Search

Introduction: Cabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels. Methods: Baseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if p < 0.05 and predictive if p < 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed. Results: In the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS. Conclusion: Cabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.

Backgrounds and aims: Even if no systemic treatment is currently validated for unresectable hepato-cholangiocarcinoma (cHCC-CCA), tyrosine kinase inhibitors (TKI), and platinum-based chemotherapy are frequently used in clinical practice. Our study aims to describe the effectiveness of first-line systemic treatments in patients with cHCC-CCA. Patients and Methods: Patients with histological diagnosis of unresectable or metastatic cHCC-CCA confirmed by a centralized review (WHO classification 2019) and who received systemic treatment from 2009 to 2020 were included retrospectively in 11 centers. The outcomes of patients with cHCC-CCA were compared with patients with hepatocellular carcinoma (HCC) treated by sorafenib (n=117) and with intrahepatic cholangiocarcinoma (iCCA, n=94) treated mainly by platinum-based chemotherapy using a frailty Cox model. The efficacy of tyrosine kinase inhibitors and platinum-based chemotherapies in patients with cHCC-CCA was assessed using a doubly robust estimator. Results: A total of 83 patients with cHCC-CCA were included and were predominantly male (72%) with underlying cirrhosis (55%). 67% of patients had extrahepatic metastases and 31% macrovascular tumor invasion. cHCC-CCAs were more often developed on cirrhosis (55.4%) than iCCA (26.6%) but less frequently than HCC (80.2%)(p

Introduction: Tislelizumab (anti-programmed cell death protein 1 antibody) showed preliminary antitumor activity and tolerability in patients with advanced solid tumors, including hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of tislelizumab in patients with previously treated advanced HCC. Methods: The multi-regional phase 2 study, RATIONALE-208, examined single-agent tislelizumab (200 mg intravenously every three weeks) in patients with advanced HCC with Child-Pugh A, Barcelona Clinic Liver Cancer stage B or C, and who had received one or more prior lines of systemic therapy. The primary endpoint was objective response rate (ORR), radiologically confirmed per Response Evaluation Criteria in Solid Tumors version 1.1 by Independent Review Committee. Safety was assessed in patients who received ≥1 dose of tislelizumab. Results: Between April 9, 2018 and February 27, 2019, 249 eligible patients were enrolled and treated. After a median study follow-up of 12.7 months, ORR was 13% (n = 32/249; 95% confidence interval [CI], 9–18), including five complete and 27 partial responses. Number of prior lines of therapy did not impact ORR (one prior line, 13% [95% CI, 8–20]; two or more prior lines, 13% [95% CI, 7–20]). Median duration of response was not reached. Disease control rate was 53% and median overall survival was 13.2 months. Of the 249 total patients, grade ≥3 treatment-related adverse events were reported in 38 (15%) patients; the most common was liver transaminase elevations in 10 (4%) patients. Treatment-related adverse events led to treatment discontinuation in 13 (5%) patients or dose delay in 46 (19%) patients. No deaths were attributed to the treatment per investigator assessment. Conclusion: Tislelizumab demonstrated durable objective responses, regardless of the number of prior lines of therapy, and acceptable tolerability in patients with previously treated advanced HCC.