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BackgroundProgrammed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune-related adverse events (irAEs) are inevitable in patients with liver cancer. Although the incidence of severe irAEs is low, but can result in fatal consequences. To date, only a few commonly used clinical biomarkers have been reported.AimTo assess commonly used clinical biomarkers associated with the occurrence of irAEs to enable better management of irAEs by clinicians.MethodsWe retrospectively reviewed patients with liver cancer treated with at least one cycle of PD-1 immune checkpoint inhibitors (ICIs) combined with tyrosine kinase inhibitors (TKIs). IrAEs were documented according to the common terminology criteria for adverse events version 5. Clinical and laboratory parameters were also evaluated.ResultsA total of 67 patients were included, 36 with irAEs and 31 without irAEs. A total of 104 adverse events occurred; 83 of these events were grade 1/2 (G1/G2), 21 were grade 3/4 (G3/G4), and one died of G4 hepatitis. Patients with irAEs had higher levels of C-reactive protein (CRP) and interleukin-6 (IL-6) and lower levels of lymphocyte subsets, except natural killer (NK) cell counts, than those without irAEs (P <0.05). Patients who experienced G3/G4 irAEs had higher levels of CRP and IL-6 and lower levels of CD4+ T lymphocytes and B lymphocytes than those who experienced G1/G2 irAEs (P <0.05). Of note, impairments in liver function and routine blood tests were also observed (P <0.05). The results of univariate and multivariate analyses for any grade of irAEs revealed that the combination of sintilimab and lenvatinib (P= 0.004, odds ratio [OR]: 7.414, 95% confidence interval [95% CI]: 1.925–28.560) and CRP ≥8.2 mg/L (P= 0.024, OR: 3.727, CI: 1.185–11.726) were independent risk factors. Univariate and multivariate analyses of the risk factors of G3/G4 irAEs suggested that the combination of sintilimab and lenvatinib was a potential risk factor (P = 0.049, OR: 8.242, CI: 1.006–67.532).ConclusionChanges in patient CRP, IL-6, and lymphocyte subsets were associated with irAE onset and may act as potential biomarkers of irAEs. Impairments in liver function and routine blood tests owing to the occurrence of irAEs may become new concerns for clinicians.

BackgroundThus far, few studies have investigated the safety and efficacy of programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) antibodies in patients with hepatitis B virus (HBV)-related liver cancer.ObjectiveTo investigate the effect of combination therapy with programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) on HBV-related liver cancer.MethodsUntil January 31, 2022, liver cancer patients with hepatitis B surface antigen (HBsAg) or HBV DNA positivity, treated with PD-1 ICIs and TKIs combined with nucleoside analogs (NAs), were retrospectively reviewed. The correlation between the change in HBV DNA and HBsAg levels and tumor response was analyzed using the χ2 test. Cox univariate and multivariate survival analyses and Kaplan–Meier curves were used to identify and compare risk factors and overall survival (OS).ResultsA total of 48 patients were enrolled in the study, with an objective response rate (ORR) of 31.3%, a disease control rate (DCR) of 66.7%; the incidence of adverse events was mostly mild. A significant decrease in HBV DNA and HBsAg levels was observed at 12 and 24 weeks compared with the baseline (p < 0.05). Compared to patients with progressive disease (PD), patients with disease control showed a more significant decrease in HBV DNA and HBsAg levels at 12 and 24 weeks (p < 0.001). Eleven patients showed elevations in HBV DNA level and one of them showed HBV reactivation; however, the reactivation was not associated hepatitis. Moreover, eight patients showed elevation in HBsAg. Elevation in HBV DNA level was associated with poor tumor response (P=0.001, OR=18.643 [95% CI: 3.271–106.253]). Cox survival analysis suggested that HBV DNA increase (P=0.011, HR=4.816, 95% CI: 1.439–16.117) and HBsAg increase (P=0.022, HR=4.161, 95% CI: 1.224–16.144) were independent risk factors associated with survival time. Kaplan–Meier curves suggested that patients who exhibited an increase in HBV DNA (6.87 months vs undefined, log-rank test: p= 0.004) and HBsAg (8.07 months vs undefined, log-rank test: p= 0.004) levels had a shorter median survival time (MST). Patients without increased HBsAg showed better baseline liver function and routine blood tests (p<0.05) than patients with increased HBsAg. An increase in C-reactive protein (CRP) and interleukin-6 (IL-6), and a decrease in T lymphocytes, CD4+ T lymphocytes, and B lymphocytes at 1-week post-treatment associated with HBsAg well-controlled.ConclusionHBV-related liver cancer patients treated with combination therapy showed improved efficacy and safety profiles. Combination therapy has some effect on HBV infection, and a correlation between tumor response and antiviral efficacy was found. Elevation of HBV DNA and HBsAg levels may indicate poorer tumor response and survival time. Better baseline liver function and early immune activation may be associated with decline in HBsAg levels.

e14612 Background: Currently, formal tyrosine kinase inhibitors (TKIs) such as sorafenib or lenvatinib in combination with PD-1/PD-L1 immune checkpoint inhibitor had achieved promising results in patients with hepatocellular carcinoma (HCC). However, a portion of patients experienced drug-resistant tumor progression and/or severe adverse events associated with TKIs during the course of treatment, resulting in unfavorable disease control and poorer overall survival. Therefore, a better medication strategy is urgently needed in aim to improve the prognosis of these patients who experienced discontinuing medication of TKIs. Methods: We reviewed the medical data of 23 HCC patients with disease progression after received sorafenib or lenvatinib combined with PD-1 antibodies from Jan Feb 2020 to Sep 2021 at the Fifth Medical Center of PLA General Hospital in China. These patients had switched to regorafenib PO for 3 weeks on/1 week off combined with primary PD-1 antibodies after experienced tumor progression and/or severe adverse events with respect to sorafenib or Lenvatinib. All patients were followed up regularly. Changes of tumor lesions, survival data and adverse events (AEs) were detailed recorded after switched. All AEs were evaluated according to the CTCAE v5. Results: Initially, 20 (87.0%) patients were treated with lenvatinib and 3 (13.0%) patients were treated with sorafenib before switched to regorafenib. Of all patients, tumor progression caused 15 (65.2%) switching and severe AEs caused 8 (34.8%) switching, and the initial daily dose of regorafenib were 80mg (95.6%) and 40 mg (4.4%), respectively. Before switched to regorafenib, the most common mild AEs were hypertension, hypothyroidism and granulocytopenia, and the most common severe AEs were rash, hepatitis, and lung infections. In contrast, the most common AEs was mild hoarseness after switched to regorafenib. During the follow-up, 12 (52.2%) patients died, 3 (13.0%) patients lost and 8 (34.8%) patients sustained survival. The overall median survival time (MST) was 22.47 months [95% confidence interval (CI): 2.98 months to 41.96 months], the MST after switched to regorafenib was 10.53 months (95% CI: 0.257 months to 20.81 months). Of note, size of tumor lesion decreased in 7 (30.4%) patients and increased in 3 (13.0%) patients, and the other 13 (56.6%) patients could not be evaluated due to incomplete data after switching to regorafenib. Conclusions: For patients who are resistant to other TKIs, switching to regorafenib showed good efficacy and manageable safety. Therefore, this treatment protocol can be considered as a potential treatment for patients without clinical benefits after first or second-line combination therapy.