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TPS498 Background: Hepatocellular carcinoma (HCC) is among the most common and deadliest cancers worldwide. In the intermediate stage the current standard of care is locoregional treatment with transarterial chemoembolization (TACE). The IMbrave150 phase 3 study has demonstrated that the combination of atezolizumab, an anti-PD-L1 antibody, and bevacizumab, an anti-VEGF antibody (atezo/bev), extends survival in comparison to sorafenib in the first-line setting in advanced HCC[1] which has led to its approval for patients with unresectable HCC. However, it is unknown whether atezo/bev is more efficacious than TACE for the treatment of intermediate HCC. ABC-HCC (NCT04803994) is a phase 3b, randomized, multicenter, open-label, investigator-initiated trial of atezo/bev versus TACE in intermediate stage HCC with high tumor burden exceeding the Milan criteria. Methods: The ABC-HCC study is recruiting patients ≥18 years of age who have a confirmed diagnosis of HCC in the intermediate stage (multifocal, exceeding the Milan criteria, no extrahepatic spread, no macrovascular invasion) and no curative treatment option. In addition, patients must have an ECOG performance status of 0, preserved liver function (Child-Pugh A), and ≥2 untreated lesions with a diameter > 10 mm and arterial hyperenhancement on cross-sectional imaging. Those who have previously received locoregional or systemic treatment are excluded. 434 patients will be randomly assigned 1:1 to systemic treatment (atezo at 1200 mg IV plus bev at 15 mg/kg IV) once every three weeks or to TACE. Both conventional and DEB-TACE are allowed. Region, AFP level (< 200 ng/mL vs. ≥200 ng/mL), and ALBI (1 vs. 2) will be used for stratification. Cross-sectional imaging (CT/MRI) will be performed every 8 weeks to determine the time to failure of treatment strategy, a novel primary endpoint. Failure of strategy is reached in case of progressive disease and any of the following: loss of clinical benefit, unacceptable toxicity, liver function deterioration, and therapy not further applicable for other reasons. Secondary endpoints are overall survival (OS), OS rate at 24 months, objective response rate, time to progression, time to loss of systemic treatment options, progression-free survival, duration of treatment, duration of response, time to deterioration of liver function, safety, and quality of life (EORTC QLQ-C30 and HCC18). Patients will be followed for survival, quality of life and subsequent anti-cancer therapy every 12 weeks after the end of study treatment. Recruitment for this study began in July 2021. FF, RK, JB and PRG contributed equally. References: 1. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894-905. doi: 10.1056/NEJMoa1915745. Clinical trial information: NCT04803994.

TPS349 Background: TACE is the most widely used locoregional therapy recommended for patients with intermediate-stage HCC (Barcelona Clinic Liver Cancer stage B). Despite the significant tumor responses that can be achieved with TACE, tumors commonly recur, progress, or are refractory. Clinical trials have explored the combination of TACE with tyrosine kinase inhibitors; however, these have not reported improved outcomes. HCC possesses a unique immunosuppressive microenvironment, which makes it an attractive target for immunotherapies, particularly immune checkpoint inhibitors. Furthermore, there is evidence that locoregional interventions induce changes in the immune environment that could promote synergy with checkpoint inhibitors. Preliminary data for the combination of TACE with nivolumab indicate an acceptable safety profile and promising efficacy (Harding et al. ASCO-GI 2020). NIVO monotherapy and NIVO+IPI combination therapy are both approved in the United States for patients with HCC previously treated with sorafenib. Together, these findings support investigation of TACE plus NIVO, IPI, or NIVO+IPI to address the therapeutic needs of patients with intermediate HCC. Methods: CheckMate 74W is a global, double-blind, placebo-controlled, 3-arm, randomized phase III trial. Patients with tumors that exceed the Beyond Milan and Up-to-7 criteria (7 being the sum of size [in centimeters] and number of tumors), eligible for TACE, with Eastern Cooperative Oncology Group performance status of 0 to 1 are eligible for enrollment. Patients must not have received prior locoregional therapies. Approximately 765 patients will be randomized in a 1:1:1 ratio to NIVO+IPI+TACE (arm A), NIVO+IPI placebo+TACE (arm B), or NIVO placebo+IPI placebo+TACE (arm C). Primary endpoints are the time to TACE progression (TTTP), assessed by blinded independent central review, and overall survival in arm A versus arm C. Secondary endpoints are TTTP and overall survival in arm B versus arm C, event-free survival, and progression-free survival. Clinical trial registry: NCT04340193. Clinical trial information: NCT04340193.

12049 Background: There is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low dose therapy with the aim to avoid toxicities whilst maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) of patients with HCC, and whether a reduced starting dose of sorafenib impacts on OS or rates of toxicity experienced by the elderly. Methods: In this international, multicentre cohort study, patients with a confirmed diagnosis of advanced-stage HCC receiving sorafenib were recruited from seven specialist centres. Demographic and clinical data including development and grade of sorafenib toxicity and sorafenib starting dose were collected prospectively. Survival time (months) was recorded prospectively. Outcomes for those < or > 75 years were determined Results: A total of 5598 patients were recruited; 792 (14.1%) were over the age of 75. The elderly were more likely to have larger tumours ( > 7cm)(39 vs 33%, p = 0.07) with Child-Pugh A liver function(67 vs 57.7%) and less portal vein thrombosis compared to those < 75years(22.1 vs 29.4)(p < 0.001). They were more likely to be commenced on lower starting dose of sorafenib i.e 400mg/200mg (38.7 vs 37.2%, P < 0.01). In terms of OS, there was no difference in the median OS of those >75 years and patients < 75 (7.3months vs 7.2months; HR 0.98 (95% CI 0.90–1.06), p = 0.63). There was no relationship between starting dose of sorafenib, 800mg vs 400mg/200mg, and OS between those < or > 75years. The elderly experienced a similar incidence of grade 2-4 sorafenib-related toxicity compared to < 75years(74.3 vs 61.7%, p = 0.051)(except for anorexia (14.0 vs 7.2%, p < 0.01) and rash (3.1 vs 6.3%, p < 0.05), irrespective of the dose prescribed. The elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p < 0.01). This did not vary between different starting doses of sorafenib. The mean duration of treatment was similar between those < and > 75 and, again, the starting dose of sorafenib did not affect treatment duration in the elderly. Conclusions: The median OS in the elderly is the same for that of patients under 75 years and is independent of the dose of sorafenib prescribed. Therefore, sorafenib should be offered to elderly patients and they should not be excluded from therapy

483 Background: SOR is approved as 1L therapy for pts with aHCC, but there is still an unmet need to help improve or maintain HRQoL. This phase 3 study compared HRQoL of NIVO vs SOR as 1L therapy in pts with aHCC as an exploratory endpoint. Methods: FACT-Hep was administered cycle 1, day 1 and every other cycle. The effect of NIVO vs SOR on HRQoL using FACT-Hep was assessed via repeated measures mixed models (MMRM). Kaplan–Meier curves and Cox proportional-hazards models determined between-treatment differences in time to first and time until definitive deterioration (TTD/TUDD) based on prespecified thresholds for minimally important differences. The GP5 item from FACT-Hep was used to assess the burden associated with treatment side effects. Results: 743 pts with aHCC were randomized to NIVO (n = 371) or SOR (n = 372). Median OS was 16.4 mo for NIVO, 14.7 mo for SOR (HR 0.85 [95% CI 0.72–1.02]; P = 0.0752). ORR was 15% for NIVO, 7% for SOR (OR 2.41 [95% CI 1.48–3.92]). HRQoL scores were completed at baseline by 94.6% and 92.5% of participants, respectively, and were similar (FACT-Hep total: NIVO 140.7 [SD 21.5] and SOR 140. 6 [SD 19.1]. Questionnaire compliance rates exceeded 70% at most visits. MMRM analyses yielded clinically meaningful and statistically significant least squares means differences favoring NIVO on FACT-Hep total (10.1 [95% CI 7.3–13.0]), physical well-being (PWB; 2.0 [95% CI 1.4–2.6]), and functional well-being (FWB; 2.5 [95% CI 1.7–3.2]) scores. No sub-scales favored sorafenib. TTD was significantly delayed in NIVO for FACT-Hep total (HR 0.62 [95% CI 0.51–0.74]), PWB (HR 0.62 [95% CI 0.52–0.74]), FWB (HR 0.73 [95% CI 0.61–0.88]), and hepatobiliary cancer subscale (HR 0.57 [95% CI 0.48–0.69]). TUDD results were consistent with TTD. A greater proportion of NIVO pts did not experience increased burden of side effects (50%–67.7%) compared with SOR (26.8%–45%) based on the GP5 item. Conclusions: These patient-reported findings demonstrate that pts taking NIVO had superior HRQoL and reduced side effect burden, further supporting clinical data showing a treatment benefit for 1L NIVO in aHCC. Clinical trial information: NCT02576509.

TPS4157 Background: C inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER). C is approved for treatment of aHCC after prior S based on improved overall survival (OS) vs placebo in the phase 3 CELESTIAL trial (Abou-Alfa NEJM 2018). Standard of care for first-line treatment of aHCC is tyrosine kinase inhibition with S or lenvatinib, and phase 3 trials of immune checkpoint inhibitors (ICIs) in first- and second- line aHCC are ongoing. C may promote an immune-permissive tumor environment, which could enhance response to ICIs. C is being evaluated in combination with the anti-PD-L1 antibody A in multiple tumor types including HCC in a phase 1 study; and dose, preliminary clinical activity, and safety have been established in aRCC (Agarwal Ann Oncol 2018). A in combination with bevacizumab, an anti-VEGF antibody, has shown preliminary clinical activity in first-line aHCC (Pishvaian Ann Oncol 2018). Here, we present the study design of a phase 3 trial of C+A vs S in pts with aHCC who have not received prior systemic therapy. Methods: This international, randomized, open-label phase 3 trial (NCT03755791) is evaluating the efficacy and safety of C+A vs S as first-line treatment for aHCC. Eligibility criteria include age ≥18 years, BCLC stage B or C, Child-Pugh A, ECOG PS 0 or 1, and measurable disease per RECIST 1.1. Patients are randomized 6:3:1 to an experimental arm of C (40 mg qd) + A (1200 mg infusion q3w), a control arm of S (400 mg bid), and an exploratory arm of C monotherapy (60 mg qd). 640 pts are planned at ~200 sites globally. Randomization is stratified by disease etiology (HBV [with or without HCV], HCV [without HBV], or other), region (Asia, other), and the presence of extrahepatic disease and/or macrovascular invasion (yes, no). OS and progression-free survival are coprimary endpoints and objective response rate is a secondary endpoint. Additional endpoints include safety, pharmacokinetics, and correlation of biomarker analyses with clinical outcomes. Enrollment in COSMIC-312 is ongoing. Clinical trial information: NCT03755791.

Purpose Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer. Patients and Methods Patients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS). Results Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B–infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C–infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%). Conclusion OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B–infected patients. OS was superior in hepatitis C–infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.

423 Background: AFP response, defined as a decrease in serum levels of the tumor marker AFP after therapy, may be associated with improved survival of patients (pts) with HCC treated with locoregional or systemic therapy, and high baseline AFP levels may be associated with poor prognosis. In the phase III CELESTIAL trial (NCT01908426), C, an inhibitor of MET, VEGFR, and AXL, significantly improved overall survival (OS) and progression-free survival (PFS) versus P in pts with previously treated advanced HCC. Here we evaluate clinical outcomes with C in CELESTIAL based on AFP response or progression on treatment. Methods: 707 pts were randomized 2:1 to receive C (60 mg daily) or P. Eligible patients had a pathologic diagnosis of HCC, Child-Pugh score A, and ECOG PS ≤ 1. Pts received prior sorafenib and ≤ 2 lines of prior systemic therapy for HCC. Serum AFP levels were measured centrally at baseline and every 8 weeks thereafter. Outcomes were evaluated for pts with baseline AFP ≥ 20 ng/mL based on AFP response ( ≥ 20% decrease from baseline) or progression ( ≥ 20% increase from baseline) at Week 8. This definition of AFP response has been used in previous studies but requires further validation in large prospective studies. Results: Overall, 331 pts (70%) in the C arm and 160 (68%) in the P arm had baseline AFP ≥ 20 ng/mL; among these pts, 236 (71%) and 111 (69%), respectively, were evaluable for AFP response at week 8. Among evaluable pts, 117 pts (50%) in the C arm vs 14 (13%) in the P arm had an AFP response, and 72 (31%) vs 75 (68%) had AFP progression. Median OS with C was 16.1 mo for pts with an AFP response versus 9.1 mo for pts without a response (HR 0.61, 95% CI 0.45-0.84), and median PFS with C was 7.3 mo versus 4.0 mo (HR 0.55, 95% CI 0.41-0.74). For pts with AFP progression, median OS with C was 8.1 mo, and median PFS with C was 3.6 mo. Hazard ratios for OS and PFS with C also favored AFP responders over non-responders when analyzed using best response through week 24. Conclusions: The AFP response rate was higher with C versus P, and AFP response was associated with longer OS and PFS with C for pts with previously treated advanced HCC. On-treatment AFP changes warrant further evaluation as a biomarker of response. Clinical trial information: NCT01908426.

186 Background: In REFLECT, Lenvatinib (LEN) demonstrated treatment effect on overall survival (OS) by statistical confirmation of noninferiority to sorafenib (SOR). OR rates for LEN versus SOR were: 24% versus 9% by investigator review and 41% versus 12% by independent review (Kudo et al 2018). Since the relationship between OR and OS in phase III HCC studies is unclear, we explored the relationship between OR and OS in REFLECT. Methods: OR assessed by investigators per mRECIST were used to analyze the association between OR and OS of pts treated with LEN or SOR. The median OS of responders (CR or PR) was compared to that of nonresponders (SD, PD, or UNK/NE) irrespective of treatment. Landmark analyses were performed by OR status at several fixed time points as sensitivity analyses, and the effect on OS was evaluated by Cox regression with OR as a time-dependent covariate, with other prognostic factors. Results: Median OS was 22.4 months for responders and 11.4 months for nonresponders. Hazard ratios (HR) of landmark analyses at 2, 4, and 6 months were 0.75 (95% CI, 0.57–0.98), 0.72 (95% CI, 0.56–0.92), and 0.73 (95% CI, 0.57–0.93). Independent predictors of OS based on unstratified Cox regression are in the table. Conclusions: In REFLECT, OR was an independent predictor of OS in pts with HCC regardless of treatment. The results indicate this correlation is worth further investigation. Clinical trial information: NCT01761266. [Table: see text]

4088Background: C inhibits tyrosine kinases including MET, VEGFR, and AXL. In the CELESTIAL trial, C improved overall survival (OS) and progression-free survival (PFS) compared with P in pts with a...

207 Background: C, an inhibitor of MET, VEGFR, and AXL, has previously shown clinical activity in pts with advanced HCC. This phase 3 trial (NCT01908426) evaluated C vs P in previously treated pts with advanced HCC. Methods: In this double-blind, global, phase 3 trial, pts were randomized 2:1 to receive C (60 mg qd) or matched P stratified by disease etiology (HBV, HCV, other), geographic region (Asia, other), and presence of extrahepatic spread and/or macrovascular invasion (EHS/MVI). Eligible pts had pathologic diagnosis of HCC, Child-Pugh score A, ECOG PS ≤1, and must have received prior sorafenib. Pts received up to two lines of prior systemic therapy for HCC and must have progressed following at least one. The primary endpoint was overall survival (OS). Secondary endpoints were investigator-assessed progression-free survival (PFS) and objective response rate (ORR) per RECIST 1.1. The study was designed to detect a hazard ratio (HR) for OS of 0.76 (90% power, 2-sided α = 0.05) at the final analysis with two prespecified interim analyses at 50% and 75% of the planned 621 events. Results: As of 1 Jun 2017, 707 pts were randomized, and 484 deaths had occurred (317 out of 470 for C; 167 out of 237 for P). Baseline characteristics were balanced between the two arms: median age was 64 years, 82% were male, 38% had HBV, 24% had HCV, 25% enrolled in Asia, 78% had EHS, 30% had MVI, 85% had EHS/MVI, and 27% had received two prior systemic therapy regimens for advanced HCC. The study met the primary endpoint at the second planned interim analysis with median OS 10.2 mo for C vs 8.0 mo for P (HR 0.76, 95% CI 0.63-0.92; p = 0.0049). Median PFS was 5.2 mo for C vs 1.9 mo for P (HR 0.44, 95% CI 0.36-0.52; p < 0.001), and ORR was 4% vs 0.4% (p = 0.0086). The most common grade 3/4 adverse events (predominantly grade 3) with higher incidence in the C vs P arm included hand-foot skin reaction (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%). Conclusion: C significantly improved OS and PFS vs P in previously treated pts with advanced HCC. Adverse events were consistent with the known safety profile of C. Clinical trial information: NCT01908426.

4001 Background: SOR is the only approved agent in uHCC and new options are needed. LEN, an inhibitor of vascular endothelial growth factor receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet derived growth factor receptor α, RET, and KIT, showed activity in uHCC in a phase II trial. We report a phase III trial of LEN vs SOR as first-line therapy for uHCC. Methods: In this randomized, open-label, noninferiority (NI) study, pts had uHCC, ≥ 1 measurable target lesion, Barcelona Clinic Liver Cancer stage B or C, Child-Pugh class A, ECOG PS ≤ 1, and no prior systemic therapy. Pts were randomized 1:1 to LEN (body weight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) or SOR 400 mg twice daily. The primary endpoint was overall survival (OS). The OS hazard ratio (HR) and its 95% CI were estimated with a stratified Cox proportional hazard model. The predefined NI margin was 1.08. Secondary efficacy endpoints were progression-free survival (PFS), time to progression (TTP) and objective response rate (ORR) by modified RECIST. Type I error rates for secondary efficacy endpoints were controlled with a fixed sequence procedure at 2-sided α = 0.05 after OS NI was claimed. Results: 954 Pts enrolled (LEN: 478; SOR: 476). Efficacy outcomes are shown in the table. A similar number of pts in both arms had treatment-emergent adverse events (TEAEs). Most common LEN TEAEs were hypertension (42%), diarrhea (39%), decreased appetite (34%), decreased weight (31%), and fatigue (30%). Median (range) treatment duration was 5.7 mos (0−35.0) for LEN and 3.7 mos (0.1−38.7) for SOR. 13% Of LEN-treated and 9% of SOR-treated pts discontinued due to adverse events. 33% Of LEN-treated and 39% of SOR-treated pts received second-line therapy. Conclusions: LEN is noninferior in OS, and achieves statistically significant and clinically meaningful improvements in PFS, TTP, and ORR, as first line therapy for uHCC. TEAEs were consistent with the known LEN safety profile. Clinical trial information: NCT01761266. [Table: see text]

238 Background: Contrast-enhanced dynamic computed tomography (CT) is preferred for initial diagnosis and post-treatment monitoring of hepatocellular carcinoma (HCC). The risk of a second cancer with diagnostic and monitoring CT radiation exposure in HCC patients is unclear. Methods: We analyzed cumulative radiation dose (CRD) for diagnostic and monitoring CT with/without transarterial chemoembolization (TACE) in patients with HCC alone (HA group) and HCC patients with a second cancer (SC group), using the big dataset of the National Health Insurance of South Korea. We performed survival analysis, with death treated as a competing risk. Results: A total of 20,073 patients with HCC were enrolled. With a median follow-up of 5.7 years, the SC group comprised 2,005 patients, resulting in a standardized incidence ratio of 1.5 (95% confidence interval [CI], 1.4-1.6) in men and 1.7 (95% CI, 1.6-1.9) in women, as compared with the general population. Use of CT/positron emission tomography (PET) was significantly higher in the SC group (p300 mSv significantly increased the risk of second malignant neoplasms in the subgroup with >7 years of follow-up (YFU) (hazard ratio [HR] 2.01, 95% CI 1.38-2.92, p300 mSv and over 7 YFU (HR 2.41, 95% CI 1.26-4.62; HR 5.69, 95% CI 1.62-20.04, respectively, p300 mSv and over 7 YFU. Conclusions: The risk of second cancers increased in HCC patients who survived over 7 years with CRD >300 mSv. Consideration of alternative monitoring tests and guidelines for reducing radiation exposure is crucial for long-term HCC survivors.

TPS4147Background: HCC is the fifth most prevalent cancer globally and the second-leading cause of cancer-related deaths. The high mortality rate is typically due to the late stage of disease at di...

329 Background: A randomised, double-blind phase II study of axitinib plus BSC [AXI] vs placebo plus BSC [PBO] was conducted in HCC pts after failure of one antiangiogenic therapy. Primary outcome was presented at ESMO 2014. No significant differences in overall survival (OS) between two arms were noted overall and in pre-specified subgroup analysis (non-Asian [nA] and Asian [A]). Interestingly, improvements favouring AXI (P < 0.01) were observed in secondary efficacy endpoints and retained among A. Methods: Exploratory efficacy/safety/biomarker analyses were performed by geographic region (nA; A; A subgroups: Japan/Korea [JK] and China/Hong Kong/Taiwan [CHT]) including: OS excluding pts intolerant to prior therapy; relationship between a subset of 26 baseline micro RNAs (miR) and AXI effect. Results: 78 nA pts (76% male, 60% with vascular invasion/extrahepatic spread) and 124 A pts (73JK/51CHT) (86% [84% JK, 90% CHT] male; 86% [82% JK, 92% CHT] with vascular invasion/extrahepatic spread) were randomized. In regional subgroups, OS HR excluding pts intolerant to prior therapy was: nA HR = 0.700 (95% CI 0.373–1.316; p = 0.1318) for AXI (45) vs PBO (16); A HR = 0.653 (95% CI 0.415–1.027; p = 0.0312) for AXI (76) vs PBO (35); JK HR = 0.479 (95% CI 0.250–0.918; p = 0.0118) for AXI (46) vs PBO (17); CHT HR = 0.918 (95% CI 0.480–1.756; p = 0.3954) for AXI (30) vs PBO (18). AXI safety profile was generally similar in regional subgroups. Differences were seen in dose modification pattern: dose reduction or discontinuation due to adverse events in 24% nA / 41% A / 51% JK / 26% CHT or in 39% nA / 22% A / 16% JK / 32% CHT, respectively. miR analysis for OS showed a trend of predictive and/or prognostic effect in overall population (e.g., let-7e-5p); a strong predictive effect of multiple miR (e.g., miR-3648) was seen in A but not in nA. Conclusions: AXI showed favorable OS vs PBO in nA and A, particularly in JK, when pts intolerant to prior therapy were excluded, suggesting that pts who progress on prior therapy are more suitable population for new agent studies in HCC. Appropriate dose modifications may also play a role in treatment duration. Baseline miR signature may have predictive value for AXI OS in A. Clinical trial information: NCT01210495.

4084 Background: mRECIST (modified Response Evaluation Criteria In Solid Tumors) was developed to overcome the limitations of standard RECIST in hepatocellular carcinoma (HCC) response assessment. Retrospective studies have correlated objective response (OR) by mRECIST with overall survival (OS) in patients treated by loco-regional therapies. We investigated whether OR by mRECIST predicted OS using data from a double-blind, placebo-controlled, randomized phase III trial. Methods: In the BRISK-PS study, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib plus best supportive care (BSC) or placebo plus BSC. Tumor assessments were performed every 6 weeks by contrast-enhanced computed tomography or magnetic resonance imaging. Assessment of response was done by central radiological review using mRECIST. Multivariate models using time-dependent covariate analysis defined variables with independent prognostic value (SPSS 18 and S...

308 Background: Reliable biomarkers are required to predict patient response to sorafenib. We attempted to investigate genomic variations associated with responsiveness to sorafenib treatment in patients with unresectable hepatocellular carcinoma (HCC) and their functional relevance. Methods: We obtained blood samples from 4 strong and 3 poor responders to sorafenib treatment and subjected these samples to whole-genome analysis. Next, we performed validation tests for candidate single-nucleotide polymorphisms (SNPs) in the samples of 174 HCC patients who were treated with sorafenib, followed by in vitro functional analysis and in silico analyses of candidate SNPs. Results: On average, 90 gigabases/sample was generated at ~34X sequencing depth. In total, 1813 genomic variations were perfectly matched to sorafenib responses in the clinical data; 708 were located within regions for sorafenib-target genes or drug absorption, distribution, metabolism, and excretion (ADME)-related genes—36 within the coding regions and 6 identified as non-synonymous single-nucleotide variants from 4 ADME-related genes (ABCB1, FMO3, MUSK, and SLC15A2), which potentially cause functional alterations. Validation tests of 174 patients confirmed sequencing results and revealed that patients with the C/C genotype for rs2257212 in SCL15A2 displayed higher risk for cancer progression than did patients with C/T or T/T genotypes (HR: 2.18; 95% CI, 1.15–4.15; P = 0.018). In vitro functional analysis revealed that cells harboring C/C genotype for this SNP displayed lower response to sorafenib treatment than did cells harboring the T/T genotype. Structural prediction analysis revealed change in protein phosphorylation levels, potentially affecting sorafenib-associated enzymatic activity. Conclusions: SLC15A2 could be a robust biomarker of response to sorafenib treatment in HCC patients.

4102 Background: RO5137382/GC33 (GC33) is a humanized monoclonal antibody against GPC3 that is frequently expressed in HCC. GC33 interacts with CD16/FcγR3 and triggers antibody-dependent cytotoxici...

4033 Background: HCC is a major health problem across the world. The global HCC BRIDGE study is the first global, large-scale, observational study to document the real-world experience of HCC patients from diagnosis to death. Methods: This longitudinal cohort study (started March 2009) includes HCC patients newly diagnosed between January 2005 and June 2011 and treated at major medical centers, with data collected retrospectively and prospectively as recorded in patient charts. Full patient enrollment is expected at the end of January 2012. Results: At the time of the first interim analysis (July 2011), 12,442 treated HCC patients were enrolled at 42 sites in Asia (n=8909, 72% [China: n=6295, 71%; Japan: n=295, 3%]), Europe (n=2040, 16%) and North America 1493 (n=1493, 12%). Mean age was 57 years; 82% were male. The predominant risk factor was HBV in Asia (76%) and HCV in Europe (48%), North America (45%) and Japan (69%). Most patients were diagnosed without surveillance (Asia, 82%; Europe, 73%; North America, 69%; Japan, 64%). In Asia, Europe and North America, the predominant BCLC stage at diagnosis was C (48%, 46%, 46%) followed by A (34%, 28%, 26%). First recorded treatments in Asia, Europe and North America were resection (31%, 15%, 21%), transplantation (1%, 3%, 1%), TACE (49%, 30%, 36%), other locoregional therapy (12%, 35%, 23%) and systemic therapy (3%, 10%, 8%). Treatments ever used (2005–2011) in Asia, Europe and North America were resection (33%, 17%, 24%), transplantation (2%, 6%, 12%), TACE (57%, 35%, 48%), other locoregional therapy (20%, 42%, 37%) and systemic therapy (9%, 20%, 21%). These results will be updated with data from the full study population (approx. 19,000 patients), and preliminary survival data will be presented. Conclusions: As the largest study of its type, in 19,000 patients worldwide, the HCC BRIDGE study provides valuable insights into global HCC disease characteristics and patient management. Based on prior analyses, differences in risk factors among regions confirm well-known trends, while other observed differences (e.g., treatment variations) may be related to country- and site-specific practices and patient characteristics.

4103 Background: Sorafenib (S) is the only approved systemic treatment for unresectable HCC. Nevertheless, there remains an unmet medical need for more effective treatment options for this disease. BAY 86-9766 (B) is an oral, allosteric inhibitor of MEK, a key component of the MAP kinase pathway. This study evaluated the efficacy and safety of a combination therapy with B plus S in patients (pts) with HCC. Methods: This is a single arm, open-label, phase 2 study. Eligible were pts with unresectable HCC, Child-Pugh Class A, performance status (PS) 0-1, and no prior systemic anticancer therapy for HCC. Pts started Cycle 1 (21 days) with B 50 mg bid orally plus S 600 mg daily (200 mg AM, 400 mg PM) orally. If there was no hand-foot skin reaction, fatigue, or gastrointestinal toxicity ≥ grade 2, S was escalated to 400 mg bid from Cycle 2 on. Treatment continued until progression or withdrawal criteria were met. Tumor assessment was performed every 6 weeks during treatment. Safety was evaluated every week for the first 6 weeks and every 3 weeks thereafter. Results: Seventy pts from Asia started study treatment. Pts were predominantly male (86%); median age was 56 years; 54% had PS of 0 and 46% PS of 1. The vast majority had liver cirrhosis (83%) and infection with HBV (76%) or HCV (17%). Sixty-five were evaluable for efficacy per protocol. Three pts (5%) had confirmed partial response and 25 pts (38%) had prolonged stable disease (≥10 weeks), with a disease control rate of 43%. Median time-to-progression was 4.1 months. Survival data are not mature, yet. The most frequent drug-related adverse events (AEs) were rash (60%), diarrhea (59%), AST elevation (43%), vomiting (30%), nausea (29%), ALT elevation (26%), and anorexia (26%). There were 4 Grade 5 related AEs (hepatic failure, sepsis/hepatic encephalopathy, tumor lysis syndrome, and unknown cause, respectively). Dose modifications due to AEs were necessary in almost all pts. The median daily dose was 64.2 mg for B and 443.3 mg for S, respectively. Conclusions: B in combination with S showed antitumor activity in pts with HCC. However, frequent dose modifications due to AEs might have limited the treatment effect of this combination.

4000 Background: The oral multitargeted tyrosine kinase inhibitor Su had antitumor activity in phase II HCC trials, leading to a phase III open-label trial comparing the efficacy and safety of Su with So. Methods: Patients (pts) with advanced HCC, Child-Pugh A, ECOG PS 0/1 and no prior systemic chemotherapy were stratified by geographic region, prior TACE and tumor invasion. Pts were randomized 1:1 to Su 37.5 mg/day or So 400 mg BID. The primary endpoint was overall survival (OS; 1-sided log-rank test; α=0.025, 90% power) with 600 pts/arm required in this superiority/non-inferiority trial design. Secondary endpoints were progression-free survival (PFS), time to progression (TTP) and safety. Efficacy and futility boundaries were set using the Lan-DeMets and O’Brien–Fleming methods for interim analyses. Results: 1,073 pts were randomized (Su 529/So 544) from July 2008 to May 2010. An Independent Data Monitoring Committee stopped the trial early for futility and safety concerns. Pts were notified. Su discont...

4577 Background: Brivanib is an orally available dual inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signaling. FGF pathway activation is of increasing importance in the setting of liver fibrosis and HCC. This phase II study aimed to assess the efficacy and safety of brivanib in patients (pts) with unresectable, locally advanced or metastatic HCC who had received either no prior systemic therapy (Cohort A) or one prior regimen of angiogenesis inhibitor (Cohort B). Methods: Eligible pts had biopsy-proven HCC or had radiological evidence of HCC and were serology positive for Hep B or C with alpha fetoprotein levels ≥ 400 μg/L. Pts received brivanib 800 mg qd. Efficacy endpoints included OS, PFS, TTP, ORR, and DCR. Safety was assessed throughout the study. Serum levels of a biomarker, Collagen IV (a component of the basement membrane of blood vessels), were measured on day 1, weeks 3 and 6, and at end of treatment. Results: Interim results are reported. From December 2006 to October 2008, 96 patients were enrolled (Cohort A: 55 pts; Cohort B: 41 pts). In Cohort B, 38 pts had failed sorafenib and 3 had failed thalidomide. In Cohort A, median OS (95% CI) was 10 (6.8,-) months. Most frequently reported grade 3/4 AEs were fatigue (16%), AST elevation (19%), and hyponatremia (41%) in Cohort A and hypertension (7.3%), diarrhea (4.9%), and headache (4.9%) in Cohort B. 24 pts died in Cohort A and 5 pts in Cohort B, none were considered treatment-related. Treatment-induced reductions in serum Collagen IV appear to correlate with long term outcome (PFS and OS). Conclusions: Brivanib has activity as both first-line and second-line post-sorafenib systemic treatment in HCC. Collagen IV, a novel serum angiogenic biomarker, appears to be associated with outcome. [Table: see text] [Table: see text]