Molecular biomarkers of sintilimab plus lenvatinib in hepatitis-B-virus-associated hepatocellular carcinoma

Sorafenib is the only standard treatment for unresectable hepatocellular carcinoma (HCC), but it provides modest survival benefits over placebo, necessitating predictive biomarkers of the response to sorafenib. Serum samples were obtained from 115 consecutive patients with HCC before sorafenib treatment and analyzed by multiple reaction monitoring-mass spectrometry (MRM-MS) and ELISA to quantify candidate biomarkers. We verified a triple-marker panel to be predictive of the response to sorafenib by MRM-MS, comprising CD5 antigen-like (CD5L), immunoglobulin J (IGJ), and galectin-3-binding protein (LGALS3BP), in HCC patients. This panel was a significant predictor (AUROC > 0.950) of the response to sorafenib treatment, having the best cut-off value (0.4) by multivariate analysis. In the training set, patients who exceeded this cut-off value had significantly better overall survival (median, 21.4 months) than those with lower values (median, 8.6 months; p = 0.001). Further, a value that was lower than this cutoff was an independent predictor of poor overall survival [hazard ratio (HR), 2.728; 95% confidence interval (CI), 1.312-5.672; p = 0.007] and remained an independent predictive factor of rapid progression (HR, 2.631; 95% CI, 1.448-4.780; p = 0.002). When applied to the independent validation set, levels of the cut-off value for triple-marker panel maintained their prognostic value for poor clinical outcomes. On the contrast, the triple-marker panel was not a prognostic factor for patients who were treated with transarterial chemoembolization (TACE). The discriminatory signature of a triple-marker panel provides new insights into targeted proteomic biomarkers for individualized sorafenib therapy.

Transarterial Radioembolization for Hepatocellular Carcinoma: Who, When… and Y(90)?

Progression-free survival: Starting point or endpoint in advanced HCC trial design?

This meta-analysis was performed to compare the efficacy and safety of a triple therapy, involving transcatheter arterial chemoembolization (TACE) + apatinib combined with a programmed-cell death protein-1 (PD-1) inhibitor versus TACE + apatinib, a dual therapy with apatinib and PD-1 inhibitor, and TACE alone for the treatment of advanced primary hepatocellular carcinoma (HCC). A computerized systematic search of databases, such as PubMed, Embase, the Cochrane Library, CNKI, Wanfang Data, and VIP e-Journals was performed to retrieve studies comparing TACE + apatinib combined with a PD-1 inhibitor versus a non-triple therapy for the treatment of advanced primary HCC. The literature search, quality assessment, and data extraction were performed independently by two researchers. Stata 16.0 software was employed to analyze the data. Heterogeneity was assessed utilizing the I2 statistic and p-value, followed by conducting sensitivity analysis. A total of 2,352 patients were enrolled from 8 studies, including 900 patients in the triple therapy group of TACE + apatinib combined with a PD-1 inhibitor, 877 patients in the TACE + apatinib group, 52 patients in the apatinib + a PD-1 inhibitor group, and 112 patients in the TACE group. The results revealed that the objective response rate (ORR) was significantly higher in the triple therapy group of TACE + apatinib combined with a PD-1 inhibitor than that in the non-triple therapy group [odds ratio (OR)=2.47, 95% confidence interval (95%CI): 1.61-3.78]. Besides, disease control rate (DCR) was greater in the triple therapy group of TACE + apatinib combined with a PD-1 inhibitor than that in the non-triple therapy group (OR=1.87, 95%CI: 1.44-2.44). Patients in the triple therapy group experienced a significant extension of overall survival (OS) (HR=0.42, 95%CI: 0.36-0.49). In addition, there was no significant difference in the overall rate of adverse events (AEs) between the two groups (OR=1.05, 95%CI: 0.89-1.22). Compared with the non-triple therapy group, the triple therapy group of TACE + apatinib combined with a PD-1 inhibitor outperformed in terms of tumor response and long-term survival with manageable AEs.

Celastrol has been shown to inhibit hepatocellular carcinoma (HCC) progression, but the underlying mechanism is unknown. Fanconi anemia complementation group D2 (FANCD2), a ferroptosis inhibitor, promotes HCC proliferation and invasion. This study aims to investigate whether Celastrol exerts its effects by targeting FANCD2. Using data from The Cancer Genome Atlas (TCGA), we identified differentially expressed genes in HCC utilizing Gene Expression Profiling Interactive Analysis 2 (GEPIA 2). FANCD2 and Celastrol were analyzed for molecular docking using Autodock, which was based on geometric matching and energy matching. The correlation between FANCD2 and survival rate was analyzed using Kaplan-Meier's estimates by log-rank (Mantel-Cox) test. HCC cell lines (SNU-423 and SNU-387) were overexpressed or silenced with FANCD2 and treated with Celastrol. Autophagy and ferroptosis were evaluated by measuring oxidative stress and related markers, and cell function experiments were performed. High expression of FANCD2 was correlated with poor survival in HCC patients. Celastrol targeted FANCD2, reducing its level in SNU-423 and SNU-387 cells. FANCD2 overexpression resulted in increased SNU-423 cell viability, migration, invasion, and tube formation ability, as well as attenuated autophagy and ferroptosis, while FANCD2 knockdown in SNU-387 cells showed opposite effects. Additionally, FANCD2 overexpression reversed the ability of Celastrol to induce autophagy and ferroptosis and to inhibit SNU-423 cell survival in vitro, while FANCD2 knockdown enhanced the effects of Celastrol in SNU-387 cells. Celastrol inhibits malignant behavior in HCC cells by targeting FANCD2 to induce autophagy-dependent ferroptosis.

e16182 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancy with dismal outcomes. Recently, lenvatinib have been approved as the first-line therapy for unresectable HCC. However, the efficacy and safety of lenvatinib with the combination of other therapy such as transarterial chemoembolization (TACE) and immune checkpoint inhibitor (ICI) therapy was still unclear. Methods: A multicenter retrospective study was conducted and 158 HCC patients treated with lenvatinib from four medical centers were enrolled between November 2018 and December 2020. According to the treatment combined with lenvatinib, all patients were classified into four groups, including lenvatinib monotherapy (LEN) group, combined ICI (c-ICI) group, combined TACE (c-TACE) group and combined ICI and TACE (c-ICI-TACE) group. Objective response rate (ORR) and disease control rate (DCR) were assessed. Overall survival (OS) and time to progression (TTP) were calculated and compared among different groups. Results: All patients (n = 158) were classified into LEN group (n = 40), c-ICI group (n = 42), c-TACE group (n = 39) and c-TACE-ICI group (n = 37). In all patients, the ORR and DCR was 29.1% and 74.1%. The median OS and TTP were 21.8 and 6.2 months, respectively. Four groups showed significant differences in ORR and DCR rates. Specifically, c-ICI-TACE group have significantly higher ORR and DCR rate compared with LEN group (ORR: 12% vs. 38%, P = 0.002; DCR: 60% vs. 89%, P = 0.004). Kaplan-Meier analysis identified that LEN group, c-ICI group, c-TACE group and c-TACE-ICI group showed significantly different TTP (median TTP: 5.0 vs. 6.6 vs. 4.9 vs. 9.5 months; P = 0.021), but similar OS (median OS: 21.8 vs. 19.6 vs. 17.5 months vs. unreached; P = 0.180). Further investigation revealed lenvatinib combined with ICI could prolong TTP compare with lenvatinib without ICI (median TTP: 8.4 vs. 5.0 months; P = 0.019), but it had no significant impact on OS (median OS: unreached vs. 20.1 months; P = 0.300). c-ICI-TACE group showed both better TTP and improved OS compared with other three groups (median TTP: 9.5 vs. 5.2 months; P = 0.004; median OS: unreached vs. 20.1 months; P = 0.034). Univariate and multivariate analysis confirmed that c-ICI-TACE was an independent protective factor for OS (hazard ratio: 0.226; 95% confidence interval: 0.10-0.50; P < 0.001) and TTP (hazard ratio: 0.55; 95% confidence interval: 0.32-0.95; P = 0.032). Most patients (152/158, 96.2%) showed adverse events (AEs) during lenvatinib treatment and the grade 3 AE occurred in 45 patients (28.5%). No significant difference of AE (P = 0.569) and grade 3 AE (P = 0.572) was found among four groups. Conclusions: Lenvatinib was an effective treatment for patients with HCC. Lenvatinib combined ICI could prolong the TTP, while lenvatinib combined ICI and TACE could improve both TTP and OS. Combined therapy wouldn’t escalate the AE and grade 3 AE rates.

OP0002 A randomised, single-centre phase 2 study of ginsenoside Rg3 plus transarterial chemoembolisation (TACE) versus TACE alone in Chinese patients with advanced hepatocellular carcinoma

BackgroundWe aimed to determine the clinical. outcomes of various immune checkpoint inhibitor (ICI) combinations for the treatment of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. The results predicted the treatment efficacy of these combinations.MethodsFrom July 15, 2016 to March 22, 2022, 85 NSCLC patients with EGFR mutations, enrolled at the Zhejiang Cancer Hospital, received ICI combinations after resistance to prior EGFR-tyrosine kinase inhibitors (EGFR-TKIs). These patients were diagnosed with EGFR mutations using an amplification refractory mutation system PCR (ARMS-PCR) and next-generation sequencing (NGS). Survival times were analyzed using the Kaplan–Meier method and log-rank test.ResultsPatients who received ICIs combined with anti-angiogenic therapy had longer progression-free survival (PFS) and overall survival (OS) than patients who received ICIs combined with chemotherapy. There was no significant difference in survival time between patients who received ICIs combined with chemotherapy and anti-angiogenic therapy and patients who received ICIs combined with anti-angiogenic therapy or ICIs combined with chemotherapy, which was due to the limitation sample size of patients who received ICIs combined with chemotherapy and anti-angiogenic therapy. Patients with L858R mutations had a longer PFS and OS than patients with exon 19 deletions. T790M negative patients benefited more from ICI combinations, compared with T790M positive patients. In addition, there was no significant difference in PFS and OS between patients with TP53 co-mutations and patients without a TP53 co-mutation. We also found that patients with prior first-generation EGFR-TKI resistance had longer PFS and OS than prior third-generation EGFR-TKI resistance patients. There was no new adverse event in this study.ConclusionsEGFR-mutated patients who received ICIs combined with anti-angiogenic therapy had longer PFS and OS than patients with ICIs combined with chemotherapy. Patients with L858R or without T790M mutation benefited more from ICI combinations. Besides, patients with prior first-generation EGFR-TKI resistance could benefit more from ICIs combinations than prior third-generation EGFR-TKI resistance patients.

403 Background: Time to progression (TTP) is widely used as the endpoint in early-phase trials for advanced hepatocellular carcinoma (HCC). However, the relevance of using TTP as a surrogate marker for overall survival (OS) in pivotal trials remains uncertain. Methods: The PubMed database and ASCO meeting library were searched for reports of randomized controlled trials that investigated patients with advanced HCC, included data for both OS and TTP, and were launched between 2009 and 2016. Correlation between hazard ratios (HRs) for TTP and OS was determined using weighted linear regression. Correlations between median OS and TTP, and between median OS and post-progression survival (PPS), defined as the period obtained by subtracting median TTP from median OS, were also evaluated. Results: The database search yielded 24 trials with 50 arms. Overall, TTP HR correlated with OS HR (R = 0.73); however, the coefficient in the regression equation was 0.48. When trials were stratified by treatment line, TTP HR was more strongly correlated with OS HR in second-line (R = 0.91) than in first-line (R = 0.77) settings. Correlation between median OS and median TTP was weak (R = 0.50), whereas the correlation between median OS and median PPS was strong (R = 0.78). Conclusions: In advanced HCC, the OS HR can be predicted from the TTP HR, especially in second-line trials, which is useful when considering whether to proceed to a pivotal trial based on the results of early-phase trials. However, TTP may not be appropriate as a primary endpoint in a pivotal trial if the trial aims to evaluate the survival benefit of novel agents because improvement of TTP cannot fully reflect improvement of OS because of the impact of PPS on OS.

Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial

BackgroundFerroptosis is related to the immunosuppression of tumors and plays a critical role in cancer progression. Fanconi anemia complementation group D2 (FANCD2) is a vital gene that regulates ferroptosis. However, the mechanism of action of FANCD2 in Hepatitis B-related hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the prognostic significance and mechanism of action of FANCD2 in Hepatitis B-related HCC.MethodsThe expression of FANCD2 in Hepatitis B-related HCC was explored using The Cancer Genome Atlas (TCGA) and validated using the Gene Expression Omnibus (GEO) database. Univariate and multivariate Cox regression analyses and Kaplan–Meier survival curves were used to analyze the relationship between FANCD2 expression and the overall survival of patients with Hepatitis B-related HCC. Protein–protein interaction networks for FANCD2 were built using the STRING website. In addition, correlations between FANCD2 expression and the dryness index, tumor mutational burden, microsatellite instability (MSI), immune pathways, genes involved in iron metabolism, and sorafenib chemotherapeutic response were analyzed.ResultsOur results indicated that FANCD2 was significantly overexpressed in Hepatitis B-related HCC and demonstrated a strong predictive ability for diagnosis (Area Under Curve, 0.903) and prognosis of the disease. High FANCD2 expression was associated with poor prognosis, high-grade tumors, high expression of PDL-1, high MSI scores, and low sorafenib IC50 in Hepatitis B-related HCC. BRCA1, BRCA2, FAN1, and FANCC were vital proteins interacting with FANCD2. The expression level of FANCD2 significantly correlated with the infiltration levels of Treg cells, B cells, CD8 + T cells, CD4 + T cells, neutrophils, macrophages, myeloid dendritic cells, and NK cells in Hepatitis B-related HCC. FANCD2 was positively correlated with the tumor proliferation signature pathway, DNA repair, and cellular response to hypoxia.ConclusionOur study indicated that FANCD2 was a potential novel biomarker and immunotherapeutic target against Hepatitis B-related HCC, which might be related to the chemotherapeutic response to sorafenib.

Background: SOR is an active agent and has favorable immunomodulatory effects in HCC. Combinations of immune checkpoint inhibitors with SOR may enhance effector T-cell function and lead to improved clinical outcomes for patients with HCC. We tested this hypothesis in an open-label, multicenter study of SOR and PEM in patients with advanced HCC. Methods: Pts with advanced or metastatic HCC, CP Class A, ECOG PS of 0/1 were included. One prior therapy was allowed. Pts were treated with SOR alone for 4 weeks (lead-in) at a stable dose (minimum 200 BID), followed by SOR plus PEM 200mg IV q3 weeks. The phase Ib part included the first 6 pts who completed the SOR lead-in and began SOR+PEM. Treatment continued until disease progression or unacceptable toxicity. Disease assessment was performed q6 weeks using the RECIST 1.1 criteria. The primary endpoint was overall response rate (ORR). The study used an exact one-stage design. With 27 evaluable pts, the study had 80% power to detect an ORR ≥20% with SOR/PEM vs. 5% with SOR alone (a=0.05). Peripheral blood mononuclear cells were collected at baseline and on-treatment for correlative analyses (flow cytometry). Results: Of the 37 total pts enrolled, 27 were evaluable (9 female). Median age was 68 years. Forty-four percent of the pts had viral hepatitis. Four pts were pre-treated with atezolizumab/bevacizumab (n=3) or tivozanib/durvalumab (n=1). The ORR was 33% (95% CI: 18 - 52%) p= 0.08. Best response was PR in 9 patients (33%), 12 patients SD (44%), and 6 (22%) had PD. One patient had a near CR. Median progression-free (PFS) and overall survival (OS) were 4.8 (95% CI: 3.4 - 16.3) and 28.5 (95% CI: 15.2 - 57.7) months respectively. Fifty-two percent of patients had a decrease in AFP >50%. One atezolizumab/bevacizumab pretreated pt with progressive disease as best response had a near-complete response to SOR+PEM. The most common grade ≥3 treatment-related adverse events (AEs) in the safety population (n=37) were hypertension (16%), immune-related AEs (11%), fatigue (8%) and diarrhea (8%). CD8+ T-cells increased by 5.5% (-35.6 - 36.9%; p=0.035) and Tregs decreased by 14.73% (-378.6 - 61%, p=0.049) from baseline to C1D1. The increase in activated Tregs prior to PEM initiation was associated with worse OS (HR: 1.8, p=0.03) while a higher Teff/Treg at C1D1 (prior to PEM initiation) was associated with improved PFS (HR: 0.4, p=0.036). An increase in the percentage of Tregs between baseline and C4D1 was associated with worse PFS (HR: 2; p=0.03). Conclusions: SOR+PEM is a safe and active treatment for pts with advanced HCC. The results of our study confirm the favorable immunomodulatory effects of SOR and support further exploration of this regimen for patients with advanced HCC. Further tissue and blood correlative analyses are ongoing. NCT03211416. Citation Format: Renuka Iyer, Sahithi Sonti, Devalingam Mahalingam, Sarbajit Mukherjee, Sayan Chakraborty, Kristopher Attwood, Anthony George, Orla Maguire, Hans Minderman, Christos Fountzilas. Phase Ib/II study of sorafenib (SOR) and pembrolizumab (PEM) in patients (pts) with advanced hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT210.

Targeted therapy for metastatic renal cell carcinoma

Targeted therapy for metastatic renal cell carcinoma

The use of immune checkpoint inhibitors (ICIs) in combination therapy is an emerging trend in tumor immunology. However, the value of combination immunotherapy remains controversial, because of the toxic effects induced by combination. The added benefit of each additional drug has not been assessed against the added toxicity. We searched for clinical trials that evaluated ICI monotherapies and combination therapies in lung cancer and melanoma patients. The overall response rate (ORR), grade 3/4 treatment-related adverse event rate, overall survival (OS), and progression-free survival (PFS) were extracted from the most recently published studies to determine the relative risk (RR), hazard ratios (HRs), and 95% confidence intervals (CIs). Seven randomized controlled trials and one open-label study were identified (n = 3,097). Treatments included combinations of several ICIs, a combination of an ICI and dacarbazine, two combinations of an ICI, paclitaxel and carboplatin, and a combination of an ICI and gp100 vaccine. Higher ORR (RR: 1.51, 95% CI: 1.03-2.20, p = 0.034), OS (HR: 0.86, 95% CI: 0.78-0.95, p = 0.000), and PFS (HR: 0.93, 95% CI: 0.72-1.14, p = 0.000) values were observed in combination therapy than in monotherapy. In addition, the toxicity of combination ICI immunotherapy was higher (RR: 1.50, 95% CI: 1.03-2.19, p = 0.036) than that of monotherapy. This meta-analysis showed that the addition of nivolumab to ipilimumab better benefits PFS and ORR. Adding sargramostim was associated with better OS and safety. The efficacy and safety of a nivolumab-ipilimumab-sargramostim combination should be investigated further.