bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and preliminary efficacy of different doses of fecal microbiota capsule transplantation combined with anti-PD-1 inhibitor for patients with advanced malignant solid tumors.
Authors: Zhu Wenyu , Chu Yunqian , Xue Ya , Hu Muni , Dai Hanjue , Xian Qingying , Jiang Hua
Published: July 2024

e14622

Background: Chemotherapy combined with anti-PD-1 inhibitors has now become the standard first-line(1L) treatment for most malignant solid tumors. However, most Phase III studies have found that overall progression-free survival (PFS) with 1L combined subsequent immuno-maintenance therapy (IMT) is still less than 1 year. Fecal microbiota transplantation (FMT) has been shown to synergize with PD-1 antibodies to enhance efficacy. In this study, we administered oral microbiota capsule transplantation to patients(pts) during 1L IMT to evaluate its safety, preliminary efficacy, optimal dosage, and explore the changes in gut microbiota composition and serum metabolism (ChiCTR2100054928). Methods: This is a dose-escalation, exploratory clinical trial. The donor capsules were derived from the feces of a healthy 10-year-old child from a rural area. Twelve late-stage pan-cancer pts who had received standard 1L chemotherapy + PD-1 antibodies and achieved stable or responsive disease were enrolled. The first 3 patients were in the i group (5 capsules po tid d1-3). If no dose-limiting toxicities (DLTs) were observed, another 3 patients were escalated to the i+1 group (10 capsules po bid d1-3). If no DLTs were observed again, another 3 patients were escalated to the i+2 group (10capsules po tid d1-3), and so forth, until the i+3 dose group (20 capsules po bid d1-3). Simultaneously, patients continued receiving the original PD-1 IMT. Fecal samples were collected at baseline (S0), after 10 days (S1), 25days (S2), and 50days (S3) of FMT. Results: From March 2023 to December 2023, 12 pts were successfully enrolled. As of the data cutoff date (December 31, 2023), the median follow-up time was 9.05 months (6.5-9.5 months), and the median PFS has not been reached, with 3 patients experiencing disease progression. Four patients (33.3%) experienced Grade 1-2 FMT-related toxicities, including diarrhea, bloating, and abdominal pain, with no Grade 3 or higher adverse events observed. Fecal metagenomic sequencing analysis showed that the relative abundance levels of Blautia and Faecalibacterium significantly increased after FMT, peaking at day 25 and remaining higher than pre-transplant levels at day 50. We also found that patients in the i+1 group exhibited the greatest changes in microbial composition before and after transplantation, with high absolute and relative transplantation indices. Further analysis of host serum metabolism revealed an increase in molecules related to fatty acid metabolism, such as L-carnitine, stearic acid, and arachidic acid, especially a more pronounced increase in the i+1 group. Conclusions: This preliminary study demonstrates that the combination of oral microbiota capsule and immunotherapy can open up a more economical, safe, and effective avenue for 1L maintenance immunotherapy in tumors. Clinical trial information: ChiCTR2100054928.
A single-arm exploratory clinical study of β-glucan combined with camrelizumab and SOX chemotherapy as first-line treatment for advanced gastric adenocarcinoma.
Authors: Zhu Wenyu , Chu Yunqian , He Xuan , Jiang Hua , Zhu Chan , Zhang Xing , Wu Fangfang , Dai Hanjue , Xian Qingying , Xue Ya
Published: July 2024

e16008

Background:The combination of immunotherapy plus chemotherapy has revolutionized the therapy pattern of advanced gastric adenocarcinoma, but the efficacy is still unsatisfactory. β-glucan has been reported to be a potential natural immune modulator for tumor growth inhibition. Therefore, we aimed to evalute the efficacy and safety of β-glucan plus immunotherapy and chemotherapy in the first-line treatment of advanced gastric adenocarcinoma. Methods:This is a prospective, single-arm, investigator-initiated trail. All included patients are adults with advanced gastric adenocarcinoma, and with an Eastern Cooperative Oncology Group (ECOG) score ≤ 2. Eligible patients received WGP β-glucan (500 mg; twice daily on days 1-14) + camrelizumab (day 2; fixed-dose 200 mg) + oxaliplatin (day 1; 130 mg/m2)+ oral S-1 (twice daily on days 1-14; body surface area < 1.25 m2: 40 mg; body surface area 1.25-1.5 m2: 50 mg; body surface area > 1.5 m2: 60 mg) every 3 weeks. The curative effect is evaluated (RECIST 1.1) every 2 cycles. Safety evaluation indicators include vital signs, laboratory indicators and treatment-related adverse events (TRAEs). The primary endpoints were objective response rate (ORR) and safety; the secondary endpoints were median progression-free survival (mPFS) and median overall survival (mOS); the exploratory endpoint treatment-related biomarker changes from liquid biopsies. Results:From April 2021 to October 2022, a total of 30 patients with average of 67.5 years old had been enrolled, incuding 20 (66.7%) males and 8 (26.7%) patients with an ECOG PS score of 2. The ORR was 60%; the mPFS was 10.4 months (95% confidence interval [CI], 9.52-11.27); the mOS was 14.0 months (95% CI, 11.09-16.91). A total of 19 patients (63.3%) had TRAEs, with 9 patients (30%) with grade ≥ 3. The most common treatment-related adverse events were nausea (53.3%) and hemangioma (33.3%). No TRAEs associated with β-glucan were observed. After 2 cycles of treatment, the levels of IL-2 and IFN-γ significantly increased ( P < 0.05), and the number of CD4+ T cells also significantly increased ( P < 0.05). Furthermore, the protein expressions of GZMA, GZMH, and CD244 were significantly lower in the responding group (CR+ PR) than in the non-responding group (SD + PD) (P < 0.05). Conclusions: This preliminary study demonstrates that β-glucan plus camrelizumab and SOX chemotherapy offers favorable efficacy and a manageable safety profile in patients with advanced gastric adenocarcinoma, and further studies are needed to verify its efficacy and safety. Clinical trial information: ChiCTR2100044088.
Modifying the gastric tumor microenvironment with tadalafil: A transcriptomic analysis of immune signatures from underserved patients of southern Arizona.
Authors: Arshad Junaid , Ding Lin , Scott Aaron J. , Mallick Palash , Shroff Rachna T. , Merchant Juanita L
Published: July 2024

e16104

Background: Gastric adenocarcinoma (GAC) is the fifth most common cancer worldwide with significant morbidity and mortality. Recently, southern Arizona has seen a concerning surge in incidence of GAC due to ineffective H. pylori screening and treatment. Moreover, peri-operative chemotherapy treatment in stage IB-III GAC represents an area of unmet need for new targets. Our center serves a catchment area that is 40% Hispanic and sees a high volume of GAC patients, making this our research focus. Our preclinical work in Helicobacter infected mice showed a subset of myeloid derived suppressor cells (MDSCs) expressing Schlafen4 (SLFN4) concurrently with gastric metaplasia, a GAC precursor. SLFN4+ MDSCs exhibit robust transcriptional signatures associated with type I interferon(IFN-I) inducible genes, coupled with T cell suppressor function. Pharmacological inhibition via phosphodiesterase (PDE) 5,6 inhibitor sildenafil resulted in the suppression of SLFN4, reversal of T cell suppression, and mitigation of metaplasia. This is the first clinical study aimed to characterize SLFN12L, the human ortholog of mouse SLFN4, and to analyze the neoplastic and immune signatures in GAC before and after PDE5 inhibition with tadalafil. Methods: Using single-cell RNA sequencing, we examined tissues from GAC patients enrolled in a "Window of Opportunity" study (NCT05709574). The patients receive tadalafil (20mg) for 14 days, followed by combined tadalafil and FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) for 8 weeks. Gastric tissue and blood samples were collected i) before treatment, ii) after 14 days of tadalafil, and iii) after 8 weeks of combined treatment. We have enrolled 3 Hispanic patients to date with ongoing enrollment. Results: Tumors exhibited responses as per radiologic and pathologic criteria. In contrast to SLFN4, primarily expressed in myeloid cells, SLFN12L was found in most CD14+T lymphocytes and natural killer cells. A prominently activated and expanded myeloid population expressing SLFN12L was identified in the gastric mucosa of GAC patients. These cells exhibited transcriptional signatures associated with IFN-I signaling and immunosuppressive activities, diminishing after tadalafil treatment. Within GAC tissue, a notable increase in exhausted T cells and regulatory T cells was observed, decreasing after tadalafil. Post-tadalafil testing showed tissue PDE5/6 inhibition and higher plasma cGMP. Effector T cells exhibited an upward trend following tadalafil, suggesting a reduction in tumor immunosuppression. Conclusions: Preliminary data of this ongoing study show that tadalafil treatment combined with FLOT, has the potential to decrease SLFN12L+ MDSC, to attenuate their immunosuppression, and potentially inhibit tumor progression. The trial is active and further analysis will be presented in due course.
Effect of triplet regimen (single-agent chemotherapy plus anti-PD-1 antibody and tyrosine kinase inhibitors) on survival compared to chemotherapy in the second-line treatment of advanced biliary tract cancer: A retrospective analysis.
Authors: Yuan Zhengang , Shang Peipei
Published: July 2024

e16132

Background: TOPAZ-1 and KEYNOTE-966 trials have demonstrated the survival benefit of immune checkpoint inhibitors (ICIs) plus chemotherapy in advanced biliary tract cancer (BTC). Although the ABC‐06 study proved the benefits of FOLFOX in 2nd line therapies, the efficacy is limited. There is no consensus regarding the optimal therapy regimen, and more effective therapeutic options are needed. This retrospective analysis aims to evaluate the efficacy of a triplet regimen compared to standard chemotherapy in 2nd line BTC. Methods: Pts > 18 years, with ECOG PS 0/1, histologically confirmed metastatic BTC and progression on 1st line Gemcitabine-based therapy were eligible. A triple regimen was referred as Cohort A: tislelizumab and other anti-PD-1 antibody, capecitabine or S-1 plus tyrosine kinase inhibitors (TKIs, lenvatinib or anlotinib). Standard chemotherapy was Cohort B: mFOLFOX or irinotecan plus capecitabine. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), overall response rates (ORR), disease control rate (DCR) and safety. Results: This study retrospectively collected and analyzed treatment and clinical information from 121 pretreated BTC pts from Oct. 2021 to Oct. 2023, with a median age of 60 (range 36-82) years and 48% (58) of the pts were female. Among them, 86 patients received the triple regimen, while 35 patients received standard chemotherapy. Pts’characteristics were well balanced between the two groups in terms of gender, age, ECOG score, primary site, CEA, CA199, or presence of distant metastasis. According to the RECIST1.1 criteria, 1 pt achieved CR and 31 pts had PR in the triple treatment cohort, ORR reached 37.2% (95%CI 27.0-48.3%), which was significantly higher than the 2.8% (95%CI 0.1-14.9%) in the standard chemotherapy cohort (p < 0.0001). Accordingly, the DCR of the two groups were 89.5% (95%CI 81.1-95.1%) and 71.4% (95%CI 53.7-85.4%) respectively. As of Oct 31, 2023, all patients developed progression, and the median PFS in cohort A was 6 months, compared to 2.0 months in cohort B (HR, 0.29, 95%CI 0.16-0.52, p < 0.0001). 64 patients of cohort A and 28 patients of cohort B developed death. The median OS in cohort A was 16.0 months, compared to 6.0 months in cohort B (HR 0.35, 95%CI 0.19~0.64, p < 0.0001). Any grade TRAEs occurred in 54.7% pts of cohort A and 42.9% of cohort B. Most common grade 3 TRAEs were hypohepatia (19.8%), hand-foot syndrome (11.6%), gastrointestinal reaction (1.2%) in cohort A, and hypohepatia (8.6%), hand-foot syndrome (2.9%) in cohort B. Conclusions: The retrospective analysis suggests that the triple regimen as second-line treatment for advanced BTC pts may help improve the efficacy and survival, and is worthy of further prospective exploration.
Second-line systematic strategy options for the progression of lenvatinib plus tislelizumab treating unresectable hepatocellular carcinoma: A retrospective study.
Authors: Xiaozhun Huang , Che Xu , Wang Chuling
Published: July 2024

e16135

Background: Lenvatinib plus Tislelizumab (LEN+TIS) is a first-line systemic treatment for unresectable hepatocellular carcinoma (uHCC) in the real world, however, most uHCC ultimately fail to respond to first-line therapy due to tumor progression or intolerable adverse effects. The progression-free survival (PFS) of Lenvatinib was approximately 8 months in both REFLECT and LEA-002 studies. Therefore, there were doubts about the second-line therapy after progressive disease (PD) of LEN+TIS, and no studies hade reported the specific switching mode. Methods: This study retrospectively analyzed the clinical data of the first-line treatment of uHCC with LEN+TIS in National Cancer Center/Cancer Hospital & Shenzhen Hospital from April 2019 to December 2023. According to the actual use of drugs, Group A changed Lenvatinib to Regorafenib while Tislelizumab was not changed after PD of LEN+TIS; Group B replaced with Regorafenib plus other immune checkpoint inhibitors (including PD-1, PDL-1) after PD of LEN+TIS. The initial dose of Regorafenib was 80 to 160 mg, which could be adjusted according to patient tolerability, with Regorafenib administered orally once daily for the first 3 weeks, every 4 weeks as a cycle; Tislelizumab given 200mg intravenously every 3 weeks. Both group A and B were subdivided into two subgroups based on whether PFS of LEN+TIS had been more than 8 months. Short- and long-term outcomes were assessed by two independent radiologists according to mRESCIST criteria, all statistical analysis was performed using SPSS version 20. Results: After rigorous screening, a total of 446 samples were recruited in this study, including 208 in group A and 238 in group B. The baseline characteristics were comparable between the two groups, all patients were Child-Pugh grade A, and the median follow-up time was 9.8 months. Group A had higher objective response rates (ORR: 31.2%vs26.9%), PFS (7.6vs6.1months), and median overall survival (mOS: 12.8vs11.2months). Subgroup analysis showed that patients in group A who had first-line PFS shorter than 8 months had a better treatment effect than those with first-line PFS longer than 8 months (ORR: 36.9%vs17.7%; DCR:69.2%vs46.8%;PFS: 8.7vs 5.1months; OS: 14.4vs8.9months; P<0.05); patients in group B who were treated with first-line systemic PFS shorter than 8 months was worse than that with first-line PFS longer than 8 months (ORR:12.2%vs38.6%; DCR:45.3%vs68.9%;PFS:5.6vs6.4months;OS:9.1vs12.6months; P<0.05). No new adverse events were observed, no treatment-related deaths occurred in either group. Conclusions: If the PFS of LEN+TIS was shorter than 8 months, Lenvatinib should be changed to Regorafenib, Tislelizumab could be not changed. And if the PFS of LEN+TIS was longer than 8 months, Lenvatinib and Tislelizumab should be changed at the same time, which seemed to achieve better results.
Transarterial chemoembolization combined with donafenib or lenvatinib as first-line treatment for unresectable hepatocellular carcinoma: A single-center real-world retrospective study.
Authors: Liu Huan , Huang Mingsheng
Published: July 2024

e16137

Background: Combined Transarterial chemoembolization (TACE) with tyrosine kinase inhibitor (TKI) treatment has been proven to be beneficial. This study aimed to retrospectively compare the efficacy and safety of Donafenib (DON)-TACE versus Lenvatinib (LEN)-TACE as first-line treatment for unresectable hepatocellular carcinoma (uHCC). Methods: From May 2020 to May 2023, a retrospective analysis was conducted on the clinical data of 93 patients with previously untreated uHCC who underwent treatment at the department of Interventional Radiology of the Third Affiliated Hospital of Sun Yat-sen University. Among them, 49 were in the DON-TACE group and 44 in the LEN-TACE group. The primary endpoint was progression-free survival (PFS) according to mRECIST, and the secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety outcome. Results: As of the data cut-off date Aug 26, 2023, the median PFS was 221 days (95% CI 141–366) in the DON-TACE group and 173 days (95% CI 108–215) in the LEN-TACE group (HR = 0.783, 95% CI 0.462–1.325, P = 0.362).ORR and DCR of the DON-TACE group were 55.1% (95% CI 40.23–69.33) and 75.51% (95% CI 61.13–86.66), respectively, while those of the LEN-TACE group were 61.36% (95% CI 45.49–75.64) and 81.82% (95% CI 67.29–91.81). No significant difference was observed either in ORR(P = 0.689) or DCR(P = 0.627) between the two groups. The incidence rates of total adverse events for any grade (85.71% vs 100.00%, P = 0.027) and ≥Grade 3 (22.496% vs 45.45%, P = 0.019) were significantly lower in the DON-TACE group. In addition, the incidence rates of AST increased (27.27% vs 56.82%, P = 0.005), diarrhea (6.12% vs 25.00%, P = 0.011), vomiting (0% vs 40.91%, P < 0.001), proteinuria (0% vs 18.18%, P = 0.011), gastrointestinal hemorrhage (0% vs 13.64%, P = 0.048) and hypertension (2.04% vs 36.36%, P < 0.001) for any grade were also significantly lower in the DON-TACE group. Conclusions: DON-TACE and LEN-TACE showed comparable efficacy as first-line therapies for uHCC patients. DON-TACE demonstrated a lower incidence of severe adverse events.
Real-world study of anlotinib monotherapy and combination therapy for unresectable hepatocellular carcinoma.
Authors: Lei Yi , He Jingchang , Kang Shuai , Liu Dingli , Yu Wenxuan , Wang Kunyuan , Chen Huaiyu , Cheng Yang , Zhu Yun
Published: July 2024

e16146

Background: Unresectable hepatocellular carcinoma (uHCC) is an aggressive tumor with poor prognosis. Anlotinib is a novel small-molecule tyrosine kinase inhibitor (TKI) that selectively targets VEGFR, FGFR, PDGFR, and c-kit receptors. Clinical trials have confirmed the efficacy and safety of anlotinib monotherapy or anlotinib-based combination therapy for uHCC. However, many patients in clinical practice fail to meet the criteria for these trials. Therefore, this study aimed to investigate the efficacy and safety of anlotinib, as monotherapy or in combination therapy, for uHCC in clinical practice in China. Methods: This multicenter, real-world study enrolled patients with uHCC who had received anlotinib-based therapy, and completed at least one post-treatment efficacy assessment between July 2020 to February 2023. Patients who did not undergo imaging after one cycle of treatment, were lost to follow-up before completing one cycle of treatment, or required systemic chemotherapy or radiotherapy for the primary lesion were excluded from the study. The efficacy assessments were performed based on the RECIST version 1.1. OS, PFS, TTP, DCR and ORR for patients with anlotinib monotherapy (n = 12) and anlotinib-based combination therapy (n = 60) were evaluated. The main statistical analysis was conducted using the Kaplan–Meier method and log-rank test. Subgroup comparisons were performed based on different combinations of anlotinib therapy and the number of treatment lines in patients with uHCC. Occurrence of adverse events (AEs) to evaluate the safety profiles of anlotinib monotherapy or anlotinib-based combination therapy was collected. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire HCC-18 (EORTC QLQ-HCC18) was used to evaluate health-related quality of life (HRQOL). Results: For the anlotinib monotherapy group, the OS, PFS, TTP, DCR and ORR were 14.2 months, 6.9 months, 7.9 months, 16.7%, and 50.0%, respectively. For the anlotinib-based combination therapy group, these values were 15.8 months, 8.6 months, 10.2 months, 25.0%, and 65.0%, respectively. There was no significant difference in OS, PFS, and TTP between the two groups. PFS were significantly decreased in the non-first-line treatment group compared to the first-line treatment group. The incidence of drug-related AEs of any grade was 93.1%, with the most common grade ≥3 treatment-related AEs being lymphopenia and elevated transaminases. The time to deterioration was 14.0 months (95%CI: 8.3–19.8) and 12.2 months (95%CI: 9.8–14.7) in the monotherapy and combination therapy groups. Conclusions: Anlotinib demonstrated satisfactory efficacy and safety as a single agent and in combination with other therapies in the treatment of uHCC, with potential benefit on health-related quality of life.
Efficacy and safety in advanced hepatocellular carcinoma between patients with negative and positive APF treated with targeted and immunotherapy.
Authors: Cheng Jiamin , Gao Shuyue , Zhang Tianlan , Li Pingping , Yu Lingxiang , Li Yinyin , Tu Bo , Song Meiru , Li Shuang , Ren Yuebo , Lu Yinying
Published: July 2024

e16162

Background: Serum alpha-fetoprotein (AFP) is widely accepted as a crucial tool for clinical diagnosis and screening of HCC. However, there are cases where patients test negative for AFP but are confirmed to have Hepatocellular Carcinoma through imaging or pathological examinations. Despite these findings, there is limited research focusing on the medicine selection for AFP-negative patients. Methods: This retrospective cohort study, involving 223 untreated advanced HCC patients, and the first-line regimen consisted of targeted therapy and TKI+ICIs therapy. Patients are categorized into negative and positive AFP groups based on initial serum levels. Main efficacy endpoint was progression free survival (PFS), evaluated in accordance with RECIST v1.1. Adverse events (AEs) were recorded according to CTCAE v5.0. Results: According to the level of serum AFP, they were divided into negative group(100) and positive group(123). The two groups showed no statistically significant differences in age, gender, Child-Pugh score and other baseline clinical characteristics( P> 0.05). At data cut-off at February 2023, median OS was not matured and mPFS in negative group was higher than positive group(8.2 vs 5.3months, P< 0.0001). In the ICIs+TKI therapy cohort, mPFS in the negative AFP group(52) was significantly higher than in the positive AFP group(70) (10 vs. 5.8 months, P = 0.0021). Considering all patients in the negative AFP group as a subgroup, an analysis of survival benefits between those receiving targeted therapy and those receiving TKI+ICIs therapy revealed no significant difference in PFS( P> 0.05). Moreover, AEs were compared between the negative and positive group, with no significant differences observed in Any Grade or Grade 3/4( P> 0.05). Conclusions: Patients with negative AFP exhibited superior survival benefits compared to those with positive AFP in first-line therapy. Regarding PFS, the TKI+ICIS therapy did not demonstrate a better benefit over targeted therapy in the negative AFP subgroup.
Des-gamma-carboxy prothrombin (DCP) as a prognostic biomarker in patients with advanced hepatocellular carcinoma treated with atezolizumab/bevacizumab.
Authors: Conner Elizabeth , Chang Jeremy , Burgoyne Adam
Published: July 2024

e16167

Background: Causes of variable disease response to first-line treatment with atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC) remain unclear. Identifying tumor markers that predict treatment response and provide prognostic information may help clinicians optimize treatment strategies and patient outcomes. The role of des-gamma-carboxy prothrombin (DCP) is not well established in Hepatitis B Virus non-endemic areas. This study aimed to investigate DCP as a predictive biomarker of treatment response as well as explore prognostic implications of DCP in patients with advanced HCC. Methods: This single-center retrospective analysis evaluated DCP and radiographic response in patients with advanced HCC who received atezolizumab/bevacizumab in the first-line setting. DCP was measured at the time of best response, determined by radiographic evaluation, and compared to day one of atezolizumab/bevacizumab initiation. Elevated DCP was defined as > = 7.5 ng/mL. DCP response was defined as a decrease of > = 50% at response assessment compared with baseline. Comparisons of treatment effects were performed using two-tailed Fisher Exact Probability Test. Overall survival (OS) was defined as the interval between the first treatment and either the date of death or the last follow-up visit. OS was analyzed using the Kaplan–Meier method and compared between groups using the log-rank test. Results: A total of 53 patients with advanced HCC treated with atezolizumab/bevacizumab were included. Radiographic treatment responses were complete response 3.8%, partial response 22.6%, stable disease 52.8% and progression of disease 20.8%, respectively. On day one of treatment 70% of patients had an elevated DCP. Patients with DCP response had ORR of 69% (odds ratio, 15.75; 95% CI, 3.50 – 70.9; p = 0.0002) and disease control rate of 100% (p = 0.047). Conversely, patients with > = 50% increase in DCP at response evaluation compared to day one of treatment had ORR of 4.5% and no response rate of 95% (p = 0.0035). Furthermore, patients who had > = 50% increase in DCP had median OS of 15.4 months compared to patients without > = 50% increase in DCP who had median OS of 28.4 months (HR = 2.48; 95% CI, 1.035 – 5.93; p = 0.042). There was no difference in ORR, or OS, between patients who had elevated DCP on day one of treatment and those who did not. Conclusions: DCP response correlates with objective radiographic response in patients with advanced HCC treated with atezolizumab plus bevacizumab in the first-line setting. DCP increase of > = 50% correlates with decreased median OS and may serve as a negative prognostic biomarker in such patients.
Lenvatinib (Lenv) plus tislelizumab (Tis) combined with or without transarterial chemoembolization (TACE) in first-line treatment of unresectable hepatocellular carcinoma (uHCC): A prospective, non-randomized, open-label, phase II cohort study.
Authors: Zhang Nan , Li Jiongyuan , Piao Mingjian , Li Chengjie , Xun Ziyu , Zhang Longhao , Wang Yanyu , Liu Kai , Wang Shanshan , Wang Hanping , Zhao Hai-Tao
Published: July 2024

e16169

Background: The synergistic potential of programmed death protein-1 inhibitors and tyrosine kinase inhibitors in treating uHCC has been established. TACE, a cornerstone in uHCC therapy, primes the tumor microenvironment for immunotherapy by releasing neoantigens and inducing ischemia. This study explores the efficacy and safety of Lenv plus Tis, combined with or without TACE, in a first-line setting. Methods: This phase II study enrolled patients (pts) with pathologically and/or radiologically diagnosed uHCC eligible for embolization, with at least one measurable lesion, Child-Pugh class A/B, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Pts received Tis (200mg every 3 weeks) and Lenv (oral dose adjusted by weight: 8mg for <60kg and 12mg for ≥60kg) with or without conventional TACE, as determined by the treating physician. The primary endpoint was the objective response rate (ORR), with secondary endpoints including overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Results: By the data cutoff on January 27, 2024, 37 pts were enrolled: 12 received Lenv+Tis (cohort 1), and 25 received Lenv+Tis+TACE (cohort 2). Median follow-up time was 10.66 months. The ORR was 33.3% in cohort 1 and 68.0% in cohort 2, with DCRs of 100% and 96%, respectively (mRECIST). Median OS was 10.85 months (95% CI, 4.76-16.95) for cohort 1 and 13.61 months (95%CI, NE-NE) for cohort 2. Median PFS was 10.85 months (95% CI, NE-NE) for cohort 1, and 11.86 months (95% CI, 6.49-16.73) for cohort 2. Grade 3-4 treatment-emergent adverse events (teAE) occurred in 50% of cohort 1 and 68% of cohort 2. No fatal adverse event was reported. The most common grade 3-4 teAE (incidence >10%) were anaemia (17%) in cohort 1, and decreased platelet count (16%), hypertension (16%), rash (16%), fatigue (12%), elevated ALT (12%) in cohort 2. Conclusions: Both Lenv+Tis and Lenv+Tis+TACE showed promising efficacy and manageable safety in the first-line treatment of uHCC. More pts were recruiting to further prove these results. Clinical trial information: NCT05842317 . [Table: see text]
Efficacy and safety of TACE combined with ablation and regorafenib for unresectable hepatocellular carcinoma: A real-world study.
Authors: Xiong YiQi , Gao WenFeng , Long Jiang , Hu CaiXia , Yuan ChunWang , Sun Yu , Shi QinSheng , Sun Bin , Zhang YingHua , Cui XiongWei , Hao MeiJun , Li Jianjun , Zhang Yonghong
Published: July 2024

e16170

Background: The purpose of our study was to determine the efficacy and safety of transarterial chemoembolization (TACE) combined with regorafenib as second-line therapy in patients with unresectable hepatocellular carcinoma (HCC). Methods: Patients with HCC at Barcelona Clinic Liver Cancer (BCLC) stage B or C who received the combined treatment of TACE, ablation, and regorafenib or regorafenib plus anti-PD-1 immune checkpoint inhibitors (ICIs) in Youan hospital between April 2020 to June 2023 were reviewed. The primary end-point was progression-free survival (PFS). Overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity were the secondary endpoints. Results: A total of 73 patients were enrolled in our study, including 63 (86.3%) males and 10 (13.7%) females. 16 (21.9%) patients had portal vein tumor thrombosis (PVTT) and 33 (45.2%) patients had extrahepatic metastasis. There were 53 (72.6%) patients with multiple tumor numbers and 23 (31.5%) patients with large tumors (≥30mm). All patients received TACE combined with regorafenib, while 37 (50.7%) patients plus ICIs and 36 (49.3%) patients not plus with ICIs. Besides, the majority of patients (N=61, 83.6%) in our cohort received ablation. The patients with AFP>400U/L were 22 (20.1%). The average follow-up of the cohort was 24.6 months. The median PFS was 7.06 months (95%CI: 4.77-9.36 months) and the median OS was 23.47 months (9.79-37.15 months). Treatment response is shown in Table 2. According to mRECIST criteria, the ORR was 58.9% and the DCR was 91.8%, respectively. No adverse effects (AEs) were reported in the 11 patients in the study. The most common any-grade treatment-related AEs were hand-foot syndrome (21.9%), diarrhea (23.28%), and hypertension (21.9%). Grade≥3 treatment-related AE occurred in 12.3% of the patients. The most common grade 3 treatment-related AE was hypertension (5.48%). Conclusions: TACE combined with ablation and regorafenib is an effective, safe, and promising second-line treatment option for patients with unresectable HCC after progression from first-line therapy. [Table: see text]
A retrospective study on the efficacy and safety of donafenib combined with transarterial chemoembolization (TACE) and with/without immunotherapy in intermediate-advanced hepatocellular carcinoma (HCC).
Authors: Chen Cong , Fu Shouzhong , Zhao Suming , Yuan Hongxin , Dai Feng , Gu Weiwei , Gu Zhuxin , Shi Rongfeng , Yang Xiaohu , Lu Xiaohua , Jia Pengfei , Si Luyi , Zhao Hui
Published: July 2024

e16171

Background: Recent phase III clinical trial ZGDH3 and several real-world studies have demonstrated the potential of Donafenib in improving overall survival (OS) in advanced HCC. This study aims to evaluate the efficacy and safety of Donafenib combined with TACE and with/without immunotherapy as first-line treatment in intermediate-advanced HCC. By retrospectively analyzing data from previous clinical trials, we will further explore the potential of Donafenib in enhancing the survival rate of patients with intermediate-advanced HCC and its safety profile. Methods: Thirty-eight patients diagnosed with intermediate-advanced HCC through pathology or clinical assessment were included in the study. We conducted a retrospective analysis of the efficacy and safety of patients treated with at least one cycle of Donafenib between September 2021 and December 2023, at the Affiliated Hospital of Nantong University and the Third People's Hospital of Nantong City. The primary endpoints were Objective Response Rate (ORR) and Progression-Free Survival (PFS). Secondary endpoints included Disease Control Rate (DCR), overall survival (OS) and safety. Safety and efficacy were assessed according to CTCAE v5.0 and mRECIST, respectively. Survival data were calculated using the Kaplan-Meier method. Results: The median age was 67 years old, and 76.3% were male. 39.5% of patients had Child-Pugh score A, 39.5% had BCLC stage B, and 60.5% had stage C. 17 patients (44.7%) received Donafenib combined with TACE treatment, while the remaining patients (55.3%) received Donafenib combined with TACE and immunotherapy. The median duration of therapy (mDOT) was 7.18 months (range, 2.14 -21.75). The ORR and DCR were 57.89% (22/38) and 89.47% (34/38), respectively. The median follow-up time was 9.17 months (range, 2.99-27.93), and the 6-month PFS rate was 81.1% (95% CI: 67.1%-98.0%). The 12-month PFS rate was 73.7% (95% CI: 56.5%-96.2%). The 6-month OS rate was 94.0% (95% CI: 86.2%-100.0%), and the 12-month OS rate was 88.1% (95% CI: 75.6%-100.0%), with the median PFS and OS not reached yet. Most patients took Donafenib 200mg twice a day. A total of 6 patients (15.79%) experienced grade 3 adverse events (AEs). The common grade 3 AEs included hand-foot syndrome (7.89%), diarrhea (2.63%), rash (2.63%), and hypertension fatigue (2.63%). No grade 4 or 5 AEs or new safety signals were found. Conclusions: Donafenib combined with TACE and with/without immunotherapy showed manageable safety and promising efficacy in intermediate-advanced HCC patients.
TACE-HAIC combined with donafenib and immunotherapy for hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT): A retrospective analysis.
Authors: Yin Linan , Liu Ruibao , Hou Xunbo , Lu Junrong
Published: July 2024

e16174

Background: The probability of Chinese hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) is relatively large and the long-term survival of this part of patients is poor. Systemic therapy, transcatheter arterial chemoembolization (TACE), and hepatic artery infusion chemotherapy are widely used in HCC patients with PVTT. We want to explore the efficacy and safety of TACE plus hepatic arterial infusion chemotherapy combined with Donafenib, anti-PD-1 antibody in uHCC patients with PVTT. Methods: We retrospectively analyzed the patients who were diagnosed as uHCC with PVTT and received the treatment of TACE plus HAIC combined with Donafenib, anti-PD-1 antibody as first-line therapy from Dec 2021 to Jun 2023 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) and safety. Results: Of 106 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 (IQR, 52-64). The study population was predominantly male (79.2%), and 79.2% were HBV-positive. All HCC patients are accompanied by PVTT, most of which are VP3(72.6%).The rate of patients with extrahepatic metastasis were 16.0%. All patients were classified as BCLC stage C and 84.0% were classified as CNLC stage IIIa. As of December 2023, 106 patients had received at least one imaging evaluation, 11 (10.4%), 60 (56.6%) and 28 (26.4%) of them achieved complete response, partial response and stable disease, and the overall objective response rate and disease control rate was 67.0% and 93.4% per modified RECIST criteria respectively. With 16.3 months of median follow-up time, the 12-month PFS rate was 81.3% and the 12-month OS rate was 90.1%. The median PFS and OS were not reached. 103 of all patients had at least one treatment-related AE (TRAE), and treatment-related deaths did not occur in this study. Grade 3 TRAEs occurred in 33 (31.1%) patients, and no grades 4 or 5 were reported. The most common Grade 3 TRAEs included aspartate transaminase increased (18.9%), platelet count decreased (14.2%) and blood bilirubin increased (8.5%). Conclusions: TACE-HAIC combined with Donafenib and immunotherapy are effective and tolerable for uHCC patients with PVTT.
The safety and efficacy of adebelimumab combined apatinib and hepatic artery infusion chemotherapy in the treatment of unresectable hepatocellular carcinoma: A retrospective study.
Authors: Chen Bin , Lin Run , Huang Yonghui , Dai Haitao , Tang Keyu , Zhang Guiyuan
Published: July 2024

e16175

Background: The combination of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) used for hepatic arterial infusion chemotherapy (HAIC) has shown promise for advanced hepatocellular carcinoma (HCC) patients. The combined therapy of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) is now an approved first-line approach for unresectable HCC. This study evaluated the safety and the effect of combining Adebelimumab (a PD-L1 inhibitors) and Apatinib (a tyrosinase kinase inhibitor) with HAIC-FOLFOX for unresectable HCC patients. Methods: The records of patients with unresectable HCC treated with HAIC from March 2023 to November 2023 at our center were retrospectively reviewed. Eligible patients were given a maximum of four cycles of FOLFOX-HAIC, along with Adebelimumab and Apatinib, until either disease progression or intolerable toxicities emerged. The primary outcome measured was the safety and the objective response rate (ORR) based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modify RECIST of combined therapy. Results: Twenty patients were enrolled in the study. The most frequent grade ≥3 or above treatment-related adverse events included elevation of AST (50%) and diminished PLT count (15%). There was no treatment related death. Based on RECIST v1.1 and mRECIST criteria, the confirmed ORR stood at 35% and 70%, with a disease control rate of 85% both. Conclusions: The combination of Adebelimumab, apatinib, and FOLFOX-HAIC demonstrated manageable safety and encouraging results for unresectable HCC.
The efficacy and safety of donafenib combined with transcatheter arterial chemoembolization and anti-PD-1 antibodies as first-line therapy for hepatocellular carcinoma: A retrospective study.
Authors: Song Danjun , Hao Weiyuan , Cao Fei , Luo Jun , Guo Liwen , Zhang Zhewei , Zheng Jiaping
Published: July 2024

e16178

Background: In Phase III study (ZGDH3), donafenib showed the survival benefit and better safety compared with sorafenib as the first-line treatment for uHCC. Recently, combination therapies have shown favorable results in patients with HCC. Some studies have shown that molecular targeted drugs combined with anti-PD1 antibodies and TACE exhibit improved anti-tumor efficacy compared with monotherapy. This study aimed to evaluate the efficacy and safety of the combination therapy of donafenib,anti-PD-1 antibodies and TACE as first-line treatments for HCC patients in the real world. Methods: This single-center retrospective study involved patients with histopathologically/cytologically or clinically confirmed HCC at Zhejiang Cancer Hospital between July 2021 and June 2023. Eligible patients were treated with donafenib (100 mg po bid) combined with TACE and anti-PD-1 antibodies until the point of disease progression, death, or intolerable toxicity. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) datas of patients were collected and analyzed according to the mRECIST, and the incidence of adverse events (AEs) was evaluated using CTCAE 5.0. Results: There were 34 patients in this study (Table). The median age was 64 years (IQR: 57, 69) at the data cut-off in January 2024, with 94.1% of the population being male and 82.4% having HBV infection. Of these patients, 5(14.7%) were classed as BCLC stage A, 11(32.3%) were classed as BCLC stage B, and 18 (52.9%) were BCLC stage C. The median PFS was 7.9 months (95%CI, 5.6–NA), and median OS was not reached, respectively, the 12-month PFS and OS rates were 46.9% (95%CI: 16.8%-72.5%) and 96.9% (95%CI: 79.8%-99.6%). The ORR and DCR for all patients were 73.5% and 97.1%, respectively, based on both mRECIST (CR 3 [8.8%], PR 22 [64.7%], SD 8 [23.5%]). The surgical conversion rate was 26.5%. Treatment-related adverse events (TRAE) of any grade were observed by 18 patients (52.9%), of which 4 patients (11.8%) had grade 3 TRAE. No grade 4 or 5 TRAE was observed. Conclusions: The study indicated that donafenib combined with TACE and anti PD-1 antibodies exhibited encouraging efficacy and favorable safety profile in patients with HCC. [Table: see text]
Effect of BCL9/BCL9L inhibition–derived Th1 cells on dendritic cells–mediated antigen presentation in hepatocellular carcinoma and on the efficacy of CAR-T immunotherapy.
Authors: Zhu Yuanyuan , Feng Mei , Wang Feng , Zhu Andrew X. , Zhu Di , Zhao Enfeng
Published: July 2024

e16180

Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited treatment options. The emerging field of tumor immunotherapy, primarily focusing on CD8+ T cells and the tumor microenvironment (TME), has garnered substantial attention. CD4+ T cells, on the other hand, play a crucial role in maintaining immune equilibrium and orchestrating immune responses through interactions with various cell types. As crucial participants and coordinators in innate and adaptive immune responses, the role of CD4+ T cells in tumor development remain further exploration. Conventional dendritic cells (cDCs) are thought to perform antigen presentation to prime CD4+ T cells or CD8+ T cells. However, the reverse regulatory impact of CD4+ T cells on cDCs remains poorly understood. Methods: Initially, we examined the role of CD4+ T cell subsets in HCC development using TCGA database. Subsequently, we established Cd4-Cre Bcl9fl/fl Bcl9lfl/fl mice to explore the impact of T cell-specific Bcl9/Bcl9l deficiency on HCC development. We further investigate the impact of Bcl9/Bcl9l deficiency in CD4+ T cells on the therapeutic efficacy of mouse CAR-T treatment. Moreover, using single-cell RNA sequencing (scRNA-seq) databases from Bcl9/Bcl9l KO tumor-bearing mice and HCC patients, we investigated the regulatory role of CD4+ T cells on the function of cDCs. Finally, we validated the mechanism by which CD4+ T cells regulate cDCs function in a mouse HCC model and explored their influence on tumor-specific CD8+ T cells response. Results: We found elevated Th1 cell infiltration in various cancers including liver hepatocellular carcinoma (LIHC). High Th1 infiltration is associated with a favorable prognosis in LIHC, but there is a significant negative correlation between the expression of B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) and the infiltration of Th1 cells. We found that blocking T cell-intrinsic BCL9/BCL9L increased frequencies of Th1 cells, thereby suppressing HCC tumor growth. The enrichment of Th1 cells inversely regulates innate immune response to augment cDCs activation. BCL9/BCL9L inhibition amplifies CD4+ T cell and cDCs crosstalk and promotes cDCs antigen presentation. The reinforced cross-presentation of tumor antigens by cDCs promotes activation and proliferation of CD8+ T cells. Moreover, genetic editing of BCL9/BCL9L in CD4+ T cells can enhance the anti-tumor immunity by promoting CAR-T cell toxicity. Conclusions: Thus, BCL9/BCL9L inhibition orchestrate an adaptive immune to innate immune circuit wherein Th1 cells triggers cDCs antigen presentation in turn activate tumor-specific CD8+ T cells response to promote cancer immunity.
Efficacy and safety of arterial FOLFOX chemotherapy plus anti-PD-(L)1 immunotherapy as first-line treatment for unresectable intrahepatic cholangiocarcinoma: A propensity score matched analysis.
Authors: Hu Yue , Lyu Ning , Zhao Ming
Published: July 2024

e16189

Background: This study aimed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) plus anti-programmed death (ligand)-1 [PD-(L)1] immunotherapy compared to systemic chemotherapy (SCT) plus anti-PD-(L)1 immunotherapy as first-line treatment for patients with unresectable intrahepatic cholangiocarcinoma (uICC). Methods: In this retrospective study, unresectable treatment-naive ICC patients who were treated with HAIC plus anti-PD-(L)1 immunotherapy [HAIC+αPD-(L)1] or SCT plus anti-PD-(L)1 immunotherapy [SCT+αPD-(L)1] were included. The clinical characteristics, therapeutic outcomes and adverse events (AEs) of patients between the two groups were compared. The propensity score matching (PSM) was performed to minimize biases between groups. Results: From January 2019 to January 2023, a total of 182 patients were enrolled, including 147 patients in HAIC+αPD-(L)1 group and 35 patients in SCT+αPD-(L)1 group. After PSM, 61 and 26 patients were included in the HAIC+αPD-(L)1 and SCT+αPD-(L)1 groups, respectively. The HAIC+αPD-(L)1 group showed longer median overall survival (OS) and progression free survival (PFS) than the SCT+αPD-(L)1 group (OS: 14.5 vs 10.5 months, P = 0.019; PFS: 6.4 vs 10.1 months, P = 0.020). The disease control rate of HAIC+αPD-(L)1 group were higher than those of SCT+αPD-(L)1 group (91.8% vs 69.2%, P = 0.007). The overall incidence of adverse events (AEs) was comparable between the two groups, but the HAIC+αPD-(L)1 group showed a lower incidence of grade 3~4 AEs related to anemia, weight loss and fatigue. Conclusions: HAIC plus anti-PD-(L)1 immunotherapy had acceptable toxic effects and might improve outcomes compared to SCT plus anti-PD-(L)1 immunotherapy as first-line treatment for patients with uICC.