinoma (uHCC). Recently, combination therapies have shown favorable results. However, triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy has not yet been investigated. Thus, we aimed to investigate the efficacy and safety of triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy in patients with uHCC. Methods: A single-center, retrospective study was performed based on the medical records of consecutive patients diagnosed with HCC who were not suitable for curative surgery or local ablation at Zhujiang Hospital of Southern Medical University from June 2021 to October 2022. Patients with ≥18 years, Child-Pugh score ≤7, ECOG PS ≤1, no prior systemic therapy, having at least one measurable lesion (per mRECIST) were enrolled. Patients were treated with donafenib 200 mg orally twice daily, anti-PD-1 antibodies intravenously every three weeks, and transarterial therapy until disease progression or unacceptable toxicity. Endpoints include objective response rate (ORR, the proportion of patients with partial or complete response according to mRECIST and RECIST v1.1), surgical conversion rate (the proportion of patients who successfully underwent resection), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: A total of 27 patients were enrolled (median age 52 years [range, 29–74], 81% males, 85% with HBV infection, 41% with cirrhosis, 48% with AFP level ≥400 ng/mL, and 67% in BCLC C). All patients received donafenib and anti-PD-1 antibodies with hepatic arterial infusion chemotherapy (HAIC, n = 10), transarterial chemoembolization (TACE, n = 8), or both (n = 9). By the cutoff date of January 6, 2023, the median follow-up duration was 6.8 months (95% confidence interval [CI], 5.9–7.7), and 17 (63.0%) patients were still undergoing treatment. The ORR and DCR were 59.3% and 92.6% by mRECIST, and 18.5% and 88.9% by RECIST v1.1, respectively. The surgical conversion rate was 22.2%, and the median surgical conversion time was 3.4 months (range, 2.2–4.6). The median PFS was 8.3 months (95% CI, 6.8–9.8), and median OS was not reached. The 6-month PFS rate and 12-month OS rate were 74.7% and 72.9%, respectively. Grade 3 treatment-related adverse events (TRAEs) were observed in 5 patients (18.5%), the most common of which was increased total bilirubin (11.1%). No grade 4/5 TRAEs occurred. Conclusions: Donafenib combined with anti-PD-1 antibodies plus transarterial therapy shows promising efficacy and manageable toxicity in patients with initially uHCC. Clinical trial information: NCT05638438 .