Advanced Hepatocellular Carcinoma Pts Research Articles

Comparative efficacy of systemic sequential regorafenib after TACE combined with first-line targeted drugs (donafenib, sorafenib, or lenvatinib) after treatment failure for advanced hepatocellular carcinoma: A retrospective, single-center, real-world study.

e16190 Background: Donafenib is a novel multikinase inhibitor, which is a 1st-line systemic treatment for advanced hepatocellular carcinoma (HCC) in China. Regorafenib is an oral multikinase inhibitor and has been approved as the 2nd-line systemic treatment for advanced HCC based on the RESORCE trial. However, the efficacy of systemic sequential regorafenib after donafenib treatment failure in advanced HCC patients(pts) remains unclear. Methods: A retrospective analysis was conducted on the clinical data of advanced HCC pts treated with donafenib combined with TACE (Dona-TACE), sorafenib combined with TACE (Sora-TACE) or lenvatinib combined with TACE (Lenva-TACE) at The First Affiliated Hospital of USTC from January 2018 to December 2023. A total of 87 of these pts with advanced HCC who received regorafenib as the 2nd-line treatment. The 1st-line targeted drugs, disease control rate (DCR) (defined by the mRECIST), progression-free survival (PFS) and adverse events (AEs) (defined by the CTCAE version 5.0) were recorded and compared. Results: After screening, 27 pts in the Dona-TACE group ,35 pts in the Sora-TACE group and 31 pts in the Lenva-TACE group were included in this study. The baseline characteristics of the three groups were similar. The median treatment duration of regorafenib was 5.2 months in the Dona-TACE group, 4.8 months in the Sora-TACE group and 3.7 months in the Lenva-TACE group. The overall DCRs of sequential regorafenib after donafenib, sorafenib or lenvatinib treatment failed were 79%, 75% and 71%(P>0.05). There was no significant difference in median PFS of regorafenib (4.8, 3.9, 4.1m) in the Dona-TACE, Sora-TACE and Lenva-TACE groups. Compared with other groups, the Dona-TACE group received regorafenib sequentially had a lowest incidence of grade 3-4 AEs (39.1%, P<0.05). All groups had no treatment-related deaths from regorafenib. Multivariate analysis showed that ECOG PS score, up-to-seven criteria, tumor blood supply and Extrahepatic metastasis were independent prognostic factors affecting PFS (HR, 3.220, 3.019, 2.753, 3.142; P < 0.05). No survival differences were observed between the patients who received 1st-line treatment with or without a combination of immune checkpoint inhibitor(ICI) reagents. Conclusions: This retrospective, single-center, real-world study demonstrated that when donafenib failed the regorafenib could still improve the prognosis of advanced HCC pts with fewer AEs. The study will continue to focus on overall survival(OS) and whether combined ICIs or not in the 1st-line/ 2nd-line treatment could have a positive effect on OS.

CVM-1118: A potent oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.

e16150 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n = 4) or C (87%, n = 27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–15.0 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 4.6 mos (range 4.67–15.0 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 10.4 mos (95% CI 2.8–13.7 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was Cmax 564 ng/mL and the AUC0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .

CVM-1118: A potent oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.

e16150 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n = 4) or C (87%, n = 27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–15.0 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 4.6 mos (range 4.67–15.0 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 10.4 mos (95% CI 2.8–13.7 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was Cmax 564 ng/mL and the AUC0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .

A study of pembrolizumab (pembro) in combination with Y90 radioembolization in patients (pts) with poor prognosis hepatocellular carcinoma (HCC) with preserved liver function.

422 Background: HCC is an aggressive cancer that is challenging to treat due to the concomitant diagnosis of cirrhosis. For HCC pts with no extrahepatic metastases and well-compensated liver function, Y90 radioembolization is a standard therapy. In observational studies, pts with multifocal disease or portal vein thrombosis (PVT) had worse outcomes with short disease control intervals of less than 6 months. Pembro is an anti-PD-1 monoclonal antibody that is FDA-approved for advanced HCC pts who have progressed on sorafenib. Given pre-clinical evidence that radiotherapy can increase PD-L1 expression and enhance tumoral T-cell recruitment, this study explored the safety and efficacy of pembro with Y90 radioembolization in pts with poor prognosis HCC. Methods: GI15-225 was a multi-center, single-arm study in poor prognosis HCC pts, defined as having multifocal disease, branch PVT and/or diffuse disease (NCT03099564). Pts with extrahepatic metastatic disease were excluded; eligible pts had disease amenable to 1-2 embolization procedures. Pts had Child Pugh A/B7 cirrhosis with no prior Y90 treatment; previous TAE, TACE, SBRT, liver resection or ablation were allowed. Treatment consisted of pembro 200mg every 3 weeks with Y90 radioembolization performed 7-10 days after first dose of pembro. The primary objective was to estimate the progression free survival (PFS) rate at 6 months per RECIST 1.1; secondary endpoints included safety, time to progression (TTP), overall response rate (ORR) and overall survival (OS). Results: A total of 29 pts were enrolled 10/23/17 to 11/24/20. Median age 66 years, 89% male, and 47% with PVT. 26 pts were evaluable for primary endpoint having received Y90 and at least one dose of pembro. The 6 month PFS rate was 57.7% (95% CI 36.9 – 76.6). Median PFS was 8.6 months (95% CI 4.1 – 13.4) and median TTP was 9.9 months (95% 4.2 – NR). Median OS was 22 months (95% CI 8.4 – 32.0). The ORR was 27% (Table). Most common treatment related grade 3-4 AEs were decreased lymphocytes (18%), increased bilirubin (11%), hypertension (11%), ascites (7%), and AST/ALT elevation (7%). One pt experienced grade 5 toxicity of hepatic failure after receiving one dose of pembro and Y90 that was attributed to Y90 and disease progression. Conclusions: Concurrent administration of pembro with Y90 radioembolization in pts with poor prognosis HCC demonstrated promising clinical activity with median TTP and OS that exceeds historical data reported in similar patients treated with Y90 alone. With a 6 month PFS rate of 57.7% and a favorable toxicity profile, the combination of immune checkpoint blockade and Y90 deserves further evaluation in larger randomized clinical trials. Clinical trial information: NCT03099564. [Table: see text]

Update on overall survival (OS) of RESCUE: An open-label, phase 2 trial of camrelizumab (C) in combination with apatinib (A) in patients with advanced hepatocellular carcinoma (HCC).

4076 Background: C+A combination therapy displayed high objective response rate, disease control rate, and durable response with a manageable safety profile in patients (pts) with advanced HCC. Here we performed an updated analysis of OS to characterize the OS benefit of C+A in HCC pts. Methods: 70 pts in first-line cohort and 120 pts in second-line cohort were enrolled. Median OS and 2-year OS rate were evaluated via updated data (data cutoff, 3 January, 2021). Median time from enrollment to data cutoff of the total population (N = 190) was 29.1 months (range, 24.0-33.7). Results: OS events had occurred in 58.6% pts in first-line cohort and 60.0% pts in second-line cohort. The median OS was 20.1 months (95% CI, 14.9-NR) and 2-year OS rate was 43.3% (95% CI, 31.3-54.7) in first-line cohort. The median OS was 21.8 months (95% CI, 17.3-26.8) and 2-year OS rate was 44.6% (95% CI, 35.5-53.3) in second-line cohort. Conclusions: Long-term follow-up of C+A demonstrated remarkable survival benefit in advanced HCC pts, which further suggested that C+A is a promising combination therapy in advanced HCC pts. Clinical trial information: NCT03463876.

Combination therapy with lenvatinib and anti-PD-1 antibodies for unresectable or advanced hepatocellular carcinoma: A real-world study.

e16610 Background: Combination therapy of anti-angiogenic therapy and anti-PD-1 antibody had shown promising anti-tumor effects for advanced hepatocellular carcinoma (HCC) in clinical trials. Here we report the effectiveness and safety of the combination therapy of lenvatinib and anti-PD-1 antibodies in a cohort of unresectable or advanced HCC pts. Methods: From Sep 2018 to Jan 2020, 77 consecutive pts received a combination treatment of lenvatinib and an anti-PD-1 antibody. Lenvatinib was given 8 mg/d regardless of patient body weight and anti-PD-1 antibody was used either q2wk (nivolumab or camrelizumab) or q3wk (pembrolizumab, sintilimab or toripalimab). pts who completed at least one efficacy and safety assessment were eligible for this study. Tumor response were evaluated with abdominal contrast-enhanced MRI/CT and/or chest CT every 2 mo (± 1 wk). Laboratory tests were monitored every 2-3 wk. Results: 59 pts were eligible for this study. Of them, 1 (1.7%) were BCLC stage A, 10 (16.9%) were BCLC stage B, 48 (81.4%) were BCLC stage C (including 20 pts in China Liver Cancer [CNLC] stage IIIa and 28 in CNLC stage IIIb). 43 (72.9%) pts were treated as first-line therapy. The table below shows efficacy results. R0 resection was performed in 6 (10.2%) pts due to tumor regression. By the data cut-off date, 13 pts died, and mOS was not mature. Overall, the combination treatment was well tolerated. 28 (47.5%) pts had at least one ≥ grade 3 treatment-emergent adverse event. 3 (5.1%) pts died from immune-related adverse events, 2 of them died from immune-related adverse events after hepatectomy. Conclusions: The combination of lenvatinib + anti-PD-1 antibody is effective and well-tolerated in pts with HCC as first-line or second-line treatment. It is also noted that initially unresectable HCC may be converted to resectable HCC following this combination treatment. [Table: see text]

A phase II randomized placebo-controlled study investigating the combination of yiv-906 and sorafenib (SORA) in HBV (+) patients (Pts) with advanced hepatocellular carcinoma (HCC).

TPS601 Background: First-line systemic treatment options for advanced HCC pts are limited to the multi-targeted tyrosine kinase inhibitors, SORA and lenvatinib. Both agents improve outcomes for pts with advanced disease, but are associated with increased rate of grade ≥ 3 treatment-related adverse events. YIV-906 (PHY906, KD018) is derived from Huang-Qin-Tang, a traditional Chinese medicine documented 1800 years ago to treat gastrointestinal ailments. Preclinical data indicate YIV-906 increases inflammation in the tumor microenvironment by M1 macrophages activation/proliferation resulting in HCC tumor rejection in vivo and reduces SORA associated toxicity. Clinical experience with YIV-906 plus SORA suggests safety and potential clinical benefit to HCC pts with chronic HBV infection. Methods: This is a proof-of-concept, international, multicenter, double-blind, placebo-controlled, randomized phase 2 study designed to compare the efficacy of YIV-906 and SORA to SORA alone in advanced HCC pts (NCT04000737). Key eligibility criteria include age ≥ 18 years, HBV-associated HCC, ≥ 1 measurable untreated lesion, Child-Pugh A liver function, and no prior systemic therapy. An estimated 125 pts will be randomized 2:1 to receive the investigational (YIV-906 plus SORA) or control (placebo plus SORA) arm until disease progression or unacceptable toxicity. Pts will be stratified by metastatic status (extrahepatic/vascular invasion vs none) and ECOG performance status (0 vs. 1). The primary endpoint is progression-free survival (PFS). Secondary endpoints include objective response rate and disease control rate by mRECIST, time to progression, overall survival, quality of life, and safety by CTCAE version 4.0. Translational correlatives include pharmacokinetics, effects on oral/gut microbiota, and exploratory soluble biomarkers analysis. For the primary endpoint, sample size of 41 pts in control arm and 84 pts in the investigational arm achieves 90% power at a 0.05% significance level to detect a hazard ratio of 0.5 assuming the median PFS of the control SORA arm is 3.6 months and that of the combination arm is 7.3 months. Clinical trial information: NCT04000737.

Plasma biomarkers to predict pembrolizumab response in HCC patients.

e14043 Background: Pembrolizumab (PEM) has been approved as second line therapy for the treatment of hepatocellular carcinoma (HCC). We conducted a single institution investigator-initiated clinical/biomarkers trial to assess potential biomarkers to predict response in unresectable HCC patients (pts) receiving PEM. Methods: PEM was administered at 200mg iv. every 3 weeks for advanced HCC pts who progressed on, were intolerant of, or refused sorafenib. The circulating levels of cytokines/chemokines included IL-1β, IL-6, IL-8, IL-12, IL-18, IFN-γ, TGF-β, IL-10, CXCL9, CCL4, CCL5, as well as PD-1, PD-L1, PD-L2 were measured by ELISA at baselines and at day 60-90. PD-L1 expression in tumor was also assessed by histopathological staining. Results: 29 pts have been treated and 28 were evaluated for response. One pt had complete response, 8 had partial response and 4 had stable disease. Among all the biomarkers tested, only TGF-β at baseline predict response. The mean of plasma TGF-β in responders were 141.9pg/ml vs. 1071.8pg/ml in nonresponders. The cut-off values was determined based on the near medians. The plasma concentration of TGF-β of ≥200pg/ml was an index for nonresponder (P = 0.003). Kaplan-Meier analysis showed that the median overall survival (OS) and progression-free survival (PFS) in pts with TGF-β ≥200pg/ml were 7 months and 2 months, respectively, while in pts with TGF-β < 200 pg/ml, the OS and PFS were over 25 months(P = 0.005 and P = 0.008, respectively). Plasma IFN-γ or IL-10 levels positively correlated with plasma PD-1/PD-L-1 (P < 0.05). Since tumor PD-L1 expression is upregulated by IFN-γ, and IL-10, and interacts with PD-1 to suppress T cell, to confirm these relationships, the linear regression was used to analyze the data. Plasma IFN-γ or IL-10 levels positively correlated with plasma PD-1 and PD-L1 levels ( P < 0.05). Nine of these 24 patients had tumor available for PD-L1 scoring (PD-L1-positive:3 pts and PD-L1-negative:6pts). Similar to plasma PD-L1 concentration, pts with positive tumor PD-L1 had high levels of plasma IFN-γ or IL-10 ( P < 0.05). Conclusions: Our study confirmed that PEM is active in HCC and TGF-β is a predictive markers for tumor response, PFS, and OS. Support by grant from Merck

A phase II study of ADI-PEG 20 and FOLFOX6 in patients (pts) with advanced hepatocellular carcinoma (HCC).

TPS477 Background: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways, and preclinical data indicate that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in HCC models. A prior phase 1 study of FOLFOX6 and ADI-PEG 20 established the safety and recommended phase 2 dose of the combination in pts with advanced gastrointestinal tumors (Harding et al. CCP 2018). For 23 treatment-refractory HCC pts who were treated at the recommended phase 2 dose on an expansion cohort of the phase 1, the objective response rate (ORR) was 21% (95% CI 7.5-43.7) and median progression-free survival (PFS) was 7.3 months. These data were favorable when compared to historic data for FOLFOX alone where the ORR was ~8% and PFS was 2.93 months and suggest greater clinical activity of the combination (Qin et al. JCO 2013). Prospective confirmation of these results is required. Methods: This is an international, multicenter, single-arm, open-label phase 2 trial of ADI-PEG 20 and FOLFOX6 for advanced HCC pts with Child-Pugh A liver function who progressed on ≥ 2 prior lines of prior systemic therapy (NCT02102022). The primary objective is to define the ORR by RECIST 1.1 as assessed by blinded independent central review. Secondary objectives include determination of safety, disease control rate (DCR), duration of response (DOR), PFS, overall survival (OS), serum arginine, citrulline and anti-ADI-PEG 20 levels over 24 weeks, and alpha-fetoprotein response. Eligible pts receive intravenous FOLFOX6 biweekly at standard doses and ADI-PEG 20 intramuscularly weekly at 36 mg/m.2 Cross-sectional imaging will be completed every 8 weeks until progression of disease. Based on a two-sided exact test of a one-sample proportion with an alpha of 0.05, under a presumed ORR of 22%, there is 80% power to yield 95% confidence interval of 15-26%, which will require 46 objective responses in 225 subjects. Futility will be assessed three times during the study based on having ORR data available for 56, 110, and 166 patients. This Phase 2 will be stopped for futility if the conditional power drops below 20% at any of these time points. Clinical trial information: NCT02102022.

Phase II multicenter pilot study of safety, efficacy, and immune cell profiling in advanced hepatocellular carcinoma (HCC) on combination of sorafenib (SOR) plus nivolumab (NIVO).

TPS464 Background: The antiangiogenic tyrosine kinase inhibitor (TKI) SOR prolongs survival in advanced HCC, but responses occur in fewer than 5% of patients (pts) and median progression-free survival (PFS) is less than 6 months. Immune checkpoint inhibition (CPI) with the PD-1 inhibitor, NIVO, achieved an overall response rate (ORR) of approximately 20% in sorafenib-naïve pts enrolled on CheckMate 040 trial though most pts had progression. In preclinical studies, TKI can inhibit regulatory T cells and myeloid derived suppressor cells, immune cell subsets which may contribute to CPI resistance. CD8+ T cells in sorafenib-resistant tumors are characterized by PD-1 expression, providing rationale for a combined approach. The combination of TKI or the anti-angiogenic bevacizumab with CPI improves anti-tumor activity in HCC mouse models and in preliminary clinical studies. This study will examine the safety, maximum tolerated dose (MTD), and ORR of the combination of SOR plus NIVO in advanced HCC pts, along with correlative analyses of tumor and circulating immune cells. Methods: Eligible pts must have Child-Pugh A liver function and advanced HCC, without prior systemic therapy and measurable by RECIST 1.1. In Part 1 (3+3 dose escalation), SOR dose will be 400 mg QD or BID plus NIVO 240 mg IV Q2 weeks. In Part 2, Arm 1, pts will start NIVO Cycle 1, Day 1 (C1D1), with addition of SOR at MTD on C1D15; in Part 2, Arm 2, SOR is given at MTD on C1D1 with addition of NIVO on C1D15. Primary endpoints are MTD of SOR (Part 1) and ORR by RECIST 1.1 with H0 7.5% vs. H1 25% (Part 2). For expected sample size of 24 evaluable pts in Part 2, the power is 83% with 1-sided alpha 5% to determine ORR >25% by Chi-square tests. Secondary endpoints are safety, duration of response, PFS, and overall survival. Exploratory endpoints include peripheral and tumor immune cell profiling, PD-L1 expression, and alpha-fetoprotein (AFP) response. An interim safety analysis will be performed after 50% enrollment in Part 2. Optional paired biopsies in Part 2 will allow for investigation of the tumor microenvironment on SOR, NIVO, and combination. Clinical trial information: NCT03439891.

365O - Phase 1 safety and clinical activity of BLU-554 in advanced hepatocellular carcinoma (HCC)

Background: Treatment for advanced HCC remains limited and outcomes are poor. However, emerging data implicate FGF19 as a key HCC driver and suggest its receptor, FGFR4 as a novel therapeutic target. A phase 1 study (NCT02508467) was initiated to assess the safety and clinical activity of BLU-554, a potent, highly-selective oral FGFR4 inhibitor. Methods: Adult patients (pts) with advanced HCC and well-preserved liver function received BLU-554 once daily on a 4-week cycle following a 3 + 3 escalation/MTD expansion design. Adverse events (AEs) per CTCAE, PK, PD and pathway activation (tumor FGF19 IHC) were assessed. Response was determined by RECIST 1.1 every 8 weeks. Results: At a 4/20/17 cutoff, 61 pts have been treated with BLU-554 including 25 in dose escalation (140-900 mg) and 36 in the ongoing dose expansion. 48 (79%) pts had metastatic disease, 54 (89%) had failed ≥1 prior systemic therapy (48 (79%) sorafenib; 11 (18%) nivolumab) and 29 (48%) had pathway activation (IHC+). Based on safety profile, PK, PD, and anti-tumor activity, 600 mg was the MTD and RP2D. Radiographic tumor reduction and objective response per RECIST 1.1 were observed in IHC+ pts in dose escalation and dose expansion. Of 19 IHC+ pts with ≥ 1 radiographic assessment, 11 (58%) pts had tumor reduction: 6 with SD, 4 with PR and 1 with CR (ORR 26%). 6 (32%) IHC+ pts had duration of treatment ≥ 6 months. In contrast, only 4 (15%) of 27 IHC negative pts had tumor reduction (all SD) and only 1 (4%) had duration of treatment ≥ 6 months. Most AEs (regardless of causality) were Grade (Gr) 1-2, including diarrhea (66%), nausea (43%), vomiting (39%), ALT increase (33%), fatigue, AST increase (29% each), abdominal pain (23%), anemia, and decreased appetite (20% each). AST (13%) and ALT (10%) increase, were the only BLU-554-related Gr 3-4 AEs occurring in ≥ 10% of pts. 2 pts experienced DLT (1 Gr 3 abdominal pain; 1 Gr 3 fatigue lasting > 7 days) at 900 mg. 36 (59%) pts have discontinued treatment: 26 disease progression; 5 AE; 3 investigator’s decision; 2 withdrew consent. Conclusions: BLU-554 is well tolerated at the recommended dose of 600 mg and demonstrates important clinical activity in FGF19 IHC+ advanced HCC pts who have failed prior systemic therapy. Clinical trial identification: NCT02508467 Legal entity responsible for the study: Blueprint Medicines Corporation Funding: Blueprint Medicines Corporation Disclosure: D. Sarker: Honoraria: Pfizer, Novartis, Bayer, Ipsen. Advisory board: Blueprint, Baxalta. S.P. Choo: Advisory board +/- honoraria: Norvatis; Celgene; Sirtex, Bristol-Myers Squibb; New Beta-Innovation Oncology; Bio-Cancer Treatment; Research grant: Bristol-Myers Squibb, Sirtex. T. Meyer: Advisory board for Merck, Bristol-Myers Squibb, Bayer and Eisai. Grants from Bayer and BTG. J-H. Yoon: Research grants from Bayer HealthCare Pharmaceuticals, Daewoong Pharmaceuticals, and Bukwang Pharmaceuticals. J-W. Park: Honoraria Support from: Bayer, Merck. Advisory Board of: Bristol-Myers Squibb, Merck. Consulting of: Bristol-Myers Squibb, ONO, Bayer. S. Faivre: Consulting of Bayer, BMS, Lilly, Merck Serono, Novartis. Y-K. Kang: Advisory Board of Blueprint, Novartis, Roche, Merck, Ono, Bristol-Myers Squibb, LSK Biopharma, Daehwa, Taiho. All other authors have declared no conflicts of interest.

Overall survival (OS) in patients (pts) with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP): A real-world retrospective study.

e15658 Background: HCC is associated with a worse prognosis in pts with high baseline AFP levels. The relationship between elevated baseline AFP and survival benefit with systemic HCC treatments in the real world setting is poorly characterized. Methods: A retrospective analysis of clinical outcomes among newly diagnosed advanced HCC pts treated in US community-based oncology practice settings was conducted. Pts treated with sorafenib or best-supportive care (BSC) between 10/1/2007 and 12/31/2013 were identified in the International Oncology Network electronic medical record (EMR) database and were followed until date of death, date of last visit, or 06/30/2014 (end of study). Baseline demographics, clinical characteristics, and AFP (≤ or > 400 ng/mL), plus date of death were extracted from the EMR and physician progress notes. Treatment differences in OS were evaluated and stratified by AFP, AST/ALT, and bilirubin using unadjusted Cox proportional hazards regression models. Results: A total of 370 advanced HCC pts receiving sorafenib (217) or BSC (153) were identified. The mean age was 65.6 years and 77.0% were male. Cirrhosis (38.4%), hepatitis C (36.8%), and alcoholic liver disease (22.4%) were common hepatic-related comorbidities. 45.1% of pts had elevated AFP ( > 400 ng/mL) at baseline. The sorafenib cohort had significantly longer median OS time than the BSC cohort (29.6 vs 19.7 weeks, p= 0.048). OS for sorafenib vs BSC cohorts with AFP≤400 ng/mL and AFP > 400 ng/mL were 45.1 vs 25.3 weeks ( p= 0.128) and 25.3 vs 13.1 weeks ( p =0.197), respectively. Cox models revealed a consistent effect of sorafenib vs. BSC, regardless of AFP level (AFP ≤400ng/mL: HR = 0.79 (95% CI 0.55-1.13), p= 0.200; AFP > 400 ng/mL: HR = 0.80 (95% CI 0.53-1.52), p= 0.297). Conclusions: This study supports the poor prognosis for advanced HCC pts with baseline AFP levels > 400 ng/mL compared to baseline AFP ≤400 ng/mL. Limitations with retrospective, real-world studies require caution in interpretation, but this analysis suggests an OS benefit with sorafenib treatment compared to BSC. There remains an unmet need for effective therapies for advanced HCC associated with elevated AFP levels.

A phase I study of mFOLFOX6 and ADI-PEG-20 in patients (pts) with advanced hepatocellular carcinoma (HCC) and other gastrointestinal (GI) malignancies.

384 Background: ADI-PEG-20 (pegylated arginine deiminase), an arginine degrading enzyme, and FOLFOX each exhibit clinical activity in a HCC pt subset. Preclinical data indicate that arginine depletion interferes with folate and pyrimidine metabolism as well as DNA damage repair pathways, suggesting a role for pairing AGI-PEG-20 with cytotoxic chemotherapy. Methods: This is a single center phase 1 trial of mFOLFOX-6 and ADI-PEG-20 in treatment-refractory advanced GI tumors to assess safety and tolerability, and to identify the recommended phase 2 dose (R2PD). mFOLFOX6 was administered intravenously biweekly at standard fixed doses and ADI-PEG-20 intramuscularly weekly at 18 or 36 mg/m2. Toxicity was assessed by CTCAE v4.03 and efficacy by RECIST v1.1. A HCC RP2D expansion was completed to explore efficacy. Serum arginine, citrulline, and anti-ADI-PEG-20 antibodies were monitored every other week. Results: 17 pts were treated—7 pts with GI tumors in dose escalation and 10 HCC pts in RP2D dose expansion. Histologies included HCC (13), pancreatic (3) and fibrolamellar carcinoma (1). All HCC pts had Child-Pugh A liver function and had progressed on sorafenib. Treatment-related grade ≥ 3 laboratory adverse events (AEs) occurred in 47% of pts, including neutropenia (4), thrombocytopenia (3), anemia (2), lymphocytopenia (2) and hyponatremia (1). Treatment-related grade ≥ 3 clinical AEs occurred in 2 pts, notably grade 3 fatigue and a grade 3 cardiac event not otherwise specified. No dose limiting toxicities, treatment-related deaths, or cases of hepatic failure were observed. Efficacy data for the 13 HCC pts revealed 3 (23%) PR, 6 (46%) SD, 3 PD and 1 NE. Arginine levels were depleted with therapy (mean ± SEM: baseline 85.3 ± 13.0 uM, 8 wks 4 ± 3.0 uM, 16 wk 1.1 ± 0.8uM). Anti-ADI-PEG-20 antibodies were not detected at 8 weeks (mean ± SEM: baseline 0.7 ± 0.5, 8 wks 1.5 ± 1). Conclusions: Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m2 weekly shows an acceptable safety profile with rapid and durable reduction in serum arginine. Further evaluation of this combination is warranted in advanced HCC pts. Clinical trial information: NCT02102022.

Comparative efficacy of sorafenib dose in patients with advanced hepatocellular carcinoma (HCC) with varying liver dysfunction.

369 Background: Sorafenib (SOR) is the only FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC). In clinical practice, there are limited efficacy data related to dose modifications, which are often required. Given the high prevalence of HCC in South Texas, we assessed the efficacy and safety of SOR therapy in relation to dose and Child Pugh score (CP). Methods: Retrospective analysis of HCC patients (pts) receiving SOR from 2008-2013. Median progression-free survival (mPFS) and median overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). A proportional hazards regression model was used to assess the significance of SOR (low, high) by CP (A, B) interaction. Results: 107 pts were included. Median age 57 (41-93). Males 83%. Hispanic 72%, White 24%. ECOG PS 0–1 93%. Causes of cirrhosis: Hepatitis C 67%, Hepatitis B 5%, EtOH 60%. Portal vein thrombosis 33%, extrahepatic disease 39%. CP (available for 106 pts): A 57%, B 43%. mOS was 10.2 months (mo) (95% CI: 7.8-13.5); mPFS was 5.2 mo (95% Cl: 3.8-7.2). In subgroup analysis, mOS for 800 mg/day was 12.8 mo vs 6.6 mo for 400 mg/day (HR 0.59, p=0.04). mPFS for 800 mg/day was 5.9 mo vs 3.5 mo for 400 mg/day (HR 0.66, p=0.07). In CP A pts, higher SOR dose did not improve survival; however, in CP B pts, there were statistically significant improvements in mPFS and mOS (Table). The effect of dosage varied significantly with CP category (A, B) for both OS (p=0.002) and PFS (p=0.03). Conclusions: Historically, CP B advanced HCC pts have worse survival and tolerability to higher doses of SOR when compared to CP A. Our study suggests CP B pts should be considered for SOR 800 mg/day to improve survival with optimal management of toxicity but warrants further prospective studies. [Table: see text]

A randomized phase II open label multi-institution study of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) in the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC).

337 Background: HCC is the 2nd most common cancer worldwide. Most pts present with advanced disease and require systemic therapy. S, a multi-targeted tyrosine kinase inhibitor (TKI) is the only approved drug for HCC. B is a mAb that binds circulating ligand of the transmembrane VEGF receptor; E is a TKI that inhibits EGFR signal transduction. Published single-arm trial data suggest clinical benefit from B+E in HCC. Methods: The study was designed to estimate the HR for OS of B+E vs S with its 95% confidence interval for a sample size of 90 evaluable pts. A difference in OS favoring the B+E arm with a HR of 0.67 was expected and of interest, based on median OS for B+E and S of 15 and 11 mos. seen in previous trials.Secondary endpoints include event-free survival (EFS), toxicity, and RR. Eligible pts had advanced HCC, Childs-Pugh Class A-B7, no prior systemic therapy, preserved organ function, ECOG PS 0-2. Patients were randomized 1:1 to receive S 400 mg orally twice daily, continuously, or B 10 mg/kg IV every 14 days and E 150 mg orally daily. Treatment cycles were 28 days, restaging every 2 cycles by investigator-assessed RR per RECIST 1.1 and subsequent independent radiologic review. Results: A total of 95 pts were registered, 43 in the S arm and 47 in the B+E arm. Pts who received at least 1 dose of study drug(s) were evaluable. Data are summarized in the table. Conclusions: Based on initial data analysis, the OS of advanced HCC pts treated with B+E is consistent with that of S, and the toxicity profile and EFS of B+E compare favorably to S. Clinical trial information: NCT00881751. [Table: see text]

745TiP - Phase Ib/Ii, Multicenter, Single-Arm Trial of the Oral C-Met Inhibitor Msc2156119J As Monotherapy in Patients with Met-Positive Advanced Hepatocellular Carcinoma with Child-Pugh Class a Liver Function Who Failed Sorafenib Treatment

ABSTRACT Background: Sorafenib remains the only approved systemic first-line medical treatment for advanced hepatocellular carcinoma (HCC) patients (pts) with no validated option at the time of sorafenib failure. c-Met/hepatocyte growth factor (HGF) activation/overexpression is associated with poor prognosis. In a Phase I trial, the selective small-molecule c-Met inhibitor MSC2156119J displayed promising antitumor activity (Falchook et al. J Clin Oncol 2013). This disease-oriented Phase Ib/II, single-arm, multicenter study evaluates the safety and antitumor activity of MSC2156119J in Met-positive (Met+) advanced HCC pts with Child-Pugh Class A liver function, pretreated with sorafenib (EudraCT# 2013–002053–30). Trial design: Primary objectives are to determine the recommended Phase II dose of MSC2156119J (RP2D; Phase Ib) in HCC pts and to investigate antitumor activity by determining the progression-free survival (PFS) status at 12 wk per investigator read (Phase II). Secondary objectives include pharmacokinetics, antitumor activity (objective tumor response, time to progression, overall survival, PFS, and disease control), biochemical response, safety, and tolerability. European adults with confirmed, advanced HCC, Child-Pugh class A liver function, life expectancy >3 mo, ECOG status 0–1, available pretreatment tumor biopsy after sorafenib failure, pretreated with sorafenib for ≥4 wks and discontinued ≥14 days prior to day 1 of MSC2156119J treatment will be recruited. In the Phase II part, only Met+ pts with moderate or strong protein overexpression, as determined by immunohistochemistry, will be entered. Key exclusion criteria are prior treatment with systemic therapy other than sorafenib or with c-Met/HGF-targeting agents, impaired cardiac function, and chronic gastrointestinal disease. For the Phase Ib part, up to 18 pts are planned (3 + 3 design; 300 mg or 500 mg MSC2156119J p.o./day; 21-day cycle). For the Phase II part, 48 pts are planned to receive the RP2D of MSC2156119J (p.o./day; 21-day cycle), as determined in the Phase Ib part. Enrollment began on 06 May 2014. A Trial in Progress abstract was submitted to ASCO 2014. Disclosure: S. Faivre: Advisory board: Merck-Serono; B. Sarholz: Employee of Merck KGaA, Darmstadt, Germany A. Johne: Employee of Merck KGaA, Darmstadt, Germany; H. Zheng: Employee of EMD Serono, Boston, MA, USA Stock ownership: Merck/EMD Serono; E. Raymond: Advisory board: Merck-Serono

744TiP - Met-Positive Advanced Hepatocellular Carcinoma and Child-Pugh Class a Liver Function in Asian Patients: a Randomized, Multicenter, Phase Ib/Ii Trial of the Oral C-Met Inhibitor Msc2156119J Vs Sorafenib

ABSTRACT Background: Advanced hepatocellular carcinoma (HCC) is associated with a poor prognosis. Sorafenib is the recommended treatment for HCC patients (pts); however, it is not widely used in Asia due to affordability and unsatisfactory efficacy. The highly selective c-Met inhibitor MSC2156119J showed promising antitumor activity in a phase I trial (Falchook et al. J Clin Oncol 2013:31[Suppl]:2506) with a recommended phase II dose (RP2D) of 500 mg/d. This phase Ib/II, open-label, multicenter trial assesses the efficacy of MSC2156119J monotherapy in first-line treatment vs sorafenib in Met-positive (Met+) advanced HCC pts (NCT01988493). Trial design: Primary objectives include confirmation of the RP2D of 500 mg MSC2156119J in HCC pts (phase Ib) and evaluation of MSC2156119J monotherapy efficacy vs sorafenib, as determined by time to progression (TTP) per independent read (phase II). Secondary objectives are preliminary antitumor activity of MSC2156119J, pharmacokinetics (phase Ib), tolerability, safety, and antitumor activity of MSC2156119J vs sorafenib (phase II: overall survival, objective response, disease control, time to symptomatic progression, progression-free survival, and TTP per investigator read). Main eligibility criteria include: Asian adults with confirmed advanced HCC of BCLC Stage C, Child-Pugh Class A liver function, ECOG status 0–2 (only phase II: Met + , defined as moderate or strong protein overexpression determined by immunohistochemistry, measurable disease according to RECIST v1.1, and eligible for sorafenib treatment), life expectancy >3 mo, no prior systemic anticancer treatment or treatment targeting the HGF/c-Met pathway (phase II only), no neoplasm other than HCC, and no impaired cardiac function, history of liver transplant, or gastrointestinal disease. The Phase Ib part is a “3 + 3” dose-escalation design (300 or 500 mg MSC2156119J p.o./d; 21-d cycle) enrolling up to 18 pts. The phase II part is planned to randomize 140 pts (1:1) who receive MSC2156119J at the RP2D p.o./d or 400 mg sorafenib p.o./twice daily (21-d cycle). Enrollment began on Jan 9, 2014. Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting. All rights reserved. Disclosure: L. Xu: Employee of Merck Serono Pharmaceutical RD H. Zheng: Stock ownership: Merck/EMD Serono Employee of EMD Serono, Boston, MA; F. Bladt: Employee of Merck KGaA, Darmstadt, Germany. All other authors have declared no conflicts of interest.

Sorafenib in hepatocellular carcinoma (HCC): Is there a role for starting patients on a total daily dose of 400mg daily?

364 Background: S at a starting daily dose of 400mg twice daily (800mg) is considered the standard systemic therapy for HCC, in pts with well preserved liver function and advanced stage HCC, based largely on data reported by the SHARP and Asia-pacific trials. Due to complaints regarding SE and reluctance to start at full dose, we decide to retrospectively look at our HCC data base. This single institution retrospective review, evaluated the impact of starting S at a 400mg daily (200mg twice daily). Methods: From 06/01/09-09/01/13, using ICD code 155, newly registered advanced HCC pts, ECOG PS 2, Childs Pugh (CP) class A or B who were started on S 400mg daily were identified : CT scans and AFP levels were followed. PFS was estimated from the date of commencing therapy to date of progression or death if this occurred first and OS was estimated from date of commencing therapy until date of death or loss to follow up. Kaplan Meier survival estimates were obtained with 95% (CI). Log rank test was used to compare the PFS according to CP class. Results: 33 pts (M:F, 21:12), mean age of 59.8y (SD: 12.40) met inclusion criteria, the median duration (MD) of follow up was 8.7 m ( 1.07-27.43). 23(69.7%) pts were CP-A. 70% had abnormal AFP and this decreased > 50% from baseline in 8 (35%). 96% of the pts received prior locoregional therapy in CP-A and 50% in CP-B. Initial dose tolerance was observed in 23 (69.7%) pts. 16 pts (48.5%) needed dose reduction (CP-A: 56.5%, CP-B: 30%) while 19 (57.6%) pts were able to escalate their dose at some point (CP-A: 60.9%, CP-B: 50%). MD of (400mg/d) was 3m prior to any adjustment (CP-A: 3, CP-B: 2). Mean duration of S use was 8.88m (A-10.04, B-6.2). During follow up, 26 pts had POD and 24 pts died. There was no difference in PFS between CP-A and B and following POD 10/19 evaluable pts continued S. OS was 79 % (95%CI: 61-89%) at 3m, 67% (95%CI: 48-80%) at 6m, 50% (95%CI: 32-66%) at 9m, and 40% (95%CI: 23-57%) at 12m. The most common reported toxicities were fatigue 87.5%, diarrhea 53.1% and HFS/rash 43.8% Conclusions: In this cohort of pts S started at 400mg/d did not seem to result in worse outcomes compared to historic controls possibly due to the ability to tolerate therapy for a longer period of time.

Economic burden of advanced hepatocellular carcinoma (HCC) in Spain among patients discontinuing first-line sorafenib.

324 Background: No treatments (Txs) are currently recommended after discontinuation (DC) of sorafenib (SOR) for advanced HCC and there are limited reports of Tx patterns. This study assessed Tx patterns, resource use, and associated costs for a select cohort of patients (pts) from Spain. Methods: Via an internet-based chart review, 50 physicians provided clinical and resource use data for 5 de-identified pts each. Medical records were eligible if the pt was ≥18 years old, was diagnosed with advanced HCC, initiated first-line SOR after 2008, subsequently discontinued SOR, survived ≥2 months post-SOR DC, and had ≥6 months of follow-up data (or had died). Unit costs for healthcare resources were obtained from publicly-available sources and applied to the number of each resource type to obtain cost estimates. All analyses were descriptive in nature. Results: From September to October 2012, physicians provided data for 250 pts. Mean pt age was 61 years and 73% were male. At SOR initiation, 35% were Barcelona Cancer Liver Clinic stage B and 63% C. From SOR initiation to DC, 43% declined in Child-Pugh status. Following SOR DC, inpatient hospitalization was reported for 45% and emergency room visits for 49%. For those reported as having received supportive care (n=209), 73% received pain interventions, 42% nutritional support, 33% antiemetics, and 17% transfusions. 28% received anti-cancer Tx (chemotherapy, procedures). For all pts, hospitalization represented about half of total costs. For pts who received further anti-cancer Tx, chemotherapy and procedures represented about one-third of costs and hospitalization less than one-third. Total costs per pt are summarized (Table). Conclusions: Following sorafenib DC, most advanced HCC pts who we studied did not receive further anti-cancer Tx. Those who received further anti-cancer Tx had greater total healthcare costs, but these costs accrued over a longer period of time. [Table: see text]

Phase I dose escalation study of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis.

TPS3111 Background: Pts with advanced HCC have limited treatment options. Sorafenib, the current standard of care, achieves only modest overall survival improvements. There is a clear etiologic association between HCC and prior/concurrent hepatitis B (HBV) or C (HCV) infection. Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation when bound by ligands including PD-L1/L2. PD-L1 overexpression has been noted on HCC tumors, and PD-1/PD-L1 interaction may contribute to viral hepatitis induced T-cell exhaustion. Nivolumab, a PD-1 receptor blocking antibody, has shown efficacy against various solid tumor types in Ph 1 trials. We hypothesized that blockade of PD-1/PD-L1 interaction could enhance T-cell activation and mediate antitumor and/or antiviral activity in HCC pts. We describe a phase I, dose-escalation study of nivolumab in advanced HCC pts. Methods: Successive pt cohorts with histologically confirmed advanced HCC with/without HBV or HCV infection (N=72 max) will be treated on 3 distinct arms with IV nivolumab at 0.3, 1 and 3.0 mg/kg (uninfected or HCV-infected pts) or 0.1, 0.3, 1 and 3.0 mg/kg (HBV-infected pts) every 2 weeks using a 3+3 escalation scheme. Pts must have progressive disease or intolerance after ≥1 line of therapy or have refused sorafenib treatment, and a Child-Pugh class A. HBV-infected pts must be receiving antiviral therapy (viral DNA <100 IU/mL) for ≥3 months. Pts with brain metastasis, encephalopathy, prior/current ascites requiring paracentesis, history of recent variceal bleeding, active coinfection with HIV, or both HBV and HCV, or concurrent hepatitis D and HBV infection will be excluded. Primary endpoints include characterization of safety, tolerability, dose-limiting toxicities and maximum tolerated dose of nivolumab. Secondary endpoints include assessment of the preliminary antitumor activity (per modified RECIST for HCC), PK and immunogenicity. Exploratory endpoints include evaluation of the relationship between tumor PD-L1 expression and clinical outcome, and nivolumab’s antiviral and immunoregulatory activity in peripheral blood and/or tumor specimens. Clinical trial information: NCT01658878.