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The present study examined the roles of peroxisome proliferator-activated receptors (PPAR) in activation of hepatic stellate cells (HSC), a pivotal event in liver fibrogenesis. RNase protection assay detected mRNA for PPAR␥1 but not that for the adipocyte-specific ␥2 isoform in HSC isolated from sham-operated rats, whereas the transcripts for neither isoforms were detectable in HSC from cholestatic liver fibrosis induced by bile duct ligation (BDL). Semi-quantitative reverse transcriptasepolymerase chain reaction confirmed a 70% reduction in PPAR␥ mRNA level in HSC from BDL. Nuclear extracts from BDL cells showed an expected diminution of binding to PPAR-responsive element, whereas NF-B and AP-1 binding were increased. Treatment of culturedactivated HSC with ligands for PPAR␥ (10 M 15-deoxy-⌬ 12,14 -PGJ 2 (15dPGJ 2 ); 0.1ϳ10 M BRL49653) inhibited DNA and collagen synthesis without affecting the cell viability. Suppression of HSC collagen by 15dPGJ 2 was abrogated 70% by the concomitant treatment with a PPAR␥ antagonist (GW9662). HSC DNA and collagen synthesis were inhibited by WY14643 at the concentrations known to activate both PPAR␣ and ␥ (>100 M) but not at those that only activate PPAR␣ (<10 M) or by a synthetic PPAR␣-selective agonist (GW9578). 15dPGJ 2 reduced ␣1(I) procollagen, smooth muscle ␣-actin, and monocyte chemotactic protein-1 mRNA levels while inducing matrix metalloproteinase-3 and CD36. 15dPGJ 2 and BRL49653 inhibited ␣1(I) procollagen promoter activity. Tumor necrosis factor ␣ (10 ng/ml) reduced PPAR␥ mRNA, and this effect was prevented by the treatment with 15dPGJ 2 . These results demonstrate that HSC activation is associated with the reductions in PPAR␥ expression and PPAR-responsive element binding in vivo and is reversed by the treatment with PPAR␥ ligands in vitro. These findings implicate diminished PPAR␥ signaling in molecular mechanisms underlying activation of HSC in liver fibrogenesis and the potential therapeutic value of PPAR␥ ligands for liver fibrosis.

513 Background: LEN, a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT with immunomodulatory activity, is approved in multiple countries for first-line treatment of uHCC. NIV is an anti-PD-1 monoclonal antibody approved in multiple countries as a second-line treatment for HCC. We report early results from a phase 1b trial of LEN + NIV in pts with uHCC. Methods: In this open-label study, pts with uHCC, BCLC stage B (not eligible for transarterial chemoembolization) or C, Child-Pugh class A, and ECOG PS ≤ 1 received LEN (bodyweight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) PO QD and 240 mg NIV IV Q2W. The primary endpoint was tolerability and safety of the combination. Objective response rate (ORR; mRECIST by investigator) was a secondary endpoint. Tolerability was evaluated by assessing dose-limiting toxicities (DLTs) during the first cycle in pts for whom no other appropriate therapy was available (Part 1). Once tolerability was confirmed, additional pts with no prior systemic therapy for uHCC were enrolled (Part 2). Results: At data cutoff (May 17, 2019), 30 pts had received LEN + NIV (Part 1: n=6; Part 2: n=24). Pts had BCLC stage B (n=17) or C (n=13) and Child-Pugh scores of 5 (n=23) or 6 (n=7). 4 pts in Part 1 (66.7%) had received prior anticancer medications (3 pts had 1; 1 pt had ≥3). No DLTs were reported in Part 1. TEAEs leading to discontinuation of LEN were reported in 2 (6.7%) pts; 4 (13.3%) pts had TEAEs leading to discontinuation of NIV. TEAEs occurred in all 30 pts; the most common were palmar-plantar erythrodysesthesia (56.7%) and dysphonia (53.3%). Adverse events were manageable. Efficacy outcomes are reported (Table). Conclusions: LEN + NIV was well tolerated with encouraging anti-tumor activity in pts with uHCC. Clinical trial information: NCT03418922. [Table: see text]

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Background To evaluate the efficacy and safety of cabozantinib in Japanese patients with advanced hepatocellular carcinoma (HCC) who had progressed following one or two lines of systemic therapy including sorafenib. An exploratory evaluation in sorafenib-naïve patients was performed. Methods In this open-label, single-arm, phase 2 trial, patients received oral cabozantinib 60 mg once daily. The primary endpoint was progression-free survival (PFS) rate at Week 24. Secondary endpoints included PFS, overall survival (OS), objective response rate (ORR, best response of complete/partial response), disease control rate (DCR, objective response or stable disease) and safety. Results Thirty-four patients received cabozantinib across 17 centers (prior sorafenib cohort, n = 20; sorafenib-naïve cohort, n = 14). PFS rate at 24 weeks was 59.8% [90% confidence interval (CI) 36.1–77.2%] in the prior sorafenib cohort, 16.7% (90% CI 4.0–36.8%) in the sorafenib-naïve cohort and 40.1% (90% CI 24.8–55.0%) overall. Median PFS was 7.4 months for the prior sorafenib cohort, 3.6 months for the sorafenib-naïve cohort, and 5.6 months overall. OS rate at 6 months was 100.0%, 78.6% and 91.1%, respectively; DCR was 85.0%, 64.3% and 76.5%, respectively. The ORR was 0.0% for both cohorts. All patients required dose modifications due to adverse events, the most common of these were palmar–plantar erythrodysesthesia syndrome and diarrhea. Three patients (8.8%) discontinued due to adverse events other than disease progression. Conclusions Cabozantinib 60 mg/day has a favorable benefit/risk profile for Japanese patients with advanced HCC who have previously received one or two lines of systemic anticancer therapy including sorafenib. (Clinical trial registration: NCT03586973)