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Background: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase related to the lipid kinases of the phosphoinositide 3-kinase (PI3K) family, which has been confirmed to be closely related to the development of a variety of human cancers. Onatasertib (ATG-008) is a 2nd generation mTOR inhibitor which inactivates both mTORC1 and mTORC2. Our previous clinical investigation (NCT01177397) has demonstrated preliminary evidence of antitumor activity of onatasertib across multiple solid and hematologic malignancies, with encouraging signals of activity in subjects with hepatitis B virus (HBV)+ unresectable, refractory HCC. Methods: Asian patients with advanced HBV+ HCC who had experienced progressive disease after at least 1 line of systemic therapy were enrolled in this study. Onatasertib was administered orally once a day (QD) at 3 dose levels (15 mg, 30 mg and 45 mg) or 20 mg twice daily (BID). The primary endpoints were pharmacokinetics (PK), safety and efficacy (NCT03591965). Results: As of July 11, 2022, 73 patients were enrolled and evaluated. The median age was 52.0 years and the median follow up duration was 26.5 months. The mean number of prior lines was 1.8. 63 patients (86.3%) had at least one Grade 3-4 treatment emergent adverse event (TEAE), and 25 (34.2%) had at least one serious adverse event (SAE). Among the 73 subjects, 3 achieved confirmed partial response (PR), all in the 45 mg QD cohort. 18 pts were enrolled in the 45 mg QD cohort, in which 11 (61.1%) pts had received at least 2 prior lines of systemic therapy and 15 (83.3%) pts had been exposed to an anti-PD-1/PD-L1 antibody. The overall response rate (ORR) in the 45 mg QD cohort was 16.7%. The median progression-free survival (mPFS) was 3.0 months (95% CI 1.9, 4.6) in the intention to treat (ITT) population and was 5.3 months (95% CI 1.9, 7.6) in the 45mg QD cohort. Median overall survival time (mOS) was not evaluable in the 45 mg QD cohort and the mOS was 13.4 months (95% CI 7.4, 19.8) in the ITT population. Onatasertib demonstrated linear pharmacokinetics between 15 mg QD and 45 mg QD in this Asian population and there was no significant exposure accumulation after multiple dosing, as previously seen in the US population. Conclusion: Onatasertib (ATG-008) showed encouraging single agent antitumor activity in patients with HBV+ advanced HCC after at least 1 prior systemic therapy, notably in the 45 mg QD dose level, in which most patients had been previously exposed to anti-PD-L1/PD-1 therapy. The results indicates that onatasertib has potential efficacy in HBV+ HCC patients who failed prior CPI treatment. Further study may be warranted, particularly in HBV+ HCC patients who have failed prior anti-VEGFR and anti-PDL1/PD-1 therapy. Citation Format: Shukui Qin, Xiaoyan Lin, Zhiqaing Meng, Zhenggang Ren, Yuxian Bai, Shanzhi Gu, Li Zheng, Qiu Li, Sun-Yong Oh, Yabing Guo, Yoong-Koo Kang, Wei-Yu Kao, Wei Li, Jung-Hwan Yoon, Helong Zhang, Pei-Jer Chen, Tsai-Sheng Yang, Jeong Heo, Zhendong Zheng, Hui Xie, Zhinuan Yu. Result of an open-label phase 2 trial of dual TORC1/TORC2 inhibitor onatasertib (ATG-008) in HBV+ advanced hepatocellular carcinoma (HCC) subjects who have received at least one prior line of systemic therapy (TORCH) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT150.

Northwest oilfield M reservoir is deep block sandstone reservoir with strong aquifer, having thin layer, large water-oil volume ratio, high temperature and salinity, strong heterogeneity, being developed more than 20 years by depletion method, influenced by bottom water, reservoir comes into high water cut period, recovery degree is only 26%, requiring for further enhanced oil recovery technology. CO2 is easily miscible with oil, but whether CO2 is applicable for the reservoir with strong aquifer or not is still unclear. No foundation can be referred to in area optimization for CO2 flooding. It is necessary to conduct research on influencing factors of CO2 flooding in the sandstone reservoir with aquifer and set up the favorable target optimization technology. Reservoir engineering method was applied to study M reservoir production pattern. Based on G&G, the geological-dynamic response law was established and productivity influencing factors were studied. Considering flowing differences between block reservoir and layered reservoir, the flowing field is affected by vertical sweep of bottom water, internal small faults have sealing effect on plane sweep, development unit division method was formed on the basis of vertical hydrodynamic characteristics. According to CO2 occurrence state and dynamic distribution in oil layer and strong aquifer, three types of favorable target have been classified, favorable target optimization technology is established for CO2 flooding in deep block sandstone reservoir with strong aquifer. Research results show that the south and middle block are structurally high, edge water intrusion is weak, main layer is relatively thick and interlayer is developed, I and II type well are the main production well. While the north block is structurally low, reservoir quality is poorer, II and III type wells amount a lot. CO2 density is higher than the oil, in the interlayer undeveloped block, CO2 migrates vertically to the oil-water interface, then spreads laterally forced by bottom water, resulting in an increase in the oil-water interface tension and a decrease in the diffusion rate to the water. The more developed the interlayer is, the larger the sweep volume of CO2 is. In high structural position, fault sealing, interlayer developed and thick layer, the enrichment degree of remaining oil is still high, important to ensure CO2 lateral sweep. As results, favorable target for CO2 flooding is classified into I, II and III type. CO2 flooding pilot test was carried out in type I favorable target. Till now, 18,000 tons of CO2 had been injected, oil exchange ratio in 1st year was 0.13. Research results lay the foundation for the efficient utilization of the remaining oil, so as to explore an effective development method for deep, ultra-deep sandstone reservoir to greatly enhanced oil recovery.

570 Background: ORIENT-32 trial (NCT03794440) assessed sintilimab (anti-PD-1 antibody) plus a bevacizumab biosimilar (anti-VEGF antibody) versus sorafenib (Sor) as first-line treatment for unresectable HCC and demonstrated a significant improvement in both overall survival and progression-free survival. Here we report the updated results of objective response rate (ORR), time to response (TTR), duration of response (DoR) and depth of response (DpR). Methods: 571 eligible patients (pts) with unresectable HCC were enrolled and randomized (2:1) to receive sintilimab (200 mg IV Q3W) plus IBI305 (15 mg/kg IV Q3W) or Sor (400 mg orally, BID) until disease progression or unacceptable toxicity. Tumors were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)and HCC-modified RECIST (mRECIST). ORR, TTR, DoR, and DpR were analyzed. The DpR was defined as the minimum percentage of (1) sum of longest diameter (SLD) change and (2) longest diameter (LD) change described as mean (standard deviation, SD). Results: At the data cutoff on Dec 30th, 2021, the median follow-up time was 26.7 months. The ORR in sintilimab plus IBI305 and Sor group was 21.0% (77/367) vs 4.7 (8/169) per RECIST 1.1 and 25.1% (92/367) vs 7.7% (13/169) per mRECIST. The median TTR in sintilimab plus IBI305 group was 2.8 (2.4–3.3) months per RECIST 1.1 and 2.6 (1.6–2.9) months per mRECIST. The median DoR in sintilimab plus IBI305gourp was 20.3 (12.3-NE) months per RECIST 1.1. The minimum percentage of SLD change was larger in the sintilimab plus IBI305 arm than in the Sor arm: (−13.4% (35.8) vs 3.2%(26.5) per RECIST 1.1). Similarly, the LD change in the largest liver lesion also favored sintilimab plus IBI305 arm (−27.6% (31.6) vs −11.5% (20.9)), including larger tumors (≥7 cm; −21.2% (30.4) vs −9.9% (23.7)) all per RECIST 1.1. Conclusions: Sintilimab plus IBI305 showed a significant improvement in ORR, TTR, DOR and DpR vs Sor in unresectable HCC. Clinical trial information: NCT03794440 .

578 Background: Immune checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 have become established treatments for advanced hepatocellular carcinoma (aHCC) but yield low objective response rates (ORRs) in treated patients (pts). Dual inhibition of LAG-3 and PD-1 pathways has demonstrated synergy in activating T-cells and improving immune response. Tebotelimab, also known as MGD013, is a bispecific tetravalent DART molecule that can bind both PD-1 and LAG-3. We initiated an open-label, single-arm, phase 1/2 dose escalation and expansion study to assess the safety and efficacy of tebotelimab in pts with aHCC. Methods: Eligible pts with aHCC who received ≥1 prior systemic treatment with or without prior CPI exposure were enrolled. The dose escalation phase evaluated doses at 120, 240, 400, and 600 mg. Tebotelimab was administered intravenously once every two weeks (Q2W) on days 1 and 15 of each 28-day cycle. The dose expansion phase consisted of one CPI-experienced cohort and one CPI-naïve cohort, both treated at recommended phase 2 dose (RP2D). Primary endpoints were safety for the escalation phase, and safety and ORR per RECIST v1.1 for the expansion phase. Investigator-assessed efficacy results are reported. Results: At data cut-off as of 27 April 2022, 13 pts received tebotelimab in the escalation phase. No dose-limiting toxicity was observed and RP2D was determined as 600 mg Q2W. In the expansion phase, 69 pts (CPI-experienced 33, CPI-naïve 36) were enrolled (median age, 57.0 years; male, 87.0%; ECOG 1, 58.0%; BCLC Stage C, 89.9%; and HBV etiology, 84.1%). Thirteen (18.8%) pts had Grade ≥3 treatment-related adverse events (TRAEs), most commonly hepatic function abnormal (n=3), amylase increased (n=2), and aspartate aminotransferase increased (n=2). Serious TRAEs occurred in nine (13.0%) pts, immune-related adverse events in 30 (43.5%), TRAEs leading to treatment discontinuation in five (7.2%), and treatment-related death in one (1.4%). Of the 30 evaluable pts in the CPI-experienced cohort, one achieved confirmed partial response (PR) and 14 achieved stable disease (SD), with a 3.3% ORR and a 50.0% disease control rate (DCR); of the 30 evaluable pts in the CPI-naïve cohort, four achieved confirmed PR and 10 achieved SD, with a 13.3% ORR and a 46.7% DCR. Median progression-free survival was 2.4 and 3.1 months for CPI-experienced and CPI-naïve cohorts, respectively, with median overall survival not reached in both. Conclusions: Tebotelimab demonstrated a manageable safety profile in pts with aHCC. Antitumor activity, mainly as disease stabilization, was observed in both the CPI-naïve setting and the CPI-experienced setting. No additional clinical trials are planned at this time. Clinical trial information: NCT04212221 .

BackgroundCombining an antiangiogenic agent with an anti-PD-1 agent is a promising strategy for unresectable hepatocellular carcinoma (HCC).AimsTo explore the effectiveness and tolerability of lenvatinib plus camrelizumab vs. lenvatinib monotherapy as a first-line treatment for unresectable HCC.MethodsThis multicenter, retrospective cohort study included patients with unresectable HCC treated with oral lenvatinib 8 mg daily and intravenous camrelizumab 200 mg every 3 weeks (L+C group) or lenvatinib 12 mg or 8 mg daily (L group) in four Chinese centers between September 2018 and February 2020. Tumor response was evaluated according to RECIST 1.1 and mRECIST. The outcomes included objective response rate (ORR), overall survival (OS), 1-year OS rate, progression-free survival (PFS), and safety.ResultsBy March 31, 2021, 92 patients were finally included, with 48 and 44 in the L+C and L groups, respectively. ORR was significantly higher in the L+C group than in the L group (RECIST 1.1: 37.5% vs. 13.6%, P=0.009; mRECIST: 41.7% vs. 20.5%, P=0.029). Median OS and 95% confidence interval (CI) was 13.9 (13.3-18.3) months in the L group and not reached in the L+C group (P=0.015). The 1-year survival rate was 79.2% and 56.8% in the L+C and L groups, respectively. Median PFS was 10.3 (6.6-14.0) months and 7.5 (5.7-9.3) months in the L+C and L groups, respectively (P=0.0098). Combined therapy vs. monotherapy was independently associated with a prolonged OS (hazard ratio=0.380, 95% CI=: 0.196-0.739, P=0.004) and a prolonged PFS (hazard ratio=0.454, 95%CI=0.282-0.731, P=0.001). The safety profile was comparable between the two groups. The most common adverse event in the L+C and L groups was loss of appetite (41.7% vs. 40.9%, P=0.941). Three patients in the L+C group and two in the L group terminated treatment owing to adverse events.ConclusionFirst-line lenvatinib plus camrelizumab showed better effectiveness than lenvatinib alone in patients with unresectable HCC.

e16166 Background: Hepatic arterial infusion chemotherapy (HAIC) showed promising outcomes for advanced hepatocellular carcinoma (HCC) and was recommended in patients with advanced HCC in Asia. HAIC with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX) was most commonly used in China. However, Continuous infusion (over 46 hours) with fluorouracil was inconvenient for arterial infusion. Raltitrexed, another antimetabolic drug with long plasma concentrations half-life, could be used in short infusions. HAIC with raltitrexed plus oxaliplatin (RALOX) was reported to be effective and safe in HCC. This study aimed to compare efficacy and safety of HAIC with raltitrexed plus oxaliplatin versus oxaliplatin plus fluorouracil in intermediate and advanced HCC. Methods: Sixty-six patients with intermediated and advanced HCC were included in this retrospective study between March 2019 and November 2020. Thirty-three patients were treated with HAIC of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracilbolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 46 h, every 3 weeks). Another thirty-three patients received HAIC of RALOX (oxaliplatin 100 mg/m2, raltitrexed3 mg/m2, every 3 weeks). Objective response rate (ORR), diseases control rate (DCR), progression-free survival (PFS) and treatment-related adverse events were analyzed. Results: The ORR was both 33.3% in the FOLFOX group and RALOX group per RECIST 1.1 criteria ( P = 1.00). The DCR was 90.9% and 87.9% in the FOLFOX group and RALOX group, respectively ( P = 1.00). The median PFS was 10.7 months in the FOLFOX group versus 7.9 months in the RALOX group ( P= 0.251). Grade 3/4 treatment-related adverse events were comparable between the two groups, including neutropenia, thrombocytopenia, elevated aminotransferase level and nausea. Conclusions: The efficacy and safety of HAIC with raltitrexed plus oxaliplatin was comparable to HAIC with oxaliplatin plus fluorouracil in intermediate and advanced HCC.

TPS4172 Background: Treatment with PD-1/programmed death ligand 1 (PD-L1) inhibitors and anti-angiogenic agents has demonstrated significant survival improvements in patients with untreated HCC. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory immune checkpoint receptor upregulated on T cells and natural killer cells in multiple solid tumors. OCI is a novel, humanized mAb that binds TIGIT with high specificity and affinity, blocking interaction with its ligands on tumor cells. TIS is an anti-PD-1 mAb that has demonstrated clinical activity in patients with previously treated, unresectable HCC (NCT03419897). BAT1706 is a similar biological product to the anti-angiogenic agent bevacizumab. OCI combined with TIS and BAT1706 could further enhance both anti-angiogenic and anti-PD-1 therapies for patients with HCC. Methods: AdvanTIG-206 is a Phase 2, randomized, open-label clinical study (NCT04948697). Patients aged ≥ 18 years with histologically confirmed advanced HCC that is not amenable to a curative treatment approach are eligible. Patients must have a Child-Pugh A score, ECOG PS ≤ 1, and have received no prior systemic therapy for HCC. Approximately 90 patients will be randomized 2:1 to OCI 900 mg combined with TIS 200 mg plus BAT1706 15 mg/kg (Arm A) or TIS 200 mg plus BAT1706 15 mg/kg (Arm B), all administered intravenously (once every 3 weeks [Q3W]). The primary endpoint is objective response rate as assessed by the investigator (RECIST v1.1). Radiological assessment of tumor response status will be performed Q6W for the first 48 weeks and Q12W thereafter. Secondary endpoints include duration of response, time to response, disease control rate, clinical benefit rate, and progression-free survival (all by investigator’s assessment), overall survival, safety, pharmacokinetics, and immunogenicity. Study enrollment is ongoing. Clinical trial information: NCT04948697.

TPS487 Background: In 2020, there were ̃905,000 new cases and ̃830,000 deaths from liver cancer globally, and a respective 410,038 and 391,152 in China (5-year overall survival [OS]: 14.1%).1,2,3 Hepatocellular carcinoma (HCC) accounts for 75%–85% of liver cancers.1 Transarterial chemoembolization (TACE) is the preferred treatment for patients with intermediate-stage unresectable HCC (uHCC); however, there are issues with the need for repeated dosing and the heterogenous target population (median OS: 13–43 mo). Treatment with TACE + systemic therapy may improve this. Although several trials reported negative results for TACE + sorafenib (sor) vs TACE alone in patients with uHCC, the TACTICS trial showed improved untreatable (unTACEable) progression-free survival (PFS) (25.2 vs 13.5 mo; P= 0.006).4 While promising, the unmet need for combination therapies remains. The recent IMbrave150 trial showed significantly improved OS with atezolizumab (atezo) + bevacizumab (bev) vs sor (19.2 vs 13.4 mo; P= 0.0009) in patients with uHCC5, making it an attractive option for combination with TACE. Methods: TALENTACE (NCT047126430) is a phase III, open-label, randomized study to evaluate the efficacy and safety of TACE + atezo + bev or TACE alone in patients with uHCC. Key inclusion criteria are ≥18 years old, HCC diagnosis, no prior systemic treatment, no prior locoregional treatment of target lesions, eligible for TACE treatment, tumor max diameter + tumor number ≥6, and not a candidate for curative therapy. Patients with tumors that have macrovascular invasion (MVI) or extrahepatic spread (EHS) are excluded. Patients will be randomized (1:1) to receive TACE + atezo + bev or TACE alone. TACE will be performed by clinical demand; atezo (1200 mg) and bev (15 mg/kg) will be administered by intravenous infusion on Day 1 of each 21-day cycle. Co-primary endpoints are independent review committee-determined TACE-PFS (randomization to unTACEable progression, TACE failure/refractoriness, or death) and OS. Secondary endpoints include investigator-determined TACE-PFS; time to unTACEable progression, progression, MVI, EHS, and MVI/EHS; objective response rate, duration of response, patient reported outcomes, and incidence of adverse events. References: Sung, H., et al. CA Cancer J Clin. 2021;71(3):209–249. World Health Organisation: Globocan 2020 – China Factsheet. Available at: https://gco.iarc.fr/today/data/factsheets/populations/160-china-fact-sheets.pdf [accessed 1 June 2021] Allemani, C., et al. Lancet. 2018, 391(10125): 1023–1075. Kudo, M., et al. Gut. 2020;69(8):1492–1501. Finn, RS., et al. J Clin Oncol. 2021;39(no. 3_suppl):267–267. Clinical trial information: NCT04712643.

TPS488 Background: Treatment with PD-1/programmed death-ligand 1 (PD-L1) inhibitors and anti-angiogenic agents has demonstrated significant survival improvements in patients with untreated HCC. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory immune checkpoint receptor upregulated on T cells and natural killer cells in multiple solid tumors. OCI is a novel, humanized mAb that binds TIGIT with high specificity and affinity, blocking interaction with its ligands on tumor cells. TIS is an anti-PD-1 mAb that has demonstrated clinical activity in patients with previously treated, unresectable HCC (NCT03419897). BAT1706 is a similar biological product to the anti-angiogenic agent bevacizumab. OCI combined with TIS and BAT1706 could further enhance both anti-angiogenic and anti-PD-1 therapies for patients with HCC. Methods: AdvanTIG-206 is a phase 2, randomized, open-label clinical study (NCT04948697). Patients aged ≥ 18 years with histologically confirmed advanced HCC that is not amenable to a curative treatment approach are eligible. Patients must have a Child-Pugh A score, ECOG PS ≤ 1, and have received no prior systemic therapy for HCC. Approximately 90 patients will be randomized 2:1 to OCI 900 mg combined with TIS 200 mg plus BAT1706 15 mg/kg (Arm A) or TIS 200 mg plus BAT1706 15 mg/kg (Arm B), all administered intravenously (once every 3 weeks [Q3W]). The primary endpoint is investigator-assessed objective response rate per RECIST v1.1. Radiological assessment of tumor response status will be performed Q6W for the first 48 weeks and Q12W thereafter. Secondary endpoints include duration of response, time to response, disease control rate, clinical benefit rate, and progression-free survival (all investigator-assessed overall survival), safety, pharmacokinetics, and immunogenicity. Study enrollment is ongoing. Clinical trial information: NCT04948697.

BackgroundImmune checkpoint inhibitors (ICIs) have been shown to be a promising and effective treatment for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, there is a lack of evidence-based data demonstrating the impact of ICIs on HBV DNA level in HBV-HCC patients undergoing nucleos(t)ide analog (NA) therapy and of HBV DNA variation on patient survival. In this study, we aimed to investigate this issue in the real world.MethodsIn this single-center retrospective study, we reviewed 182 baseline hepatitis B surface antigen (HBsAg)-positive HBV-HCC patients who were treated with ICIs and pre-emptive NAs. The demographic characteristics, tumor status, treatments, HBV DNA, HBsAg, liver function, antitumor response, and patient survival were investigated. The primary endpoints were the virological breakthrough (VB) rate, HBV reactivation (HBVr) rate, and long-term HBV DNA control; the secondary endpoints were the overall survival (OS) and progression-free survival (PFS).Results(1) VB and HBVr occurred in 18.1% (33/182) and 4.4% (8/182) of patients with a median occurrence time of 3.9 months (range, 0.7–16.0) and 8.0 months (range, 3.0–16.0), respectively. The HBV DNA negative rates were 26.1% and 0 at 24 and 48 weeks in the VB group and 12.5% and 0 in the HBVr group, respectively. A baseline HBsAg level ≥200 IU/mL was the only risk factor for VB (OR 9.9, 95% CI 2.2 to 45.2, p=0.003); (2) patients with VB had much shorter median OS and median PFS than those without (12.3 months vs 18.1 months, p=0.035; 4.5 months vs 7.5 months, p=0.011).ConclusionsThere was a high risk of VB and a moderate risk of HBVr in HBsAg-positive HBV-HCC patients (with poor long-term HBV DNA control) undergoing ICI and pre-emptive NA therapies. The only risk factor for VB was the pretreatment HBsAg level. Further, VB might be considered as a clinical biomarker predicting inferior OS and PFS in the patients.