Qijiong Li

Introduction: The prognosis for unresectable intrahepatic cholangiocarcinoma (ICC) remains poor. This retrospective study aims to evaluate the efficacy and safety of HAIC combined therapy in advanced ICC. Methods: Between April 2021 and July 2024, patients with advanced ICC treated with either HAIC of oxaliplatin plus systemic chemotherapy of gemcitabine, lenvatinib and PD-(L)1 inhibitors (HSLP) or systemic chemotherapy plus PD-(L)1 inhibitors (SP) were consecutively enrolled. Propensity score matching (PSM) was used to minimize selection bias. Primary endpoint was objective response rate (ORR) and secondary endpoints included overall survival (OS), progression-free survival (PFS) and safety. Results: A total of 110 patients were recruited in this study with 53 in HSLP group and 57 in SP group. Prior to PSM, ORR was significantly higher (47.2% vs. 24.6%; P = 0.023) and both median OS and PFS were prolonged in HSLP group compared to SP group (OS: 15.2 vs. 12.3 months, P = 0.002; PFS: 11.3 vs. 7.3 months, P = 0.004). After 1:1 PSM, outcomes remained superior in the HSLP group, with a significantly higher ORR (43.2% vs. 18.9%; P=0.032) and longer median OS (15.4 vs. 11.8 months; P=0.018) and PFS (11.9 vs. 6.9 months; P=0.019). Multivariate analysis identified the treatment regimen as an independent prognostic factor for OS and PFS. All events were manageable with supportive care, and no additional toxicities were observed in the HSLP group. Conclusion: HAIC plus systemic chemotherapy, lenvatinib and PD-(L)1 inhibitors represents a promising therapeutic regimen for advanced ICC patients, with tolerable toxicity.

Supplementary Table 4. Immune-related adverse events.

Purpose:Immune checkpoint inhibitor (ICI)–related trials in hepatocellular carcinoma (HCC) have strict restrictions on hepatitis B (HBV) DNA load because of HBV reactivation. This study aimed to compare the HBV reactivation between patients with HCC with low or high HBV DNA loads receiving ICIs and antiviral therapy.Patients and Methods:This prospective observational study (NCT04680598) recruited hepatitis B surface antigen–positive patients with HCC who received concurrent antiviral therapy with initial ICI treatment. Participants were divided into HBV DNA–low (≤500 IU/mL) and HBV DNA–high (>500 IU/mL) groups. The primary endpoint was the HBV reactivation rate.Results:Between December 25, 2020, and February 23, 2024, 356 and 659 participants were enrolled in the HBV DNA–low and HBV DNA–high groups. The HBV DNA–high group included significantly higher proportions of patients with hepatitis Be antigen positivity (24.1% vs. 7.0%, P < 0.001), albumin–bilirubin grade 2 to 3 (49.9% vs. 33.7%, P < 0.001), and Barcelona Clinic Liver Cancer stage C (83.3% vs. 72.5%, P < 0.001). The HBV reactivation rate (4.5% vs. 6.1%, relative risk, 1.24; 95% confidence interval, 0.81–1.89; P = 0.29), frequencies of HBV reactivation–associated hepatitis (1.7% vs. 2.3%, P = 0.53), and interruptions in ICI treatment (25.8% vs. 30.5%, P = 0.12) were comparable in the HBV DNA–low group and HBV DNA–high group.Conclusions:There was no significant difference in the risk of HBV reactivation between patients with HCC with HBV DNA ≤500 IU/mL and those with HBV DNA >500 IU/mL when treated with ICIs and concurrent antiviral prophylaxis.

Supplementary Table 8: Representativeness of study participants

Supplementary Figure 2. Survival analysis. Kaplan‒Meier curves of overall survival of patients in HBV DNA-low and HBV DNA-high groups, using (A) 1000 IU/mL and (B) 2000 IU/mL as cutoff, respectively.

Supplementary Table 1. Detailed characteristics of participants with HBV reactivation.

Supplementary Table 6. Tumor response in patients received ICIs monotherapy or combination therapy

Supplementary Table 3. Treatment-related adverse events.

Supplementary file 1: Study protocol.

Supplementary Table 7. Univariate and multivariate analysis of HBV DNA reactivation among two cohorts.