bluuebunny/crossref_metadata_2025 huggingface dataset:
A sequential therapy with sorafenib followed by regorafenib against single-line atezolizumab and bevacizumab in advanced hepatocellular carcinoma (HCC): Indirect treatment comparisons (ITC) using the RESORCE study.
Authors: Partridge Jamie , Aceituno David , Paracha Noman , Thom Howard
Published: January 2023

537

Background: Our objective was to explore ITC of sequential therapy with sorafenib followed by regorafenib (sorego) against atezolizumab+bevacizumab (atezobev) in HCC. Naïvely comparing median Overall Survival (OS) from sorafenib initiation on sorego in the RESORCE trial with atezobev from IMbrave150 is biased by population imbalance and selection of patients who survived on sorafenib in RESORCE. We used unanchored Matching Adjusted Indirect Comparison (MAIC) and novel survivorship bias adjusted anchored ITC (SBITC) to overcome these limitations. Methods: Overall Survival (OS) from sorafenib initiation in RESORCE on sorego were compared with reconstructed Individual Patient Data (IPD) OS based on Kaplan-Meier curves from IMbrave150 on atezobev. In MAIC, the sorego arm of RESORCE was weighted on reported baseline characteristics to match the IMbrave150 atezobev arm. In SBITC, sorafenib IPD from IMbrave150 were sampled with replacement and added to the RESORCE BSC arm to correct for “survivorship bias”. Sample size was sufficient for follow-up prior to RESORCE randomisation to be within 5% of sorafenib follow-up in IMbrave150. Anchored Bucher ITC was used to compare to unadjusted IMbrave150 with bootstrapping to obtain standard errors. Hazard Ratios (HRs) were used to compare OS. Results: MAIC gave an OS HR of 0.75 (95% confidence interval 0.60, 0.93; p-value=0.007). Effective sample size (ESS) was reduced from 379 to 271.75. SBITC gave a HR of 0.63 (0.52, 0.76; p-value <0.001) requiring an average of 83 sorafenib patients to be added from IMbrave150. Conclusions: We proposed MAIC and SBITC to overcome biases in naïve comparisons of OS on sorego with atezobev in HCC. However, MAIC is limited to baseline characteristics in IMbrave150 and does not adjust for “survivorship bias”. SBITC depends on sample size from IMbrave150, and makes no adjustment for imbalance in baseline characteristics. Despite these limitations, our methods were consistent with naïve comparisons and suggested longer OS with sorego compared to atezobev in patients with HCC.
Malignant portal vein tumor thrombosis (PVTT) in patients with hepatocellular (HCC) carcinoma: Insights from a Western single-institutional cohort.
Authors: Vikash Sindhu , Bteich Fernand , Jiang Julie , Kanmaniraja Devaraju , Acuna-Villaorduna Ana , Saenger Yvonne M. , Goel Sanjay , Kaubisch Andreas
Published: January 2023

552

Background: Macrovascular tumor invasion in the portal vein system is associated with poor survival and response to therapy. The Japanese portal vein invasion (Vp) classification is based on anatomical location of the thrombus and has been reported to predict prognosis in Asian cohorts of patients. Systemic treatment (ST) options have been increasing over the last decade, coupled with a refinement of radiation (RT) delivery and surgical techniques. Modern literature about HCC and PVTT is scarce in the West. Aim of this study was to characterize outcomes of PVTT patients stratified by Vp categories and by treatment strategies in a Western cohort of HCC patients. Methods: A total of 837 patients with HCC, treated at our tertiary referral center between 2010 and 2022, were retrospectively reviewed. 136 (16.3%) patients with PVTT at the time of diagnosis were identified. PVTT was diagnosed by contrast-enhanced computed tomography or magnetic resonance imaging. The extent of portal tumor-in-vein burden was characterized according to the Liver Cancer Study Group of Japan classification. Treatment modalities were delineated. Median OS was calculated for each group. Cox proportional hazard was used to compare OS between groups. Results: Etiology of liver disease was chronic hepatitis B in 18 (13%) patients, chronic hepatitis C in 79 (57%), alcohol in 53 (39%) and NASH in 10 (7%). Our group comprised 8 Vp1, 16 Vp2, 53 Vp3 and 59 Vp4 patients. 42% were in class Child-Pugh A, 42% B and 16% C. 14 (10%) patients underwent surgical resection of their tumor, 31 (23%) received radiation therapy, 90 (68%) were treated with systemic therapy, while 27 (23%) only received best supportive care (BSC). Median OS was 7.2 months in all comers; 16.0, 3.6, and 1.9 months when stratified by Child-Pugh class A, B, C respectively. Patients lived longer when they had more limited PVTT extent (Table). There was a trend towards worse OS in patients with Vp4 tumors compared to more peripheral thrombi (median OS 4.7 vs 12.8 mo, p=0.055). Patients treated with both ST and RT had a better OS than those treated with either alone (median OS 17.7 vs 5.7 mo, p=0.022). Median OS by treatment type is shown in Table. Conclusions: This retrospective study confirms an association between the extent of PVTT and OS in a Western HCC cohort. Patients with adequate hepatic reserve may benefit from more aggressive multi-modality treatment approaches. OS by PVTT extent and treatment modality.[Table: see text]
Outcomes of patients with hepatocellular carcinoma (HCC) treated in the lenvatinib (LEN) and immunotherapy era (2018-2021) compared to the sorafenib (SOR) era (2008-2018).
Authors: Lim Chloe , Amaro Carla Pires , Ding Philip Q. , Cheung Winson Y. , Tam Vincent C.
Published: January 2023

553

Background: SOR was the standard first-line treatment for HCC for about a decade until the approval of LEN. Subsequently, atezolizumab + bevacizumab (A+B) were shown to have superior efficacy outcomes. The aim of this study was to compare effectiveness outcomes of HCC patients treated in the SOR era compared to the post-SOR era, when most HCC patients received first-line LEN or A+B. Methods: All HCC patients who started first-line systemic therapy at cancer centres in the Canadian province of Alberta between January 1, 2008 and December 31, 2021 were included in this study. Overall survival (OS), progression-free survival (PFS), and clinician-assessed response rate (RR) were retrospectively analyzed. Since LEN was first available to patients in Canada in August 2018, patients who started first-line systemic therapy between January 2008 to July 2018 were classified as treated in the “SOR era”, while patients treated from August 2018 to December 2021 were classified as being treated in the “post-SOR era”. Results: Of 372 total patients included, 230 were treated in the SOR era and 142 in the post-SOR era. Demographic and clinical characteristics are as follows for the SOR era and post-SOR era groups, respectively: median age was 63 and 64 years, 80% and 81% were male, 24% and 11% were of East Asian ethnicity. Most patients were ECOG 0-1 (85% and 91%), Child-Pugh A (84% and 85%), and ALBI grade 1 or 2 (96% and 98%) prior starting first-line therapy. Most common causes of liver disease included excess alcohol use (24% and 30%), Hepatitis C (37% and 48%), and Hepatitis B (27% and 15%). Most patients had advanced (BCLC C) stage disease in both groups (91% and 87%). Prior to systemic treatment 40% and 33% received TACE, 7% and 9% received TARE, and 3% and 14% received SBRT respectively. See table for first-line treatments received and outcomes. Median treatment duration was 3.2 months and 4.8 months, and median follow-up time was 9.6 and 11.0 months for SOR era and post-SOR era, respectively. Conclusions: In this real-world multicenter retrospective study, patients treated in the post-SOR era, where LEN and A+B were the more common first-line treatments, had superior overall survival, first-line response rates and progression-free survival. This study confirms the real-world progress that has been made in improving outcomes of HCC patients through systemic treatment advancements over the last 15 years.[Table: see text]
Safety of drug-eluting beads transarterial chemoembolization under the combination therapy with immune checkpoint inhibitors in unresectable hepatocellular carcinoma.
Authors: Chiu Sung-Hua , Chang Wei-Chou , Hsieh Chung-Bao , Feng An-Chieh
Published: January 2023

556

Background: To analyze the safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) under the combination treatment with immune checkpoint inhibitors (ICI) in unresectable hepatocellular carcinoma (HCC). Methods: In this retrospective single-institution study, 208 HCC patients (152 male and 56 female; mean age, 64.70±11.46 years) who received DEB-TACE between 2018.Nov and 2021.Dec were enrolled. There were 74.0% patients had Barcelona Clinic Liver Cancer stage B HCC, 90.4% were Child-pugh A patients, 63.0% patients had albumin-bilirubin (ALBI) grade 2, and 51.0% patients were up-to-seven out. Among them, 50 patients (24.0%) who received ICI with interval less than 30 days with DEB-TACE were categorized as DEB-ICI group; the remaining 158 patients (76.0%) were categorized as DEB group. ALBI grade before and 90 days after DEB-TACE were recorded to evaluate liver function change. Complications within 90 days after DEB-TACE were considered as TACE-related and were compared between two groups. Results: DEB-ICI group had significant higher incidence rate of liver abscess than DEB group (14.0% versus 5.1%, p=0.0337); other TACE-related complications showed no difference between two groups. There were 23.9% patients in DEB-ICI group had elevated ALBI grade after DEB-TACE, which revealed no difference in comparison with 22.4% in DEB group ( p=0.8460). Univariate analysis confirmed that combination with ICI was an independent risk factor of liver abscess formation after DEB-TACE (odds ratio = 3.0523, 95% confidence interval: 1.0474-8.8947, p=0.0409). Among DEB-ICI group, patients received ICI before DEB-TACE had a trend to have higher risk of liver abscess formation than those who received DEB-TACE before ICI (23.8% versus 6.9%, p-value=0.0922). Conclusions: Combination treatment of ICI with DEB-TACE with interval less than 30 days increased risk of liver abscess formation after DEB-TACE.
Efficacy of atezolizumab/bevacizumab combination therapy in BCLC-C cirrhotic patients with hepatocellular carcinoma (HCC) according to the type of disease progression.
Authors: Pantzios Spyridon , Syriha Antonia , Mandilara Dionysia , Stathopoulou Ioanna , Barla Georgia , Galanis Petros , Elelfsiniotis Ioannis
Published: January 2023

557

Background: HCC recurs in 70-80% of cases following potentially curative liver resection (LR) or radiofrequency ablation (RFA) and the immune component of the liver microenvironment plays a key role in early recurrence. The aim of our study was to retrospectively evaluate, under real life conditions, the overall survival (OS) of patients with advanced HCC (BCLC-C stage), either initially presented in the advanced stage or migrating from BCLC-A to BCLC-C stage within 2 years after curative LR or RFA, treated either with atezolizumab-bevacizumab (ATZ/BEV) combination or with TKIs sequentially (sorafenib as first line and cabozantinib as second line treatment). Methods: Sixty cirrhotic patients with advanced HCC (53 males, mean age 67y, 35% with diabetes, CPT-A=68.3%/CPT-B=28.3%, mean MELD/Na=11, ALBI grade I=28.3%/ALBI grade II=61.7%, 45% with varices) who either initially presented on the BCLC-C stage and were treated with ATZ/BEV (group A, N=19) or TKIs (group B, N=15) or who migrated from BCLC-A to BCLC-C stage within 2 years after LR or RFA and were treated with ATZ/BEV (group C, N=12) or TKIs (group D, N=14) were evaluated. Results: The four groups were comparable for all the baseline parameters evaluated (age p=0.9, gender p=0.1, platelets p=0.4, chronic liver disease etiology p=0.6, coexistence of diabetes p=0.3, presence of varices p=0.1, CPT stage p=0.1, ALBI grade p=0.3). Median OS was significantly higher for group C patients (mean survival 33.7m, median OS was not reached at the time of evaluation) compared to group D (mOS=27m), group A (mOS=13m) and group B (mOS=8m) patients, as presented in figure 1. It is important to note that the survival after HCC recurrence for group C patients (mean survival=18.2m, median OS was not reached at the time of evaluation) was significantly higher compared to those of group D patients (mOS=9m). Conclusions: Median survival of TKI-treated patients after HCC recurrence is less than 12m and is comparable to survivals observed in patients who initially classified in BCLC-C stage, irrespective of treatment schedule. ATZ/BEV combination therapy significantly prolongs survival in patients after early HCC recurrence, a finding that strongly supports the rationale for adjuvant ATZ/BEV therapy in high risk of recurrence patients.
Liver-directed combined radiotherapy for downstaging of over the Milan advanced hepatocellular carcinoma converting to liver transplantation.
Authors: Kim Yong Tae , Lee Jae Geun , Seong Jinsil
Published: January 2023

561

Background: Recent success of combined immunotherapy sheds a light to the future of advanced hepatocellular carcinoma patients but still remains as a palliative setting. The best oncologic outcome for HCC can be obtained by curative surgery either by resection or liver transplantation (LT). Efficacy of liver-directed combined radiotherapy (LD-CRT) for downstaging and subsequent surgical resection in locally advanced HCC had been reported earlier by our team. In this study, we investigated the role of LD-CRT as a downstaging strategy for converting advanced hepatocellular carcinoma to LT. Methods: We reviewed 55 hepatocellular carcinoma patients who had undergone downstaging LD-CRT and subsequent liver transplantation from January 2009 to February 2022. Patients within Milan criteria at the time of receiving radiotherapy were excluded and clinical characteristics and histopathology of explant liver were evaluated. The overall survival and disease-free survival were assessed using the Kaplan-Meier method. Results: The median follow-up period was 48.6 months (range 6.9 – 151.7 months). Of 55 patients, 24 (43.6%) were treatment naïve. At the time of RT, 36 patients presented large tumor (tumor diameter >5 cm) or multiple lesions (>3 lesions), 37 with major vessel involvement or portal vein tumor thrombosis, and 7 with extrahepatic lesion. LD-CRT was given as localized concurrent chemoradiation (CCRT) for 41 patients (74.5%) and transarterial chemoembolization (TACE) plus RT for 10 patents (18.2%). Substantial downstaging has been achieved in 38 (69%) patients with initially over the Milan to within Milan. Specifically, 29 of 37 patients initially with major vessel invasion or with tumor thrombosis were successfully converted to microscopic vessel invasion or tumor thrombus-free status in explant liver. 5-year overall survival was 68.1% and 2-year disease-free survival was 51%, respectively. Recurrence after transplantation was observed in 18 patients(4 intrahepatic recurrence and 14 extrahepatic metastasis) and the majority (14/18) occurred within 2 years. Conclusions: Liver-directed combined radiotherapy as a downstaging strategy for liver transplantation achieved favorable oncologic outcomes in advanced hepatocellular carcinoma patients. This study suggests that active adoption of radiotherapy needs full consideration for locally advanced HCC patients, opening a chance for curative LT.
Combined transarterial chemoembolization and external beam radiotherapy for identifying surgical candidates for hepatocellular carcinoma with macroscopic vascular invasion: A propensity score-weighted analysis.
Authors: Yoon Sang Min , Lee Sumin , Jung Jinhong , Choi Jonggi , Shim Ju Hyun , Song Gi-Won , Park Jin-hong
Published: January 2023

562

Background: To evaluate the role of hepatic resection in patients with objective responses after combined transarterial chemoembolization (TACE) and radiotherapy (RT) for hepatocellular carcinoma (HCC) with macroscopic vascular invasion (MVI). Methods: We retrospectively reviewed the patients treated with combined TACE and RT as a first-line treatment for HCC with MVI between 2010 and 2015. Some patients with objective responses underwent hepatic resection or liver transplantation. Surgical resectability was determined by the hepatobiliary and transplant surgeons of the multidisciplinary team for liver cancer. To investigate the role of surgery, patients with objective responses who did not undergo surgery were selected as a control group. The survival outcomes between the patients who received surgery and those who did not were compared using a propensity score-based stabilized inverse probability of treatment weighting method to minimize selection bias. Time-dependent survival analysis by surgery was performed. Results: Of the 170 patients with objective responses after combined TACE and RT, surgery was performed for 41 patients, including 8 liver transplantations. The unweighted surgery group was younger and had a higher proportion of solitary tumor and unilateral vascular involvement. After adjustment, the overall survival rates at 3 years were 61.0% and 28.6% in surgery and non-surgery groups, respectively. The most important prognostic factor for overall survival was surgery (adjusted Cox hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.17–0.46; p-value < 0.001). Complete response after TACE and RT was also a significant prognostic indicator for overall survival (adjusted HR, 0.41; 95% CI, 0.27–0.61; p-value < 0.001). There was no surgical mortality. Four patients (9.8%) required additional surgery for postoperative bleeding or graft failure. Conclusions: Hepatic resection was significantly associated with improved overall survival in patients with objective responses after combined TACE and RT for HCC with MVI.
Comparison of liver-directed combined radiotherapy versus sorafenib in patients with locally advanced hepatocellular carcinoma with portal vein tumor thrombosis: An Asian Liver Radiotherapy Group Study.
Authors: Seong Jinsil , Kim Jina , Cheng Jason Chia-Hsien , Nam Taek-Keun , Kim Jin Hee , Huang Wen-Yen , Aikata Hiroshi , Kim Myungsoo , Yue Jinbo , Lee Victor Ho-Fun , Zeng Zhaochong
Published: January 2023

565

Background: While systemic treatment is the mainstay for advanced hepatocellular carcinoma (HCC), numerous studies have highlighted the added value of local treatment. This study aimed to investigate the clinical efficacy of liver-directed combined radiotherapy (LD-CRT) compared to sorafenib, a recommended treatment until recently in locally advanced HCC presenting portal vein tumor thrombosis (PVTT) using a multinational patient cohort. Methods: We identified HCC patients presenting PVTT treated with either sorafenib or LD-CRT in 10 tertiary hospitals over Asia during 2005-2014. Propensity score matching (PSM) was performed to minimize the imbalance in patient and tumor characteristics of the two groups. The primary endpoint was overall survival (OS), and secondary endpoints were distant metastasis free survival (DMFS), local failure free survival (LFFS), and treatment related toxicity. Results: Total 1,035 patients including 360 patients in the sorafenib group and 675 patients in the LD-CRT group were enrolled. The majority of patients in the sorafenib group received 400 mg of sorafenib twice a day initially, and the dose was reduced to 50% or 25% if adverse reactions were noted. LD-CRT was given in liver-directed concurrent chemoradiotherapy in 502 (74.4%) patients, followed by transarterial chemoembolization plus radiotherapy in 149 (22.1%) patients. After PSM, 336 patients from each group were matched, and all features were well balanced between the two groups. At a median follow up of 28.8 months (interquartile range, 16.5-63.6), the median OS was 11.0 and 17.1 months for the sorafenib and LD-CRT groups, respectively ( p=0.001). In addition, LD-CRT group showed significantly improved DMFS and LFFS compared to the sorafenib group (median DMFS 14.9 vs 9.6 months, p=0.004, and median LFFS 15.7 vs 9.6 months, p=0.002). Conversion rate to curative surgery was significantly higher in the LD-CRT group (8.6% vs 0.9%, p=0.002). Those who underwent surgery had younger median age (54 vs 59, p=0.024), smaller median tumor size (6.5 cm vs 8.9 cm, p=0.012), and more unilateral disease (75.0% vs 43.8%, p<0.001). OS and LFFS were significantly prolonged in patients who underwent surgical treatment. Grade 3 or higher toxicity was more frequently noted in the sorafenib group compared to the LD-CRT group (7.7% vs 0.7%, p<0.001). Conclusions: Analysis of a propensity score matched multinational patient cohort revealed that liver-directed combined RT improved survival outcomes of locally advanced HCC patients presenting PVTT. While further prospective studies are warranted, we carefully suggest active multimodal local treatment for locally advanced HCC presenting PVTT.
A prospective single-arm phase II study of blank-microsphere transarterial chemoembolization (bTACE) plus lenvatinib (LEN) and sequential microwave ablation (MWA) in patients with large hepatocellular carcinoma (L-HCC, ≥ 7 cm): The Talem trial.
Authors: Huang Zhimei , Han Xue , Jiang Yiquan , Gu Ling , Zhang Tianqi , Wang Jianwei , Huang Jinhua
Published: January 2023

567

Background: Blank-microsphere transarterial chemoembolization (bTACE) has been demonstrated to have great efficacy, low toxicities and few adverse events. We report results of efficacy, safety and immunomodulatory effects from a phase II study of bTACE plus low-dose Lenvatinib (LD-LEN) and sequential microwave ablation (MWA) in patients with large hepatocellular carcinoma (L-HCC, ≥ 7 cm). Methods: Patients with large HCC with tumor number ≤ 3 and tumor diameter ≥ 7 cm (BCLC stage A/B) were treated with bTACE plus LD-LEN (4-8mg/day) and sequential MWA. bTACE was performed using blank microspheres and low-dose chemotherapeutic agents. Peripheral blood mononuclear cells (PBMC) were isolated before and after b-TACE plus LD-LEN for the evaluation of immunomodulatory effects. The primary endpoint was objective response rate (ORR) per modified-RECIST (mRECIST) criteria. Secondary endpoints included progression free survival (PFS), overall survival (OS), down-staging rate (DSR), complications and adverse events (AEs). Results: From November 2019 to March 2022, a total of 46 patients were enrolled in the study. The ORR per mRECIST was 93.02% (CR, n=26; PR, n=14) and DSR was 83.7 (36/43). Eight patients reached CR without MWA. The 1-year and 2-year OS rates were 89.4% and 67.5%, respectively. The 1-year and 2-year PFS rates were 57.8% and 34.8%, respectively. The median PFS were 16.7 months (95% CI, 8.6-not reached). The majority of the AEs observed were grade 1-2 (n = 21, 48.8%) and no treatment related death was observed. PBMC samples from 18 patients undergoing bTACE plus LD-LEN were investigated. Among myeloid cell populations, we observed a marked decline after treatment in CD11b+CD33+HLA-DR- MDSCs ( p <0.005). Increased numbers of activated CXCR5+CD8+ and CXCR5+CD4+ T cells were found after treatment ( p < 0.005), exerting anti-tumor immunity. Conclusions: From November 2019 to March 2022, a total of 46 patients were enrolled in the study. The ORR per mRECIST was 93.02% (CR, n=26; PR, n=14) and DSR was 83.7 (36/43). Eight patients reached CR without MWA. The 1-year and 2-year OS rates were 89.4% and 67.5%, respectively. The 1-year and 2-year PFS rates were 57.8% and 34.8%, respectively. The median PFS were 16.7 months (95% CI, 8.6-not reached). The majority of the AEs observed were grade 1-2 (n = 21, 48.8%) and no treatment related death was observed. PBMC samples from 18 patients undergoing bTACE plus LD-LEN were investigated. Among myeloid cell populations, we observed a marked decline after treatment in CD11b+CD33+HLA-DR- MDSCs ( p <0.005). Increased numbers of activated CXCR5+CD8+ and CXCR5+CD4+ T cells were found after treatment ( p < 0.005), exerting anti-tumor immunity. Clinical trial information: NCT05555316 .
Sorafenib plus tislelizumab as maintenance therapy for patients with advanced hepatocellular carcinoma treated with transarterial chemoembolization: A phase II study.
Authors: Cai Mingyue , Hong Xiaoyang , Huang Wensou , Guo Yongjian , Shi Wenbo , Liang Licong , Zhou Jingwen , Lin Liteng , Chen Ye , Zhu Kangshun
Published: January 2023

574

Background: Tyrosine kinase inhibitor combined with immune checkpoint inhibitor has been reported to confer a survival benefit in patients with unresectable hepatocellular carcinoma (HCC). This phase II study (NCT04599777) aimed to evaluate the safety and efficacy of sorafenib plus tislelizumab (Sor-Tis) for patients with advanced HCC who received transarterial chemoembolization (TACE). Methods: The key inclusion criteria were: age ≥ 18 years; BCLC C stage HCC; no prior systemic therapy; Child-Pugh score ≤7; ECOG PS ≤1. The key exclusion criteria were: tumor thrombus involving the main portal vein or vena cava; central nervous system metastasis; history of malignancies other than HCC; history of organ and stem cell transplantation. Sorafenib (400 mg Bid) and tislelizumab (200 mg Q3W) was started at 3-7 days after the first TACE (TACE was repeated on demand). The primary endpoint was overall survival (OS). The secondary endpoints included treatment-related adverse events (TRAEs), progression free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results: Thirty patients were enrolled in this study. Among these patients, 27 (90.0%) had macrovascular invasion, 12 (40.0%) had extrahepatic metastasis and 14 (46.7%) had intrahepatic tumor number >3. The mean largest tumor diameter was 11.4±3.9 cm. Till cutoff date (September 15th, 2022), the mean follow-up for the patients was 16.6±3.8 months. The median OS was not reached. The ORR per RECIST 1.1 and mRECIST was 20.0% and 53.3%, respectively. The DCR per RECIST 1.1 or mRECIST was 86.7%. During follow-up, 29 patients (96.7%) experienced disease progression (per RECIST 1.1 or mRECIST). The median PFS was 6.8 (95% confidence interval [CI] 4.5-9.0) months. TRAEs occurred in 28 patients (93.3%) and ≥grade 3 TRAEs was observed in 11 patients (36.7%). There was no treatment-related death in these patients. Conclusions: Sor-Tis showed preliminary clinical benefits and was tolerated in advanced HCC patients treated with TACE. This study is still ongoing and further follow-up is required to obtain final survival results. Clinical trial information: NCT04599777 .
Discovery of novel interactions with LCK in cholangiocarcinoma using proximity-dependent biotinylation.
Authors: Tomlinson Jennifer L , Watkins Ryan D , Mun Dong-Gi , Conboy Caitlin , Pandey Akhilesh , Smoot Rory L
Published: January 2023

575

Background: Cholangiocarcinoma (CCA) is a lethal hepatobiliary adenocarcinoma with increasing incidence and poor outcomes. Treatment success has been hindered by resistance, and new therapeutic strategies are necessary. The Src-family tyrosine kinase, LCK, activates Yes-associated protein (YAP), a known oncogene in CCA. While YAP has been historically difficult to target, we recently described LCK inhibition as a potential therapeutic option in CCA. We probed the LCK interactome employing biotinylation site identification technology (BioSITe) to discover molecular co-dependencies in the LCK-YAP axis. Methods: LCK-deficient HuCCT1, wild-type HuCCT1, and wild-type RBE cells were transfected with pEF-LCK-TurboID and used to reveal protein-protein interactions. Biotinylated peptides were enriched using anti-biotin antibodies followed by mass spectrometry analysis. Co-immunoprecipitation (Co-IP) was used to confirm interactions between LCK and identified interactors. Phosphoproteome profiling of human CCA tumors and patient derived xenografts was conducted to identify active kinase signatures in CCA. Tyrosine phosphorylated peptides were enriched using anti-phosphotyrosine antibody beads and analyzed by high-resolution mass spectrometery/liquid chromatography. Immunoblot analysis of HuCCT1 and LCK-deficient HuCCT1 cells was used to map the mechanistic interaction between LCK and epidermal growth factor receptor, EGFR. Inhibitors of EGFR and LCK, afatinib and NTRC 0652-0, respectively, were tested in vitro on human and murine CCA cell lines. Cell viability was determined with CellTiter-Glo; Calcusyn software was used to determine synergistic drug effects. Results: We discovered intracellular interactors of LCK in CCA using BioSITe. We identified both known and novel LCK interactors, including EGFR. Given that EGFR functions as a molecular driver of tumorigenesis and is increasingly recognized as a biomarker of resistance in a variety of tumors, we performed a phosphoproteomic evaluation of CCA tumors in which activated EGFR was identified by the presence of EGFR-Y1092, Y1197, and Y1172 phosphorylation. EGFR phosphorylation decreased under conditions of genetic LCK knock out and inhibition by NTRC 0652-0. Co-IP confirmed the interaction of EGFR with LCK. EGFR-Y1092 phosphorylation was downregulated with genetic knockout of LCK by immunoblot. Finally, EGFR inhibition was evaluated as a therapeutic strategy utilizing afatinib. Effects on cell viability were noted in both human and murine CCA cells. Afatinib and NTRC 0652-0 demonstrated a synergistic effect in vitro, with calculated combination indices of 0.007 – 0.790. Conclusions: A novel interaction between EGFR and LCK in CCA was identified using an unbiased proximity-dependent biotinylation technique. Dual blockade of LCK and EGFR is synergistic in CCA and may be a viable therapeutic approach for patients.
Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: A large, real-life, worldwide population.
Authors: Rimini Margherita , Casadei-Gardini Andrea , Persano Mara , Tada Toshifumi , Suda Goki , Shimose Shigeo , Kudo Masatoshi , Cheon Jaekyung , Finkelmeier Fabian , Rimassa Lorenza , Presa Josè , Masi Gianluca , Yoo Changhoon , Lonardi Sara , Tovoli Francesco , Scartozzi Mario , Burgio Valentina , Cascinu Stefano , Cucchetti Alessandro
Published: January 2023

579

Background: Atezolizumab plus bevacizumab and lenvatinib have not been compared in a randomized controlled trial. We conducted a retrospective multi-center study to compare the clinical efficacy and safety of lenvatinib and atezolizumab with bevacizumab as a first-line treatment for patients with unresectable HCC in the real-world scenario. Methods: Clinical features of lenvatinib and atezolizumab plus bevacizumab patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival was the primary endpoint. Results: The analysis included 1,341 patients who received lenvatinib, and 864 patients who received atezolizumab plus bevacizumab. After IPTW adjustment, atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib HR 0.97 (p=0.739). OS was prolonged by atezolizumab plus bevacizumab over lenvatinib in viral patients (HR: 0.76; p=0.024). Conversely, OS was prolonged by lenvatinib in patients with NASH/NAFLD (HR: 1.88; p=0.014). In the IPTW-adjusted population, atezolizumab plus bevacizumab provided better safety profile for most of the recorded adverse events. Conclusions: Our study did not identify any meaningful difference in overall survival between atezolizumab plus bevacizumab and lenvatinib. Although some hints are provided suggesting that patients with NASH/NAFLD might benefit more from lenvatinib therapy and patients with viral etiology more from atezolizumab plus bevacizumab.
Final results of a phase 1b/2 study of tivozanib in combination with durvalumab in patients with advanced hepatocellular carcinoma in both previously untreated patients and patients progressing on atezolizumab and bevacizumab.
Authors: Li Daneng , Dayyani Farshid , Mahalingam Devalingam , Rowe Julie Haewon , Abrams Thomas Adam , Kasturi Vijay , Iyer Renuka V.
Published: January 2023

585

Background: The approval of atezolizumab + bevacizumab for untreated advanced HCC was a significant benefit for patients, but with an increased risk of potentially severe bleeding complications. Tivozanib (a selective VEGFR 1, 2, & 3 tyrosine kinase inhibitor [TKI]) has been combined with durvalumab in the DEDUCTIVE study; preliminary results presented in January 2022 showed that this combination was well tolerated with comparable efficacy to other immune checkpoint and VEGF containing regimens in patients with previously untreated HCC ( J Clin Oncol 40, no. 4 suppl 462-462). We now report the final results of this cohort (cohort A) of patients as well as those with previously treated HCC, including safety results for all the patients. Methods: Major eligibility criteria included age >18 yrs with documented advanced HCC, Child-Pugh Class A, ECOG 0 or 1, and creatinine clearance >40 ml/min. Major exclusion criteria included co-infection with HBV and HCV and significant organ dysfunction. Patients were treated with 0.89 mg tivozanib p.o., 21 days on followed by 7 days off and 1500 mg durvalumab i.v. every 28 days. The primary objective was to determine the safety and tolerability of this combination in patients with advanced HCC; secondary objectives included assessing objective response rate (ORR), progression free survival, and overall survival (OS). The study was amended in 2021 to include a cohort of patients previously treated with atezolizumab and bevacizumab (cohort B). Results: 21 patients were enrolled in cohort A and 6 in cohort B; the median age was 67, 88% of patients were male, and 24% were Asian. The median follow-up time was 13.2 mos and 3.4 mos for cohorts A and B, respectively. Data were available for 25 of the 27 patients enrolled. For cohort A, the ORR was 25% (5/20) and 1-year OS was 76%. For safety analysis, 24 (96%) patients had at least 1 treatment-emergent adverse event (TEAE); 92% were attributed possibly to either tivozanib or durvalumab; 32% were serious TEAEs and there was 1 TEAE leading to death (unrelated). Of the 8 (32%) serious TEAE, 2 were coronavirus infection. 2 patients had serious (grade 3) treatment-related AEs: 1 pneumonitis and 1 with gastrointestinal hemorrhage and anemia. There were no grade 4 or 5 treatment-related AEs. Conclusions: Treatment with the combination of tivozanib and durvalumab in patients with either untreated advanced HCC or those previously treated with atezolizumab and bevacizumab was well tolerated; no severe bleeding events occurred in this study. Efficacy outcomes were comparable to other IO-TKI combinations in HCC. Data for PDL1 status, HBV/HCV status was collected and will be presented along with final safety and efficacy results for both cohorts. Clinical trial information: NCT03970616 .
Effect of AXL on cholangiocarcinoma survival and sensitivity to cytotoxic chemotherapy.
Authors: Takaichi Shohei , Tomlinson Jennifer L , Yu Mincheng , Abdelrahman Amro M , Werneburg Nathan W , Gores Gregory J , Smoot Rory L
Published: January 2023

591

Background: Cholangiocarcinoma (CCA) is a lethal disease with limited therapeutic options. We have demonstrated the interaction of Src-family kinase LCK with AXL, a TAM receptor tyrosine kinase (RTK), by phosphoproteomic analysis in CCA ( J Hepatol 2022). AXL is reported to act as a mechanism of acquired drug resistance in solid cancers. However, the role of AXL in CCA remains to be elucidated. Here, we investigated the significance of AXL expression as a potential therapeutic target in CCA. Methods: We first evaluated the expression levels of AXL in CCA and the associations with patient outcome using publicly available data from The Cancer Genome Atlas (TCGA). Next, to evaluate whether AXL inactivation sensitizes CCA cells to gemcitabine and cisplatin (GemCis) therapy as a standard therapy. AXL downregulation was achieved via siRNA approach and the selective inhibitor bemcentinib. We examined 50% inhibitory concentration (IC50) value of HuCCT1, a well characterized CCA cell line, on GemCis therapy with and without AXL knockdown using CellTiter-Glo cell viability assay. Then we assessed the efficacy of the combinatorial therapy of GemCis and bemcentinib utilizing Calcusyn software. Finally, apoptosis was evaluated by Annexin V assay. In vivo efficacy was assessed using a SB-1 (murine CCA cell line) and syngeneic murine model of CCA in C57Bl/6J mice treated with vehicle, GemCis, bemcentinib, and the combination of GemCis and bemcentinib. Results: In the TCGA cohorts, AXL is significantly expressed in CCA (P < 0.01), and disease-free survival and overall survival in low AXL expression group are significantly longer than those in high AXL expression group (P = 0.04, 0.01). In in vitro study, IC50 value of GemCis was decreased from 685nM to 129nM after AXL knockdown. Synergy effect was observed with the value of CI = 0.17 and Fa = 0.50 in the combinatorial therapy. The combinatorial therapy caused significantly increased apoptosis compared to GemCis or bemcentinib alone (P < 0.01, P < 0.01). In in vivo study, the combinatorial therapy significantly suppressed the tumor growth compared to GemCis or bemcentinib alone (P = 0.04, 0.01). Conclusions: Targeting AXL sensitizes CCA cell lines and preclinical models to standard of care GemCis combinatorial therapy. Our study suggests that the addition of AXL targeted therapy to cytotoxic chemotherapy can increase the response in CCA patients and is a promising combination.
Effect of EGFR and ERBB2 amplifications and activating alterations on efficacy of lenvatinib in hepatocellular carcinoma.
Authors: Lim Mir , Yang Dong , Imperial Robin John Lester , Majeed Umair , Tsai Jill , Franses Joseph Wang , Hsieh David
Published: January 2023

600

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is associated with a high mortality burden. Lenvatinib is an effective frontline tyrosine kinase inhibitor for HCC but is associated with primary and acquired resistance in most patients. Molecular mechanisms of resistance to lenvatinib remain unclear. Methods: We retrospectively analyzed 227 patients with HCC who underwent baseline ctDNA profiling as a component of routine clinical care, including 46 patients who had serial ctDNA analysis done at baseline and after progression to lenvatinib or ICI. Clinical data including demographics, treatment history, tumor responses, and survival outcomes were abstracted from the electronic medical record. Tumor response was categorized according to RECIST 1.1. A national registry of HCC that underwent ctDNA testing using Guardant360 was analyzed to determine the prevalence of EGFR/ERBB2 alterations in HCC. Results: Nearly a third of patients who progressed on lenvatinib demonstrated a gain in EGFR/ ERBB2 amplifications or activating mutations. No consistent trend in EGFR/ ERBB2 amplifications and alterations was found among ICI refractory HCC. Disease control rates (including complete response, partial response, and stable disease) were 20% in EGFR/ERBB2 altered HCC treated with lenvatinib, 62.5% in EGFR/ERBB2 wildtype HCC treated with lenvatinib (p = 0.05), and 58% in EGFR/ERBB2 altered HCC treated with ICIs (p = 0.09). PFS was also longer in EGFR/ERBB2 wildtype HCC treated with lenvatinib (5.9 months) and EGFR/ERBB2 altered HCC treated with ICIs (7.1 months) compared to EGFR/ERBB2 altered HCC treated with lenvatinib (2.2 months, p = 0.002). In a national cohort of 1739 patients with HCC, EGFR amplifications and activating mutations occurred in 6.5% and 1.5% of cases, respectively, and ERBB2 amplifications and activating mutations occurred in 1.9% and 0.7% of cases, respectively. Among EGFR/ERBB2 mutations, we identified recurrent gatekeeper mutations, including multiple A547T and T790M mutations, in 31% of patients. Conclusions: Our study substantiates EGFR/ERBB2 amplifications and mutations as putative drivers of lenvatinib resistance in patients with HCC and identifies the genetic mechanisms for EGFR pathway activation in refractory cancers. EGFR/ERBB2 alterations may thus represent predictive and pharmacodynamic markers of lenvatinib resistance. These findings lend support to the use of EGFR inhibitors combined with lenvatinib in previously untreated or lenvatinib refractory cancers.
Concordance in oncogenic alterations between primary and recurrent/metastatic cholangiocarcinoma pairs using targeted next-generation sequencing.
Authors: McIntyre Sarah Margaret Helena , Preston William , Walch Henry S. , Sigel Carlie S. , Sharib Jeremy , Chen Wei , Lidsky Michael , Kundra Ritika , Cercek Andrea , Harding James J. , Abou-Alfa Ghassan K. , Balachandran Vinod P. , Drebin Jeffrey A. , Soares Kevin , Wei Alice Chia-chi , Kingham T. Peter , D'Angelica Michael Ian , Iacobuzio-Donahue Christine A , Schultz Nikolaus , Jarnagin William R.
Published: January 2023

604

Background: The genetic background of cholangiocarcinoma (CCA) commonly involves alterations in kinase signaling, tumor suppression, oxidative stress modulation, and proto-oncogenic coupling pathways. Novel agents targeting such pathways have shown promise in systemic treatment; however, studies examining differences in the mutational landscapes between primary and recurrent, metastatic, or progressive disease after systemic therapy are lacking. The present study aimed to determine if recurrent, metastatic, or progressive disease genetically parallels the primary or not. Methods: Patients with biopsy proven CCA (primary tumor and paired recurrent/metastatic or progressive disease) from two institutions (MSKCC and Duke) were identified. Targeted next-generation sequencing (Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT)) capturing single nucleotide variants, copy number alterations, and structural variants was used to compare driver alteration concordance across the paired samples. Subgroup analyses were performed based on exposure to systemic therapy in patients with disease progression and tumor type (intrahepatic versus extrahepatic). Results: Sample pairs from 65 patients with intrahepatic (ICCA, n=54) and extrahepatic CCA (ECCA, n=11) were analyzed. Median time between samples was 19.6 months (range 2.7 - 122.9). Some de novo alterations were identified in recurrent/metastatic samples, but overall concordance (70%) was demonstrated between patient pairs for common oncogenic driver genes (Table). Subgroup analyses of summative ICCA and ECCA mutations revealed concordance of 65% and 88%, respectively. Concordance was also demonstrated between pairs exposed to systemic therapy between sample collections (n=50, 71%). Conclusions: In this dataset of CCA patients, a concordance rate of 70% was identified in the genomic alterations between primary and recurrent/metastatic pairs, and this did not appear to be altered by prior treatment with systemic chemotherapy. While limited by sample size, concordance in ICCA pairs was lower than that seen in ECCA. [Table: see text]
CD34 immunostaining for microvascular invasion analysis in hepatocelullar carcinoma.
Authors: Diniz Paulo Henrique Costa , Gama Henrique Valladao Pires , Albuquerque Ronniel Morais , Wanderley David Campos , Xavier Marcelo , Osorio Fernanda Maria Farage , Couto Claudia Alves , Ferrari Teresa Cristina de Abreu , Lima Agnaldo Soares , Chaves Gabriela Freitas , Vidigal Paula Vieira Teixeira
Published: January 2023

609

Background: Hepatocellular carcinoma is the most common primary neoplasia of the liver. Microvascular invasion predicts outcome and defines tumor staging. However, its diagnosis is still a challenge. The present study aims to evaluate inter and intraobserver agreement in identifying the presence of microvascular invasion using conventional and immunohistochemistry histology. Methods: Three pathologists performed the analysis of 76 hepatocellular carcinoma explants to characterize the presence of microvascular invasion using the hematoxylin/eosin stain and immunohistochemistry for CD34. The evaluations were made individually, in two distinct moments. Results were analyzed by the Kappa’s coefficient and ROC curves. Results: Our study demonstrated similar agreement for microvascular invasion between hematoxylin/eosin and CD34 methods. However, the intraobserver agreement values for both methods were higher than the interobserver ones. The accuracy of CD34 in relation to hematoxylin/eosin by ROC curves in intraobserver analysis tends to a high specificity, ranging from 82.1 to almost 100%, with sensitivity of 46.9 to 81.1%. In interobserver analysis, CD34 also has a high specificity (84.3 to 85.5%) while its sensitivity is a little shorter (81.2 to 84.3%). Conclusions: Intraobserver higher agreement allows us to suppose that pathologists employed own criteria to evaluate vascular invasion, reinforcing the need of standardization. ROC Curves analysis showed that the CD34 method is more specific than sensitive. Therefore, immunohistochemistry for CD34 should not be used routinely, but it could be useful to help confirming invasion previously seen by conventional histology.
Serum vitamin D3 levels and overall survival (OS) in patients (pts) with advanced biliary tract cancer (BTC): Analysis of the NIFTY trial cohort.
Authors: Lee So Heun , Cheon Jaekyung , Kim Ilhwan , Kim Kyu-Pyo , Ryoo Baek-Yeol , Jeong Jae Ho , Kang Myoung Joo , Kang Byung Woog , Ryu Hyewon , Lee Ji Sung , Yoo Changhoon
Published: January 2023

613

Background: Although growing number of studies have explored the role of vitamin D3 on various cancer types, no study has been conducted in the prospective cohort of advanced BTC. This analysis aimed to evaluate the predictive or prognostic implication of serum vitamin D3 in pts with advanced BTC treated with second-line chemotherapy. Methods: The analysis is the preplanned subgroup analysis of the NIFTY trial, a multicenter, open-label, randomized, phase 2b study which compared the second-line liposomal irinotecan plus 5-FU/leucovorin and 5-FU/leucovorin in pts with advanced BTC. Serum vitamin D3 (25-hydroxyvitamin D [25(OH)D]) levels were measured at baseline (i.e., C1D1) in a total of 176 pts out of 178 pts in the ITT population and were included in the current analysis. Correlation between OS and serum vitamin D3 as a continuous variable was analyzed for linear and non-linear associations. Results: The median age was 64 years (range, 37–84) and 75 patients (42.6%) were women. The baseline serum vitamin D3 levels ranged from 1.39 ng/ml to 140.02 ng/ml in the overall pts. There was no significant difference in the mean vitamin D3 concentration according to the sex (male vs. female: 24.1 vs. 26.7; p=0.43), body mass index (BMI) (<25 vs. 25-29.99 vs. ≥30: 24.0 vs. 30.0 vs 15.9; p=0.18), previous surgery (no vs. yes: 24.1 vs. 27.4; p=0.40), ECOG performance status (0 vs. 1: 24.1 vs. 25.5; p=0.66), and primary tumor site (intrahepatic vs. extrahepatic vs. gallbladder: 25.7 vs. 23.2 vs. 26.2; p=0.74). After adjustment for key prognostic factors including chemotherapy regimens, metastatic sites, or baseline CA 19-9 levels, there was no significant association between baseline serum vitamin D3 and OS (HR=1.06 per 10 increase; 95% CI, 0.97–1.15; p=0.22). In addition, there was no non-linear association between vitamin D3 and OS (p=0.52 for the linear model and p=0.62 for the model with restricted cubic splines). In the subgroup analysis, higher vitamin D3 levels were associated with poorer OS (HR=1.16 per 10 increase; 95% CI, 1.04–1.30; p=0.0072) in female pts. Conclusions: Serum vitamin D3 levels did not show significant relationship with survival in pts with advanced BTC treated with second-line chemotherapy. High vitamin D3 levels might be associated with poorer survival in female pts. Further larger studies are needed.