bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of low dose sorafenib and capecitabine in the management of hepatocellular cancer.
Authors: Mateen Abdul , Abdullah Famya , Akhtar Muhammad Saeed , Quraishi Arif Moin , Sattar Amir , Hashmi Quratul Ain , Sanwal Isharat Shehrood , Jamil Faryal , Safdar Rida , Adil Allah Rakha
Published: June 2023

e16117

Background: Hepatocellular cancer (HCC) is one of the commonest cancers in Pakistan due to endemic hepatitis B and C diseases. Its incidence is continuously rising due to lack of public awareness and lack of routine screening of the affected population. Most of the patients present in advanced stage of the disease excluding option for curative surgical options. These patients are mostly not fit enough to tolerate systemic therapies in full doses. So, we have to adapt ourselves to lower dosage so that it can be tolerated without many untoward side effects. Methods: This study was aimed to assess the efficacy of low dose sorafenib (400 mg daily in two divided doses) and capecitabine (1000 mg daily in two divided doses) in advanced hepatocellular carcinoma. Patients were prescribed this treatment for six months and then response was assessed using computed tomography or ultrasound and alpha fetoprotein (AFP) levels. Progression-free survival (PFS) and overall survival (OS) were also assessed. Results: Total of one-hundred fifty-five patients were enrolled. One hundred thirteen patients completed the treatment for six months and were evaluated for response. A total of 28 (25%) of patients progressed during treatment and were shifted to other treatment options. Nine patients (8%) had complete response, thirty-four (30%) had partial response, forty-two (37%) had stable disease and twenty-eight (25%) had progressive disease. Seventy-four patients (65%) showed significant reduction in AFP levels. A total of 85/113 (75%) patients were available for assessment of PFS and OS. Two-year PFS and OS were 32% and 43% respectively. Mean and median PFS (year) were 1.82 ±0.19 (95% confidence interval 1.48 to 2.17) and 1.27±0.16 (95% confidence interval 0.94 to 1.57) respectively. Mean and median OS (year) were 2.73 ±0.24 (95% confidence interval 2.39 to 3.16) and 2.27±0.13 (confidence interval 2.02 to 2.54) respectively. Twenty-six patients had one or more episode of grade 2 diarrhea, eleven patients developed encephalopathy, thirteen patients developed hand foot syndrome and nineteen patients showed grade 2 thrombocytopenia. Conclusions: Low dose sorafenib and capecitabine is effective in the treatment of advanced HCC with excellent tolerability and minimal toxicity.
Anti–PD-1 combination regimen as first-line therapy in advanced biliary tract cancer and biomarker exploration: A retrospective study.
Authors: Guo Jingyi , Zhou Qun , Zhou Mingzhen , Dai Hengheng , Li Lin , Liu Baorui , Shen Jie
Published: June 2023

e16130

Background: Combination strategy of immune checkpoint inhibitors has potential to replace chemotherapy as a new first-line therapy for advanced biliary tract cancer (BTC). The aims of this study were to assess the efficacy of anti-PD-1 combination therapy in the first-line treatment of advanced BTC and to find reliable biomarkers associated with overall survival (OS). Methods: Clinical data from patients with advanced BTC who received chemotherapy or anti-PD-1 combination therapy as first-line were collected. The primary outcome of this study was OS. Blood test results were collected from patients who received anti-PD-1 in the week prior to treatment to calculate inflammation scores and analyze their relationship with OS. A total of eight scores were selected for analysis, including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein (CRP) ratio (LCR), lymphocyte-to-monocyte ratio (LMR), CRP to-albumin ratio (CAR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), and pan-immune-inflammation value (PIV). Moreover, archival tissues were collected for genetic testing and immunohistochemical staining to analyze genetic changes and the infiltration of immune cells in tumor tissues in relation to survival. Results: From January, 2018, to July, 2022, 64 patients were recruited: 11 were in the chemotherapy group, 21 were in the anti-PD-1 plus chemotherapy group, 21 were in the anti-PD-1 plus targeted therapy group and 11 were in the triple group (anti-PD-1 plus chemotherapy and targeted therapy). The median overall survival (mOS) was 7.9 months, 11.3 months, 12.8 months and 28.7 months, respectively. Compared to first-line chemotherapy, mOS was significantly prolonged in the triple group ( p= 0.031). The results of inflammation scores showed that patients with high LCR (≥0.4), high LMR (≥2.5), low CAR ( < 0.18), high PNI (≥44.3) or low PIV ( < 480.9) had significantly prolonged mOS compared to those with different scores ( p< 0.05). Genetic testing results suggested that patients with poor survival all had TP53 mutations and had higher levels of KRAS and ERBB2 mutations. Immunohistochemical results showed that a low FOXP3/CD8 ratio (≤0.27) was associated with prolonged OS ( p= 0.029). With CD4-low, CD8-high, CD56-positive, CD163-high, FOXP3-high and MPO-high in TME as one factor, we calculated immunoscore according to the number of factors. The high immunoscore group ( > 2) showed significantly superior OS ( p= 0.003). Conclusions: First-line anti-PD-1 antibody combination therapy was superior to chemotherapy, and triple therapy significantly improved survival. Peripheral blood immune-inflammation score, FOXP3/CD8 ratio and immunoscore have potential as biomarkers for predicting the efficacy of first-line anti-PD-1 antibody therapy in advanced BTC.
Donafenib combined with anti-PD-1 antibodies plus transarterial therapy for initially unresectable hepatocellular carcinoma.
Authors: Wen Yaohong , Fu Shunjun , He Guolin , Cai Lei , Liu Yahong , Li Xinmin , Xu Yuyan , Wang Chunming , Zhong Kaihang , Zhang Cheng , Xie Qingyu , Pan Mingxin
Published: June 2023

e16135

Background: Given its clear efficacy and high safety demonstrated in the phase 3 ZGDH3 study, donafenib has been recommended by the Chinese guidelines for the first-line treatment of unresectable hepatocellular carcinoma (uHCC). Recently, combination therapies have shown favorable results. However, triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy has not yet been investigated. Thus, we aimed to investigate the efficacy and safety of triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy in patients with uHCC. Methods: A single-center, retrospective study was performed based on the medical records of consecutive patients diagnosed with HCC who were not suitable for curative surgery or local ablation at Zhujiang Hospital of Southern Medical University from June 2021 to October 2022. Patients with ≥18 years, Child-Pugh score ≤7, ECOG PS ≤1, no prior systemic therapy, having at least one measurable lesion (per mRECIST) were enrolled. Patients were treated with donafenib 200 mg orally twice daily, anti-PD-1 antibodies intravenously every three weeks, and transarterial therapy until disease progression or unacceptable toxicity. Endpoints include objective response rate (ORR, the proportion of patients with partial or complete response according to mRECIST and RECIST v1.1), surgical conversion rate (the proportion of patients who successfully underwent resection), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: A total of 27 patients were enrolled (median age 52 years [range, 29–74], 81% males, 85% with HBV infection, 41% with cirrhosis, 48% with AFP level ≥400 ng/mL, and 67% in BCLC C). All patients received donafenib and anti-PD-1 antibodies with hepatic arterial infusion chemotherapy (HAIC, n = 10), transarterial chemoembolization (TACE, n = 8), or both (n = 9). By the cutoff date of January 6, 2023, the median follow-up duration was 6.8 months (95% confidence interval [CI], 5.9–7.7), and 17 (63.0%) patients were still undergoing treatment. The ORR and DCR were 59.3% and 92.6% by mRECIST, and 18.5% and 88.9% by RECIST v1.1, respectively. The surgical conversion rate was 22.2%, and the median surgical conversion time was 3.4 months (range, 2.2–4.6). The median PFS was 8.3 months (95% CI, 6.8–9.8), and median OS was not reached. The 6-month PFS rate and 12-month OS rate were 74.7% and 72.9%, respectively. Grade 3 treatment-related adverse events (TRAEs) were observed in 5 patients (18.5%), the most common of which was increased total bilirubin (11.1%). No grade 4/5 TRAEs occurred. Conclusions: Donafenib combined with anti-PD-1 antibodies plus transarterial therapy shows promising efficacy and manageable toxicity in patients with initially uHCC. Clinical trial information: NCT05638438 .
Efficacy and safety of tislelizumab combined with lenvatinib and FOLFOX4-HAIC in conversion therapy of middle-advanced stage hepatocellular carcinoma (HCC): A real-world retrospective study.
Authors: Tan Kai , He Xiaojun , Zhang Hu , Zhao Shoujie , Gong Chenyu , Zhao Yaoyao , Nan Haiyan , Zang Li , Luo Zhonghua , Yin Jikai , Du Xilin
Published: June 2023

e16137

Background: Conversion therapy achieve tumor downstaging and provide middle-advanced stage HCC patients with opportunities for radical resection. Lenvatinib combined with immune checkpoint inhibitors (ICIs) and FOLFOX-HAIC has shown high conversion success rates. This study aimed to evaluate the efficacy and safety of tislelizumab combined with lenvatinib and FOLFOX4-HAIC as first-line conversion therapy in this population. Methods: Between April, 2021, and April, 2022, we retrospectively analyzed clinical data of HCC patients with BCLC stage B or C who underwent tislelizumab combined with lenvatinib and FOLFOX4-HAIC. The primary outcome included objective response rate (ORR), disease control rate (DCR), conversion resection rate (CRR) and treatment-related adverse events (TRAEs). Data were expressed as median(range). Results: A total of 18 patients (17 male, 1 female) completed conversion therapy assessment until the last follow-up time (December 27, 2022). The patients were characterized with a median age of 55.5 years (37-72), body mass index 24.9(19.8-33.9), 1 patient with BCLC stage B, 16 patients with BCLC stage C, and 1 patient with HCC postoperative recurrence with intrahepatic metastasis. According to mRECIST criteria, tumor shrinkage was observed in all patients, with an ORR of 94.4% (17/18, including 61.1% [11/18] complete response), DCR of 94.4% (17/18), and median time to response(mTTR) of 1.4 months (0.7-3.0). Successful conversion was observed in 11 (61.1%) of 18 patients per mRECIST. As of cut-off date, the actual CRR and pathological complete response(pCR) were 38.9% (7/18) and 57.1% (4/7), respectively. No surgical deaths occurred, and at the last follow-up review, there was disease free survival in all patients after operation. With a follow-up time of 20.7 months, median progression-free survival (PFS) and overall survival (OS) were not reached, with a 3- and 6-month progression-free survival rate of 94.4% and 83.3%. During the follow-up period, 6 patients developed disease progression with a median time to progression (mTTP) of 5.4 months (1-6.7), of whom 3 died due to disease progression. Most common TRAE was aspartate aminotransferase (AST) increased (16 patients, 88.9%). Grades ≥3 TRAEs occurred in 12 patients (66.7%), with only one grade 4 TRAE (AST increased). All TRAEs were tolerable and manageable. Conclusions: Tislelizumab combined with lenvatinib and FOLFOX4-HAIC showed high conversion rate and acceptable toxicity in the treatment of middle-advanced stage HCC, suggesting that this combination could be considered as a new conversion strategy in this population.
OS analysis of patients with different short-term response and progression patterns of donafenib versus sorafenib as first-line therapy for advanced hepatocellular carcinoma: An exploratory subgroup analysis of ZGDH3.
Authors: Qin Shukui , Bi Feng , Xu Jianming , Du Chengyou , Fan Qingxia , Zhang Longzhen , Tao Min , Jiang Da , Wang Senming , Chen Yongping , Sheng Jifang , Zhuang Xuelong , Wu Jun
Published: June 2023

e16143

Background: Donafenib, a deuterated derivative of sorafenib, significantly prolonged overall survival (OS) in patients with advanced hepatocellular carcinoma in an open, randomized, parallel-controlled phase II/III trial (ZGDH3) compared with sorafenib. The purpose of this study was to explore and analyse the OS benefits of donafenib and sorafenib treatment in patients with different short-term response and progression patterns. Methods: This analysis was based on the ITT population of ZGDH3 study (defined as all randomized patients). The median OS of donafenib and sorafenib was assessed by the Kaplan-Meier method and was compared according to different short-term response (SD, others) and progression patterns (intrahepatic lesion growth, intrahepatic new lesion, extrahepatic lesion growth, extrahepatic new lesion). The stratified Cox proportional hazard model was used to calculate the hazard ratio and its 95% confidence interval. Results: 668 patients were included in the analysis (334 in each group). Donafenib was associated with a trend of improved OS benefit when compared with sorafenib in most subgroups (HR < 1), including best short-term response of SD or others, confirmed short-term response of SD or others, intrahepatic lesion growth or not, intrahepatic new lesion or not, extrahepatic new lesion or not, no extrahepatic lesion growth. The benefit was statistically significant in the following subgroups: in patients with response of SD, the mOS of donafenib and sorafenib were 19.3 and 15.5 months, respectively (HR 0.714, 95%CI 0.550-0.928). Among patients with confirmed response of SD, the mOS was 29.0 and 22.8 months, respectively (HR 0.641, 95% CI 0.418-0.983). Among patients without extrahepatic lesion growth (defined as lesion growth ≥20% from baseline), the mOS was 12.6 months and 10.0 months, respectively (HR 0.783, 95% CI 0.648-0.945). Among patients without new extrahepatic lesions, the mOS was 13.1 months and 11.0 months (HR 0.816, 95% CI 0.677-0.998), respectively. Conclusions: Donafenib exhibited better survival benefit than sorafenib in most subgroups, especially in patients with the best response and confirmed best response of SD, which further confirmed the excellent efficacy of donafenib in first-line treatment of advanced HCC. Clinical trial information: NCT02645981 . [Table: see text]
Transarterial chemoembolization combined with camrelizumab and apatinib in the treatment of advanced hepatocellular carcinoma: Preoperative or postoperative combination? A prospective clinical study.
Authors: Xie Hui , Yang Yuqing , Liu Yane , Wen Zhenyu , Wang Junxiao
Published: June 2023

e16150

Background: The timing of the combination of an antiangiogenic agent (apatinib) and an immune checkpoint inhibition inhibitor (camrelizumab) in patients with advanced hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is unclear. Therefore, this study aims to evaluate the efficacy and safety of TACE combined with camrelizumab and apatinib for advanced hepatocellular carcinoma (HCC), and to explore the timing of the combination therapy. Methods: The institutional Review Board approved our study and registered it in the Chinese Clinical Trial Registry (ChiCTR2000034155). Between June 2020 and January 2022, we prospectively recruited patients with unresectable HCC not receiving systemic therapy and randomly divided them into preoperative and postoperative medication groups according to the timing of drug administration. Patients in the preoperative medication group received camrelizumab 200 mg per 2 weeks intravenously and oral apatinib 250 mg/day orally prior to TACE. Patients in the postoperative medication group received the same dose of camrelizumab and apatinib after recovery of liver function following TACE. The primary endpoint of the study was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events. Results: A total of 33 patients were enrolled in this study. There were 15 patients in the preoperative medication group and 18 patients in the postoperative medication group. Median OS was significantly longer in the postoperative medication group than in the preoperative medication group (20 months vs. 12 months; P = 0.034). Patients in the postoperative medication group achieved a higher DCR than that in the preoperative medication group [17 cases (94.4%) vs. 10 cases (66.7%), P = 0.039] Multivariate Cox regression analysis showed that post-TACE combination of apatinib and camrelizumab provided better OS than pre-TACE combination drug therapy (HR = 0.353, 95% CI:0.131-0.953, P = 0.040). No serious adverse events were observed in the two groups. Conclusions: TACE combined with apatinib and camrelizumab treatment in the patients with advanced HCC showed promising efficacy and a manageable safety profile. Compared to pre-TACE with apatinib plus camrelizumab, post-TACE with apatinib plus camrelizumab significantly improved OS and DCR in patients with advanced HCC. Clinical trial information: ChiCTR2000034155 . [Table: see text]
A study of cadonilimab combined with regorafenib as second-line or later therapy in patients with advanced hepatocellular carcinoma (aHCC).
Authors: Qi Qi , Liu Yang , Li Rentao , Liu Yayue , Zhang Xihao , Lu Wei , Li Huikai
Published: June 2023

e16154

Background: Current second-line treatment options for aHCC patients (pts), including single TKI or anti-PD-1+anti-CTLA4, result in limited survival benefits, objective responses or increasing concerns regarding adverse effects. An exploration of safer and more effective second-line or later therapies for aHCC is paramount. Cadonilimab is a first-in-class bispecific, humanized IgG1 antibody targeting PD-1 and CTLA-4, which has the potential to boost immune surveillance in HCC. Previous data indicated that cadonilimab possesses an improved safety profile and an encouraging anti-tumour activity compared to combined administration of anti-PD-1 plus anti-CTLA-4 antibodies. Regorafenib was the first TKI that approved globally as a second-line treatment of aHCC. Here, we evaluated the safety of cadonilimab plus regorafenib as second-line or later therapy in pts with aHCC. Methods: The study population derived from prospectively collected retrospectively analyzed data (10/2022-02/2023) of pts treated with cadonilimab plus regorafenib as second-line or later therapy for aHCC at Tianjin Cancer Hospital Airport Hospital. The primary endpoint was safety. Results: We identified 29 pts with aHCC who received cadonilimab plus regorafenib. The median age was 59 years; 86.2% were male; 72% were ECOG PS 0; 72% had a Child-Pugh score of A at diagnosis. High risk factors for HCC included MVI (3pts), ≥3 tumour lesions (10pts), tumour diameter ≥5cm (5pts), AFP≥400ng/mL (5pts). Six pts (21%) received cadonilimab plus regorafenib in the second-line while the rest of pts (79%) received it as third-line or later. All pts previously received at least one line of immunotherapy combined with anti-angiogenic target agents. Seven pts received triple combination regimens (ICIs+TKIs/Bev+HAIC) before. At time of data extraction, no pts were assessed for efficacy due to the COVID-19 pandemic (especially the outbreak in early December 2022) and short follow-up time, we focused on the safety and tolerability in this report. Any grade treatment related adverse events (TRAEs) occurred in 24pts (83%). The most common TRAEs of any grade were hypoalbuminemia (24%), lymphocyte count decreased (21%), rash (14%), nausea (14%) and infusion reaction (14%). Only four (14%) patients experienced grade 3 TRAEs including infusion reaction (2pts), lymphocyte count decreased (1pt) and gastrointestinal hemorrhage (1pt, regorafenib related). No grade 4-5 TRAEs were observed. Conclusions: The combination of cadonilimab plus regorafenib was generally well tolerated. The prospective trail of cadonilimab combined with regorafenib as second-line or later therapy for aHCC is ongoing (NCT05644379). Although it needs to be reconfirmed, the treatment responses of some patients are encouraging (including sharp decrease in AFP level and/or reduced tumor size). Related data will be reported in the future.
Phase II study of fruquintinib as second or further-line therapy for patients with advanced biliary tract cancer.
Authors: Zhang Pengfei , Yang Yu , Gou Hongfeng , Li Qiu
Published: June 2023

e16161

Background: Biliary tract cancer (BTC) is a rare but aggressive disease, and most patients present with unresectable or metastatic disease. Gemcitabine combined with cisplatin (GP) has been established as the standard first-line treatment in patients with unresectable BTC. Nevertheless, no standard second or further-line treatment regimen has been approved in this disease. Fruquintinib is an oral multi-kinase inhibitor targeting vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2 and VEGFR3. In this single arm phase II study, we explored the efficacy and safety of fruquintinib as a novel second or further-line therapy in advanced or metastatic BTC. Methods: BTC patients with ECOG PS 0-1 and adequate liver, kidney and bone marrow function were given fruquintinib (5 mg, PO, D1-21, Q4W) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The exploratory endpoint was the correlation of clinical outcomes with biomarkers. Results: 20 patients were enrolled in the study. 9(45.0%) were men, and the median age was 57.5(36-78) years. 18 patients were diagnosed with ICC, 1 with ECC, and 1 with GBC. 6 (30%) patients were refractory to second-line treatment, and 5 (25%) patients were refractory to third-line treatment. 18 patients were assessable for response. The median PFS was 4.6 months (95%CI: 2.1-7.1 months). ORR was 5.6%, and DCR was 66.7%. The incidence of treatment-related grade 1-2 adverse events (TRAEs) was 83.3%, and the most common grade 1-2 AEs were hand-foot syndrome (66.6%), fatigue (61.1%), stomatitis (44.4%), and hypertension (38.9%). Conclusions: Fruquintinib showed promising efficacy and acceptable toxicity as second or further-line therapy in advanced or metastatic BTC. Clinical trial information: NCT04156958 .
Chemoembolization plus hepatic arterial infusion chemotherapy combined with donafenib, anti-PD-1 antibody for unresectable hepatocellular carcinoma (uHCC): A retrospective analysis.
Authors: Yin Linan , Liu Ruibao , Li Shijie , Hou Xunbo
Published: June 2023

e16163

Background: Chemoembolization plus hepatic arterial infusion chemotherapy significantly improved ORR and PFS over chemoembolization alone in patients with uHCC in previous study. And donafenib showed the survival benefit and better safety compared with sorafenib in a Phase III trial. In consideration of synergism, we evaluated the safety and efficacy of TACE plus hepatic arterial infusion chemotherapy combined with donafenib, anti-PD-1 antibody in patients with uHCC. Methods: We retrospectively analyzed the patients who were diagnosed as unresectable hepatocellular carcinoma and received the treatment of TACE plus HAIC combined with donafenib, anti-PD-1 antibody as first-line therapy from Nov 2021 to Nov 2022 in Harbin Medical University Cancer Hospital. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progress free survival (PFS), overall survival (OS), time to response (TTR) and safety. Results: Of 36 patients included in the analysis, all of them received first-line treatment of TACE (embolization of pirarubicin hydrochloride 40mg, iodized oil 10-20ml with or without gelatin sponge) plus HAIC (oxaliplatin 85 mg/m2 2h, leucovorin 400 mg/m2 1h, fluorouracil bolus 400 mg/m2 in the first 10 minutes, and fluorouracil infusion 2400 mg/m2 for 46h) combined with donafenib 200mg bid, anti-PD-1 antibody Q3W. The median age was 58 years (range, 44-80). The study population was predominantly male (75%), and 89% were HBV-positive. Patients were classified as BCLC stage A (8.3%), stage B (8.3%) and stage C (83.4%). The rates of patients with portal vein tumor thrombus and extrahepatic metastasis were 69% and 11% respectively. 30.6% patients received interventional therapy before the combination treatment. By Feb 2023, 23 patients had received at least one imaging evaluation, 19(82.6%) of them achieved partial response, ORR and DCR were 82.6% and 100% per modified RECIST criteria respectively. And the median TTR was 1.1 months. With 3.8 months of median follow-up time, the 6-month PFS rate was 51.2%. The median PFS and OS were not reached. All 36 patients had at least one treatment-related AE (TRAE), and treatment-related deaths did not occur in this study. Grade 3 TRAEs occurred in 8 (22.2%) patients, and no grades 4 or 5 were reported. The most common TRAEs included alanine aminotransferase increased (77.8%), alkaline phosphatase increased (77.8%), platelet count decreased (69.4%) and blood bilirubin increased (63.9%). Conclusions: Chemoembolization plus hepatic arterial infusion chemotherapy combined with donafenib, anti-PD-1 antibody are effective and tolerable for uHCC patients.
Atezolizumab and bevacizumab in advanced hepatocellular carcinoma: Real-world data.
Authors: Bezalel Nomi , Davidov Yana , Likhter Mariya , Cohen Ezra Oranit , Inbar Yael , Halpern Naama , Boursi Ben , Beller Tamar , Pery Ron , Shmueli Einat S , Nachmany Ido , Ben Ari Ziv , Margalit Ofer
Published: June 2023

e16167

Background: Treatment of advanced unresectable hepatocellular carcinoma (HCC) has advanced substantially in the past few years with the use of immunotherapy. The IMbrave 150 phase III study assessed the combined treatment of atezolizumab plus bevacizumab (atezobev) and has demonstrated better overall and progression-free survival compared with sorafenib. We aimed to assess the efficacy and toxicity of atezobev in real-world data. Methods: We reviewed the medical records of patients with a diagnosis of advanced HCC treated at the Sheba Medical Center between January 2020 and February 2023. Eligible patients were those treated with atezobev as first line systemic therapy. Adverse events were recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response assessment was performed according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Results: We identified 37 patients that were treated with atezobev, mean age of the study population was 70 (IQR 60-72), 19% were females (n = 7), median ECOG performance status was 1 (IQR 0-1.5) and HCC etiology was non-viral in 35% (n = 13) and viral (HBV/HCV) in 65% of patients (n = 24). Overall response rate (ORR) was 29.7% (n = 11), stable disease was noted in 27.0% (n = 10) and progressive disease in 43.2% (n = 16) of patients. In comparison, the ORR reported in the IMbrave 150 study was 27%. There was no difference in response rate according to previous local treatment or HCC etiology. Grade 3/4 adverse events included grade 3 hepatitis (10.8%, n = 4), grade 3 diarrhea (2.7%, n = 1), and grade 4 infusion-related reaction (2.7%, n = 1). In comparison, the IMbrave 150 study reported grade 3/4 hepatitis, diarrhea, and infusion-related reaction in 7.0%, 1.8% and 2.4% of patients, respectively. Conclusions: In this cohort of advanced HCC patients treated in a large tertiary medical center, the efficacy and toxicity profile of atezobev was similar to that reported in the IMbrave 150 phase III study.
Genomic profiling of biliary tract carcinomas by their location.
Authors: Gatalica Zoran , Edwards David K. , Flannery Cynthia A. , Hall David W. , Hoag Jess R , Therala Nishitha , LoBello Janine R. , Thakkar Snehal Govind , Basu Gargi D. , Abdelrahim Maen
Published: June 2023

e16175

Background: Historically, biliary tract cancers have had a poor prognosis. Genomic profiling allows identification of alterations in genes with FDA-approved matched therapies either in these cancers ( FGFR2/3 fusions, certain IDH1 missense mutations), in all solid tumors (e.g. BRAF V600E mutations), or in other cancers (e.g. BRCA1/2 loss-of-function mutations) that could inform treatment. Here we examine the frequency of matched therapies in biliary tract carcinomas and the association with tumor location. Methods: All biliary tract carcinoma patient samples receiving the OncoExTra assay between April 2018 and November 2022 were included. The assay uses tumor-normal, whole-exome, whole-transcriptome sequencing to identify genomic alterations. Alterations in genes with FDA-approved matched therapies in any cancer, with matched clinical trials, or with evidence in cancer guidelines or the literature for possible matched therapies were recorded. Results: A total of 155 patient samples were processed: 92 intrahepatic CCA, 34 gall bladder carcinomas, 9 extrahepatic CCA, and 20 ampulla of Vater carcinomas. Targetable alterations were found in 153 (98.7%) samples; 31 (20.3%) had FDA-approved matched therapies, including 5 (3.3%) with microsatellite unstable and/or tumor mutational burden-high (eligible for immunotherapy) and 7 (4.6%) homologous recombinational repair deficient. Alterations of several genes showed a significant association with tumor type (Table). Cancers in the ampulla of Vater were enriched for KRAS, APC and ARID2 alterations; TP53 alterations were less frequent in biliary tract/intrahepatic cancers. Among the 15 FGFR1/2/3 alterations, there were 3 amplifications (1 FGFR1, 1 FGFR2, 1 FGFR3), 3 missense FGFR2 mutations, and 9 FGFR2 fusions. Conclusions: Comprehensive genomic profiling of biliary tract cancers identifies numerous targetable alterations. The distribution of altered genes varies, suggesting that appropriate therapies may differ by location, reflecting different lineage types. [Table: see text]
Changing survival of intrahepatic cholangiocarcinoma based on Surveillance, Epidemiology, and End Results Database (2000–2018).
Authors: Wang Yating , Reap Leo Edward , Chang Kevin Wei-Lun , Terebelo Howard R. , Lyons Susan Elizabeth , Yu Zhiyong , Yu Qian
Published: June 2023

e16182

Background: Intrahepatic cholangiocarcinoma (iCCA) is a primary hepatic malignancy arising from peripheral intrahepatic bile ducts with poor survival and increasing incidence. Treatment regimen has changed in the last two decades, whereas new molecular targeted therapies have emerged. The present study aims to characterize changes in treatment outcomes of iCCA using a national representative database. Methods: Data were retrieved from the Surveillance, Epidemiology and End Results (SEER) 18 Research Plus Database. Overall survival (OS) was analyzed based on age, gender, race, histological grade, stage, and treatment. Predictors of OS were evaluated by Cox regression models. Statistical analysis was performed with Stata 15.1 (STATA Corp., College Station, TX, USA). Results: The overall observed OS from 2000 to 2018 at 12, 36, and 60 months were 42.6%, 16.4%, and 10.2%, respectively. The median survival time (MST) increased from 6 to 11 months from 2000-2004 time period to 2015-2018 (p < 0.0001). Such an improved trend was observed in all stage groups (p < 0.0001). Among patients diagnosed after 2015, the 12, 24, and 36 month OS were 45.9%, 26.4% and 17.4 %, respectively; the MST were 25, 13, and 6 months for patients with localized (12-month OS: 72.7%; 36-month OS: 37.5% ), regional (12-month OS: 51.4%; 36-month OS: 18.9%), and distant diseases(12-month OS: 28.2%; 36-month OS: 4.5%), respectively (p < 0.0001). On multivariable analysis, older age, female, grade, stage, whether surgery, chemotherapy or radiotherapy was performed were statistically significant predictors of OS (p < 0.001). Conclusions: Survival outcomes of iCCA improved in the last twenty years in all cancer stages. Age, gender, grade, stage, and whether interventions were performed were prognostic factors.
Molecular profiling of Chinese patients with advanced hepatocellular carcinoma using circulating tumor DNA.
Authors: Zhu Jianjiao , Li Mingwei , Ma Xiaoxue , Qin Jiayue , Cao Shanbo
Published: June 2023

e16186

Background: Hepatocellular carcinoma (HCC) has limited treatment options. Molecular analysis of its mutational landscape may enable the identification of novel therapies. Noninvasive strategies are critical to HCC given the challenge of obtaining liver tissue biopsies. Recent studies show that circulating tumor DNA (ctDNA) can reflect tumor genomic profiles. Thus, we aimed to analyze the molecular characteristics of HCC using ctDNA. Methods: A total of 308 plasma samples and 32 matched tumor tissues from Chinese patients with hepatocellular carcinoma (n = 308) were analyzed by Acornmed panel with 808 cancer-related genes. Results: A total of 4984 somatic variations were identified in 96.1% (296/308) ctDNA, including 4202 single nucleotide variants, 772 copy number variations and 10 fusions, and the median blood tumor mutation burden (bTMB) was 4.36 mut/Mb. Alterations in TP53 (152/308, 49.4%) were the most prominent variation, followed by those in TERT (48/308, 15.6%), ARID1A (37/308, 12.0%), CTNNB1 (34/308, 11.0%), NF1 (16/308, 7.7%), BRAF (16/308, 7.7%), PTEN (22/308, 7.1%) and EGFR (19/308, 6.2%). Interestingly, in MET and MYC, amplifications occurred more frequently than mutations. Moreover, we systematically evaluated clinically actionable mutations and totals of 587 potential drug-related targets from 211 patients (68.5%) were identified. In addition, in 32 patients with matched tumor tissues and plasma samples, sequencing detected alterations in 96.9% (31/32) tumor tissue DNA (tDNA) and 100% (32/32) ctDNA, respectively. Further analysis found that 25.4% of mutations of tissues were founded in ctDNA and 32.5% of mutations of ctDNA were detected in tissues. Among them, 68.8% (22/32) patients had at least one overlapping variant called by tDNA and ctDNA. The most common shared mutation was TP53 (8/32, 25.0%), followed by PTEN (2/32, 6.3%) and ARID1A (2/32, 6.3%). Meanwhile, two shared copy number variants were detected in two patients (6.3%), respectively. Conclusions: This study contributes to the understanding of the molecular characteristics of HCC using ctDNA and suggests potential clinical utility for this technology. Furthermore, it can more comprehensively reflect the molecular mutation status of patients by combining tissue and ctDNA detection.
Real-world experience with atezolizumab plus bevacizumab in the management of non-resectable hepatocellular carcinoma refractory to first-line systemic therapy: Review of literature.
Authors: Devarkonda Vishal , Byreddi Laxman Yashwant , Balmuri Shravya , Gudi Thulasi , Gaddam Shiva Jashwanth , Keerty Dinesh
Published: June 2023

e16189

Background: Hepatocellular carcinoma is the fifth most common cancer worldwide and the third leading cause of cancer-associated deaths. In 2020, the positive results of the IMbrave 150 trial and FDA (Food and Drug Administration) approval subsequently revolutionized the management of non-resectable hepatocellular carcinoma as the first-line treatment. However, their role as second-line therapy in people refractory to systemic therapy needs to be better studied. We perform a comprehensive literature review evaluating outcomes of atezolizumab plus bevacizumab in patients refractory to first-line systemic therapy. Methods: We performed a comprehensive literature search of PubMed, Embase, and Cochrane, evaluating the outcomes of atezolizumab plus bevacizumab in patients refractory to first-line systemic therapy. Results: Conclusions: Atezolizumab plus Bevacizumab is Safe and effective in the patient’s refractory to prior systemic therapy. However, when used as a second-line therapy, patients tend to have lower Median Odds of survival and Median progression-free survival. The outcome also changes with the type of prior systemic chemotherapy, with initial hyper-progression reported with prior therapy with lenvatinib. The AFP response at six weeks could be a predictive indicator of disease progression. [Table: see text]
Donafenib combined with camrelizumab and transarterial chemoembolization (TACE) as conversion therapy for unresectable hepatocellular carcinoma (uHCC): A prospective, single-arm, phase II study.
Authors: Cao Yajuan , Zhang Xuebin , Yue Yang , Peng Jin , Li Binghua , Shi Jiong , Tang Min , Chen Chaobo , Su Ke , Zhang Laizhu , Cheng Chunxiao , Yu Decai
Published: June 2023

e16203

Background: Approximately 64% of Chinese patients with HCC were evaluated as China Liver Cancer Stage (CNLC) II/III tumors, equivalent to Barcelona Liver Cancer Stage (BCLC) B or C. The conversion of an initially unresectable HCC (uHCC) to a resectable HCC may be an optimal approach to achieve better outcomes. Although donafenib, camrelizumab and transarterial chemoembolization (TACE) were recommended for uHCC in Chinese guidelines, the effect of these agents in the pre-operative setting was unclear. The present study was to assess the feasibility and safety of donafenib plus camrelizumab with TACE as conversion therapy in patients with uHCC. Methods: Patients were enrolled if they were aged 18 to 70 with primary CNLC stage IIb/IIIa uHCC, Child-Pugh classification A or B (≤7 points) and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. The patients received donafenib (100 mg po Bid), camrelizumab (200 mg iv Q3W) and TACE for up to 4 cycles (usually 2 cycles, increased to 3 or 4 cycles if necessary), followed by investigator assessment. The primary endpoint was the rate of major pathologic response (MPR), defined as ≤10% residual viable tumor in postoperative specimens. The secondary endpoints were the R0 resection rate, event-free survival (EFS), objective response rate (ORR) and disease control rate (DCR) by mRECIST criteria, and safety. Results: Sixteen patients, 11 men (68.8%) and five women (31.2%), of median age 58 years (range 49-70 years) were enrolled from May 2021 to July 2022. At the data cut-off (November 2022), one patient was still awaiting surgery, whereas 12 (80.0%) of the remaining 15 patients were successfully converted to resectable. Of the 12 patients who underwent successful hepatectomy (R0 resection), 6 (50%) achieved MPR. Based on mRECIST criteria, the ORR was 81.3%, and the DCR was 93.8%. Median EFS was 9.0 months (95%CI 7.1-10.9 months). Most treatment-related adverse events (TRAEs) were grade 1-2. Grade 3 TRAEs occurred in 4 patients. No patient experienced a Grade 4 or 5 TRAE. Conclusions: These preliminary results suggested that conversion therapy with donafenib, camrelizumab and TACE was safe and effective for uHCC. Clinical trial information: ChiCTR2100043462 .[Table: see text]
A prospective, single-arm, phase II clinical study of tislelizumab in combination with lenvatinib for perioperative treatment of resectable primary hepatocellular carcinoma with high risk of recurrence.
Authors: Song Tianqiang
Published: June 2023

e16218

Background: Surgery is the main radical treatment for hepatocellular carcinoma (HCC), but the high postoperative recurrence rate makes the survival benefit of patients limited. Neoadjuvant therapy mainly reduces postoperative recurrence by controlling micrometastasis and reducing preoperative tumor load and other high recurrence risk factors, but there are limited data on its application in liver cancer. Tislelizumab, a PD-1 monoclonal antibody, has shown promising efficacy with acceptable safety profile in combination with lenvatinib in the first-line treatment of advanced HCC. This study aims to explore the safety and feasibility of tislelizumab combined with lenvatinib in the neoadjuvant therapy and adjuvant therapy of resectable HCC. Methods: This prospective, single-center, single-arm phase II study (NCT04834986) enrolled patients with histologically confirmed resectable HCC who were at high risk of recurrence, as assessed by the investigators before surgery. Patients did not have any medical treatment in the past, with ECOG of 0-1, and had adequate organ and bone marrow function. Eligible patients received 4 cycles with tislelizumab (200mg, d1, Q3W) combined with Lenvatinib (8mg/kg, PO, qd) and surgery was performed within 4 weeks after treatment. At 4-8 weeks after surgery, adjuvant therapy was started with tislelizumab (200mg, d1, Q3W) and lenvatinib (8mg/kg, PO, qd) for at least half a year or until disease progression or intolerance of adverse reactions. Primary endpoints were safety and feasibility; secondary endpoints were ORR, 1 and 2-years DFS%, pCR, and DFS. Results: From Sep 7,2021 to Nov 9,2022, 24 patients (median age, 57.5 years) were enrolled, with most patients were males (95.8%) and 22 patients (91.7%) had HBV infection. All patients had Child-Pugh grade A and ECOG PS 0. The median treatment period was 4 cycles. In 24 patients, 17 patients (70.8%) underwent R0 resection, 3 patients (3/17, 17.6%) achieved complete pathological response (PCR), and 6 patients (6/17, 35.3%) achieved major pathological response rate (MPR, necrosis > 70%). 3 patients (12.5%) had significant tumor shrinkage and refused surgery. 1 patient (4.2%) is waiting surgery. 3 patients (12.5%) developed disease progression. According to RECIST1.1, ORR was 54.2% (13/24, CR 1, PR 12), DCR was 87.5%. According to mRECIST, ORR was 75.0% (18/24, CR 6, PR 12), DCR was 87.5%. No grade 3 or above adverse events were observed during neoadjuvant treatment period. The most common adverse events of any grade were rash (14/24,58.3%), hypertension (5/24,20.8%) and diarrhea (4/24,16.7%). Conclusions: Tislelizumab in combination with lenvatinib was well tolerated and showed promising efficacy as a neoadjuvant therapy for resectable HCC with high risk of recurrence. Clinical trial information: NCT04834986 .
Adjuvant therapy in localized vs regional biliary tract cancers: A SEER analysis.
Authors: Wei John X , Wang Christina , Pintova Sofya
Published: June 2023

e16221

Background: Biliary Tract Cancers (BTC) are aggressive malignancies. Treatment of early-stage disease involves surgical resection, but whether adjuvant therapy offers a clear survival benefit remains inconclusive. This study aims to explore the impact of demographic factors and adjuvant therapy on survival outcomes at a population level through the lens of the latest SEER (Surveillance, Epidemiology, and End Results) registries. Methods: Cases were filtered by the following criteria: histologic type (adenocarcinoma), anatomic location (gallbladder, intrahepatic, extrahepatic), stage (local and regional), microscopically confirmed diagnosis, and confirmed surgical resection. Cases with incomplete entries were excluded. A Cox proportional hazard model was used to analyze survival in the context of race, gender, income, and type of adjuvant therapy (none, chemotherapy (AC), chemo-radiotherapy (CRT), and radiation (RT)). Data analysis was performed in RStudio. Results: Between 2005 and 2019, 3565 patients were identified. Patients with regional BTC demonstrated improved median survival with AC (27 vs 23 months, HR 0.72, CI 0.63-0.82, p ≤.05) and CRT (28 vs 23 months, HR 0.63, CI 0.56-0.72, p ≤.05). Median survival in localized BTC was 52 months. Adjuvant therapy of any type did not impact survival for localized BTC. Analysis of race as a covariate in localized BTC showed that all minority groups had improved survival compared to non-Hispanic whites (Asian, HR 0.33; Black, HR 0.50; Hispanic, HR 0.38, p≤.05). In regional gallbladder BTC, this survival benefit was limited to Asians only (HR 0.52, p≤.05). Conclusions: Our data show that AC and CRT may improve survival in patients with regional BTC across all anatomic subtypes. In our cohort, adjuvant therapy had no impact on survival in localized BTC. Differences in outcomes may exist among racial groups for different subtypes of BTC. Future adjuvant clinical trials for BTC should consider stratifying for regional and localized disease. [Table: see text]
Ultra-sensitive baseline-informed MRD assay to predict prognosis outcomes in patients with resectable hepatocellular carcinoma.
Authors: Hu Jie , Tang Haoran , Xie Feng , Zhang Yue , Jia Shidong , Zhou Jian
Published: June 2023

e16228

Background: The detection of minimal residual disease (MRD) has been shown to be a potential biomarker for the prognosis and post-surgery treatment of resectable hepatocellular carcinoma (HCC). However, the application of MRD in HCC has been limited by the traditional requirement of carrying out MRD over 30 days post-surgery, which is often incompatible with the time window for adjuvant treatment decisions. Additionally, MRD results may be impacted by post-surgery imbalances if assayed too soon after surgery. Methods: This retrospective study enrolled 255 early-stage HCC patients who received surgical resections and had complete information on relapse and survival. Matched tumor and normal tissue samples were collected at the time of surgery and plasma samples were collected as early as 7 days post-surgery. An ultra-sensitive, baseline-informed MRD assay (PredicineBEACON) was used to evaluate the correlation between peri-surgical MRD status and prognosis outcomes. Somatic mutations were identified through PredicineWES+ whole exon sequencing, and up to 50 somatic mutations were selected for the design of a patient-specific capture panel, in addition to a fixed panel of 500 actionable variants. Results: The study has completed MRD tests for 58 patients, of which 8 were called MRD positive with ≥0.005% tumor fractions. The tumor fraction proportion of MRD-positive patients ranged from 0.008% to 5.653% (median 0.315%). The relapse-free survival (RFS) and overall survival (OS) were correlated with MRD status: the median RFS of MRD-positive patients was 13.9 months compared to not reached after 44.4 months for MRD-negative patients (p = 0.1), and the median OS of MRD-positive patients was 27.2 months compared to not reached after 55.5 months for MRD-negative patients (p = 0.03). Conclusions: Our results demonstrate the feasibility of using an ultra-sensitive, baseline-informed MRD assay to detect strong correlations between MRD status and prognosis outcomes in peri-surgical plasma samples collected as early as 7 days post-surgery in resectable HCC patients. This study highlights the clinical utility of MRD testing in peri-surgical settings.
Effect of UBR7 deficiency on glycolysis and PDAC resistance to gemcitabine by promoting PRMT5 stability.
Authors: Bi Lei , Zhao Miaoqing , Ru Kun , Tang Bo , Wang Yunshan
Published: June 2023

e16265

Background: Pancreatic ductal adenocarcinoma (PDAC) is a common malignant tumor of the digestive tract. Although gemcitabine and other therapeutic agents are effective in patients with advanced and metastatic pancreatic cancer, drug resistance has severely limited their use. However, the mechanisms of gemcitabine resistance in pancreatic cancer are poorly understood. Methods: In this study, ATAC-seq, ChIP-seq, and RNA-seq were performed to compare chromatin accessibility and gene expression in a patient-derived tumor xenograft (PDX) model of pancreatic cancer with or without gemcitabine resistance. Results: Analyzing these sequencing data, we found a dramatic change in chromatin accessibility in the PDX model of gemcitabine-resistant tissues and identified a key gene, UBR7, which plays an important role in mediating gemcitabine resistance. Further research found that depletion of UBR7 significantly increased pancreatic carcinogenesis and the immunosuppressive microenvironment. Mechanistically, depleted UBR7 increased the stability of PRMT5, thereby promoting glycolysis in pancreatic cancer cells. Finally, an inhibitor that blocks PRMT5 (DS-437) significantly reduced gemcitabine resistance in pancreatic cancer caused by UBR7 depletion. Conclusions: In conclusion, our results indicated that the UBR7-PRMT5 axis is a key metabolic regulator of PDAC and a promising target for the clinical treatment of gemcitabine resistance in PDAC.