bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of regorafenib plus ICIs as second-line treatment in advanced HCC post-frontline treatment failure: A real-world study from a single center.
Authors: Meng Lingzhan , Li Hu , Yu Peng , Cao Li , Wang Zizheng , Yan Jin , Shao Yanling , Shi Bin , Zhu Zhenyu 
Published: July 2024

e16141 Background: Tyrosine kinase inhibitor or bevacizumab (TKI/Bev) combined with immune checkpoint inhibitors (ICIs) currently represent the preferred frontline therapy for patients with Hepatocellular Carcinoma (HCC). Despite this, clinical evidence guiding therapeutic choice for patients unresponsive to this initial immunotherapy regimen remains scarce. This real-world study aimed to assess the efficacy and safety of regorafenib combined with ICIs in patients with HCC who have exhibited disease progress during treatment with TKI/Bev plus ICIs. Methods: This retrospective analysis encompassed a cohort of patients who transitioned to a combined regimen of regorafenib and immune checkpoint inhibitors (ICIs) after the progression of hepatocellular carcinoma (HCC) following treatment with tyrosine kinase inhibitors (TKIs) or a combination of bevacizumab and ICIs, from January 2019 to November 2023. Key efficacy metrics included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The adverse events (AEs) were systematically classified in accordance with the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0). Results: A total of 37 patients were included; 56.8% were Child-Pugh A and 43.2% were Child-Pugh B. Treatment regimens prior to regorafenib and ICIs were lenvatinib plus ICIs in 83.8% of patients, sorafenib plus ICIs in three patients, apatinib plus ICIs, donafenib plus ICIs, and bevacizumab plus ICIs each in one patient. The ORR was 27.0% (10/37), and the DCR was 92.0% (28/37) according to mRECIST criteria. The median PFS was 7.8 months (95% CI, 6.0-9.6). The 6-month and 12-month PFS rates was 60.6% (95% CI, 46.4-79.2) and 40.0% (95% CI, 26.0%-61.6%). The median OS post-regorafenib and ICIs was 16.3 months, with 12-month and 24-month OS rates of 67.0% and 49.7%, respectively. The median OS since first-line treatment initiation was 35.8 months, with OS rates of 94.4% and 72.3% at 12-month and 24-month since first-line treatment initiation, respectively. Subgroup analysis indicated no statistical significance in median PFS between patients with lung metastasis and those without lung metastasis [3.9 months (95% CI, 3.0-4.8) vs 7.80 months (95% CI, 6.1-9.5); P=0.178], but there was a trend toward survival benefit in patients without lung metastasis. Grade 3-4 adverse events were reported in 16.22% of the patients, with no treatment-related fatalities. Conclusions: Regorafenib with ICIs is a promising and tolerable second-line treatment for advanced HCC after initial therapy failure.
CVM-1118: A potent oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.
Authors: Yen Chia-Jui , Huang Yi-Hsiang , Yeh Kun-Yun , Chen Pei-Jer , Lu Sheng-Nan , Gutheil John , Melink Teresa J. , Chen Yen-Ling , Chen Chun-Man , Chao Ting-Yu , Chu Yi-Wen , Chien Du-Shieng 
Published: July 2024

e16150 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n = 4) or C (87%, n = 27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–15.0 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 4.6 mos (range 4.67–15.0 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 10.4 mos (95% CI 2.8–13.7 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was Cmax 564 ng/mL and the AUC0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .
Transcatheter arterial chemoembolization combined with immune checkpoint inhibitors plus bevacizumab or lenvatinib in hepatocellular carcinoma: Results from a retrospective dual-center cohort study.
Authors: Jiang Yi , Shu Mingzhi , Yao Zheng , Liang Weiren , Sheng Jiayi , Ding Yinan , Zheng Jiaping , Shao Guoliang , Mao Junjie , Luo Jun 
Published: July 2024

e16159 Background: Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent cancer worldwide. Notably, over 80% of HCC cases are diagnosed at an intermediate to advanced stage. Transcatheter arterial chemoembolization (TACE) is globally acknowledged as the standard local treatment for intermediate HCC and remains the predominant care for advanced HCC, While lenvatinib (LEN) or the combination of bevacizumab (BEV) and atezolizumab is recognized as a first-line systemic therapy for HCC. Moreover, TACE+LEN+immune checkpoint inhibitors (ICIs) in the treatment of HCC significantly enhances OS and PFS compared to the TACE+LEN. However, comparative studies between TACE+ICI+BEV and TACE+ICI+LEN are still forthcoming. Methods: This retrospective study encompasses data from 64 patients diagnosed with intermediate to advanced unresectable HCC at two medical centers in China between January 2021 and June 2023. The study's primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included tumor response and conversion rates. Additionally, the study assessed the safety by adverse events (AE) across the two groups. Results: Of the 64 enrolled patients, 31 were treated with TACE+ICI+BEV and 33 with TACE+ICI+LEN. There was no significant difference in PFS between the two groups (5.7 months [95% confidence interval (CI) 5.2 to 7.9] versus 4.9 months [95% CI 4.5 to 7.7], P=0.404). The median OS for the TACE+ICI+LEN group was 21.3 months (95% CI 15.1 to 27.5), whereas the median OS in TACE+ICI+BEV group was not reached. A markedly higher proportion of patients in the TACE+ICI+BEV group achieved surgical conversion (22.6% versus 3.0%, P=0.047). Patients presenting with an alanine aminotransferase (ALT) level ≤40 u/L (hazard ratio [HR]=5.61, 95% CI 1.09-28.80, P=0.039) and without hepatic vein invasion (HR=31.6, 95% CI 1.03-9.68, P=0.044) appeared to derive greater benefit from the TACE+ICI+BEV regimen. Furthermore, patients with a Child-Pugh score of class A exhibited enhanced response to the triple-combination therapy (HR=6.17, 95% CI 1.86-20.53, P=0.003). Both therapeutic strategies were characterized by favorable safety profiles. Conclusions: TACE+ICI+BEV has demonstrated notable potential in increasing surgical conversion rate in the management of intermediate to advanced HCC, suggesting enhanced outcomes particularly in patients with superior liver function. [Table: see text]
Plasma growth hormone as a prognostic biomarker to durvalumab and tremelimumab in patients with advanced hepatocellular carcinoma.
Authors: Chamseddine Shadi , LaPelusa Michael Brian , Xiao Lianchun , Abugabal Yehia I. , Lee Sunyoung S. , Hu Zishuo Ian , Hu Zishuo Ian , Hatia Rikita , Hassan Manal , Yao James C. , Duda Dan G. , Datar Saumil , Amin Hesham M. , Kaseb Ahmed Omar 
Published: July 2024

e16161 Background: In this study, we explored the potential of plasma growth hormone (GH) as a prognostic biomarker in patients with advanced HCC treated with durvalumab plus tremelimumab (D+T). Methods: In this study, we included 24 patients with advanced HCC who received D+T at MD Anderson Cancer Center between 2022 and 2023. Plasma GH levels were measured from prospectively collected blood samples from 16 of the 24 patients and were correlated with progression-free survival (PFS) and overall survival (OS). The cutoff for normal GH levels in women and men was defined as ≤3.7 μg/L and ≤0.9 μg/L, respectively. The Kaplan-Meier method was employed to compute the median OS and PFS, while the Log-rank test was applied to compare the survival outcomes between the GH-high and GH-low groups. Results: Twenty-four patients were included in this analysis, four female and twenty male, with a median age of 66.5 years. Of these 24 patients, 16 had GH levels available for analysis. At the time of the analysis, the 6-month OS rate was 100% among GH-low patients (6 patients) and 30% among GH-high patients (10 patients). OS was significantly longer in GH-low patients (not evaluable) compared to GH-high patients (3.94 months) (p = 0.030). PFS was also significantly longer in GH-low patients (not evaluable) compared to the GH-high patients (1.87 months) (p = 0.036). Conclusions: Plasma GH is a prognostic biomarker in patients with advanced HCC treated with D+T. Given the relatively small patient cohort size, this finding should be further validated in larger randomized clinical trials in advanced HCC patients.
Tislelizumab in combination with GEMOX and lenvatinib for conversion therapy of unresectable extrahepatic biliary tract carcinoma (eBTC): A prospective, single-arm, phase 2 study.
Authors: Liu Qu , Chang Zhengyu , Zhao Guodong , Gao Yuanxing , Tan Xianglong , Zhang Xuan , Jin Hailong , Liu Rong 
Published: July 2024

e16163 Background: Resection is the only possibility for cure but only less than 1/3 patients with BTC are diagnosed at resectable stages. PD-1 monoclonal antibody plus GEMOX and Lenvatinib regimens have shown promising efficacy for intrahepatic cholangiocarcinoma. However, owing to the extrahepatic and intrahepatic BTC are highly heterogeneous, the efficacy of combination regimen on eBTC is not clear. In this study, we explored the efficacy and safety of Tislelizumab plus GEMOX and Lenvatinib for conversion therapy of unresectable eBTC. Methods: In this prospective, single-arm phase 2 study, major eligible criteria were unresectable locally advanced or metastatic extrahepatic BTC, no previous systemic treatment, ECOG PS 0 or 1. Patients received tislelizumab (200 mg, iv, d1, every 3 weeks) in combination with GEMOX (gemcitabine: 1000 mg/m2, iv, d1,d8, every 3 weeks; oxaliplatin: 85 mg/m2, iv, d1, every 3 weeks) and Lenvatinib (bodyweight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day, po) until disease progression, intolerable toxicity or surgery. Surgery was performed after treatment response was assessed to meet the criteria of resection. Primary endpoint was the rate of radical resection. Second endpoints included ORR, DCR per RECIST 1.1, and safety, major pathologic response (MPR), PFS, OS. Results: Between Mar 1st 2022 and Feb 1st 2024, 35 patients were enrolled with a median age of 57.5 years (range 52-65); 20 males (57.1%), 15 females (42.9%); ECOG PS 0 (n = 13, 37.1%) or 1 (n = 17, 62.9%); 7 distal cholangiocarcinoma (20.0%), 16 hilar cholangiocarcinoma (45.7%), 12 gallbladder carcinoma (34.3%). 30 patients were evaluated for tumor response. The best overall responses were 2 complete response (6.7%), 16 partial response (53.3%), 9 stable disease (30.0%) and 3 progressive disease (10.0%). The ORR was 60.0% and DCR was 90.0%. 7 patients (20.0%) received radical resection and the complete pathological response (pCR) rate was 42.9% (n = 3). Any-grade adverse events (AEs) occurred in 91.4% (n = 32) patients. Grade 3-4 AEs occurred in 20.0% (n = 7) patients. The most frequent grade 3-4 AEs (incidence > 5%) were thrombocytopenia (8.6%), elevated AST/ALT (8.6%), neutropenia (5.7%) and leukopenia (5.7%). No grade 5 AEs. Conclusions: Tislelizumab plus GEMOX and Lenvatinib showed promising efficacy with manageable safety profile for conversion therapy of unresectable extrahepatic BTC. More patients were recruiting to further prove these results. Clinical trial information: ChiCTR2200056808.
A retrospective analysis of efficacy and safety of lenvatinib combined with PD-1 inhibitor and chemotherapy in advanced biliary tract cancer (BTC).
Authors: Li Hu , Meng Lingzhan , Yu Peng , Cao Li , Wang Zizheng , Yan Jin , Shao Yanling , Shi Bin , Zhu Zhenyu 
Published: July 2024

e16173 Background: Lenvatinib combined with PD-1 inhibitor and chemotherapy has showed a relatively high antitumor activity for ICC in phase 2 clinical trials. This study retrospectively analyzes the efficacy and safety of real-world lenvatinib combined with PD-1 inhibitor and chemotherapy in BTC. Methods: Patients with advanced BTC who received lenvatinib combined with PD-1 inhibitor plus oxaliplatin and gemcitabine (Gemox) chemotherapy were retrospectively screened. The overall survival, progression-free survival, objective response rate, disease control rate and safety were evaluated. Results: From Jan 2021 to Apr 2023, 27 pathologically-confirmed advanced BTC pts were enrolled. The median age is 61 (range, 39-74) years, 18 (66.7%) were male. Fourteen patients had TNM stage Ⅳdisease, and 7 patients had stage III. Twenty-six (96.3%) patients had an ECOG performance status of 1. All patients were child-pugh A. Fourteen patients had metastasis, 8 patients with lymph node metastasis, 4 with bone metastasis. 11 (40.7%) had positive PD-L1 expression. At baseline, 18 (66.7%) patients had a CA19-9 level > 200 U/mL. The median CEA level was 3.56 ng/mL; 48.1% of the patients had a level > 5 ng/mL. At the date cut off (Dec 15, 2023), the median follow-up time was 10.4 months (range: 4.8-25.7). ORR was 70.4% (19/27), and disease control rate (DCR) was 85.2% (23/27). Three pts with locally advanced disease were down-staged and then underwent resection. They remained disease-free survival at the end of last follow-up. The median PFS was 9.0 months (95% CI: 4.0-14.0) and median duration of response (DOR) was 9.8 months. The median OS was 20.4 months (95% CI: 13.6-27.2). 12-months OS rate was 73.3% (95% CI: 57.5%-89.2%).20/27 pts experienced treatment-related adverse events (AE). No grade 5 AE was observed. The most common AE was fatigue 66.7% (18/27), headache 7.4% (2/27). Grade 3 fatigue and grade 3 kidney injury occurred in 1 patient separately. Conclusions: Lenvatinib combined with PD-1 inhibitor and Gemox chemotherapy provided remarkable efficacy with reasonable tolerability in advanced BTC patients.
Liquid biopsy-based prediction of clinical benefit from immune checkpoint inhibitors in advanced biliary tract cancer.
Authors: Zhang Nan , Wang Yunchao , Yuan Mingming , Shao Jing , Chen Rongrong , Piao Mingjian , Li Jiongyuan , Li Chengjie , Zhang Longhao , Xue Jingnan , Wang Yanyu , Xun Ziyu , Wang Shanshan , Li Yiran , Sun Huishan , Wang Hanping , Zhao Hai-Tao 
Published: July 2024

e16179 Background: Immune checkpoint inhibitors (ICIs) show promising efficacy as first-line therapy for advanced biliary tract cancer (aBTC), but validated predictive biomarkers are lacking. Here, we identified liquid biopsy-based biomarkers and developed a prediction model. Methods: aBTC patients who received ICIs-based combination therapy as the first-line treatment were prospectively enrolled in this study (NCT06074029). Plasma samples were collected before the first and second immunotherapy infusion to perform cell-free DNA (cfDNA) sequencing of 1021 genes. Circulating tumor DNA (ctDNA) concentration was calculated by multiplying the mean variant allele frequency by the cfDNA concentration and ctDNA fold change was calculated by dividing on-treatment ctDNA concentration by the pre-treatment ctDNA concentration. Tumor mutation burden (TMB) was normalized using the cfDNA concentration. In addition, RNA was extracted from peripheral blood mononuclear cells to profile the leukocyte transcriptome using whole transcriptome sequencing, and the relative proportions of immune cells in leukocytes was deconvoluted using CIBERSORT algorithm. Log-rank and univariate Cox regression were used to evaluate the relationship between features and progression-free survival (PFS). Results: 37 patients were enrolled, with 62.2% having intrahepatic cholangiocarcinoma. The median age was 61 years and 54.1% of patients were females. The median PFS was 4.4 months. Variables related to PFS with the log-rank p value smaller than 0.05 (Table) were entered into a multivariate Cox regression using a stepwise approach for final variable selection. As a result, ctDNA fold change, KRAS mutation, and resting memory CD4 T cell level were used to construct a COX regression model to predict clinical benefit from ICIs. The model predicting 6-month PFS demonstrated an AUC of 0.909 (95% CI, 0.795-1.024). Internal validation, performed through a bootstrap analysis with 100 iterations, yielded an optimism-adjusted AUC estimate of 0.859. Conclusions: Our preliminary results support the excellent performance of this liquid biopsy-based multivariable model to early predict durable benefit from ICIs in aBTC. A large sample size and verifying this model with internal and external data are warranted. Clinical trial information: NCT06074029 . [Table: see text]
Effect of immune checkpoint inhibitor administration timing on survival outcomes in advanced biliary tract cancers: A single-center propensity score matching analysis.
Authors: Zheng Yichen , Shi Fanfan , Peng Wei , Ma Ji 
Published: July 2024

e16186 Background: Circadian rhythms in the immune system and anti-tumor immune responses have not received adequate attention in terms of their impact on cancer immunotherapy. Recent advances in immune checkpoint inhibitors (ICIs) have marked a significant breakthrough in the treatment of advanced biliary tract cancer (BTC), but not all patients benefit from this therapy. Our study aimed to investigate whether the timing of ICI administration affects the treatment outcomes in BTC patients. Methods: We included patients with advanced BTC patients at West China Hospital of Sichuan University who received at least two ICI treatments from October 2019 to May 2023, with follow-up until December 2023. The primary outcome was overall survival (OS), with secondary outcomes including progression-free survival (PFS), objective response rate (ORR), and adverse event incidence. Propensity score matching (1:2 ratio, nearest-neighbor caliper width of 0.1) and COX regression were used to analyze the relationship between the proportion of ICI administrations after 16:30 and both OS and PFS, while the Chi-square test was used to compare the ORR and adverse event rates between groups. Results: A total of 207 patients were eligible for analysis. Before matching, 37 patients had more than 20% of their ICI administrations after 16:30, and 170 had less than 20%. After matching, 34 patients receiving more than 20% of ICIs after 16:30 were compared with 65 who did not. The former group showed significantly shorter OS (median 10 months [95%CI: 8-14 months] vs. 17 months [95%CI: 12-20 months], HR = 2.067 [95%CI: 1.226-3.485, P = 0.00645]) and PFS (median 5 months [95%CI: 4-7 months] vs. 9 months [95%CI: 8-12 months], HR = 2.093 [95%CI: 1.315-3.331, P = 0.00183]), with these results remaining robust after multivariate Cox regression analysis. No significant difference in ORR (χ^2 = 2.287, p = 0.131) was observed. Safety analysis showed no difference in the incidence of adverse events, including Grade 3/4 adverse events, immune-related adverse events, and medication discontinuation due to adverse events (all p > 0.050). Sensitivity analyses in patients receiving at least three ICI treatments revealed similar results. Conclusions: The timing of ICI administration influences the efficacy of immunotherapy in advanced biliary cancer, with administrations before 16:30 associated with better survival outcomes. Further research with larger sample sizes and prospective studies is needed to validate these findings.