bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase Ib/II, multicenter, open-label study of AK104, a PD-1/CTLA-4 bispecific antibody, combined with chemotherapy (chemo) as first-line therapy for advanced gastric (G) or gastroesophageal junction (GEJ) cancer.
Authors: Ji Jiafu , Shen Lin , Gao Xiangyu , Ji Ke , Chen Ye , Xu Nong , Liu Tianshu , Yang Nong , Zhong Haijun , Li Ziyu , Li Changzheng , Guo Zengqing , Fan Qingxia , Lin Xiaoyan , Yao Zhifang , Liu Wei , Li Baiyong , Xia Yu 
Published: January 2022

308 Background: Anti-PD-1 agent plus chemo as first-line therapy for advanced G/GEJ cancer (Checkmate-649) yields OS and PFS benefits compared to chemo alone, indicating synergistic activity between immune checkpoint inhibitors and chemo. The combination of anti-PD-1 and anti-CTLA-4 has consistently demonstrated higher response rate compared to PD-1 monotherapy but higher toxicity. Here, we performed this phase Ib/II study to evaluate the efficacy and safety of AK104, a PD-1/CTLA-4 bispecific antibody, combined with XELOX (capecitabine combined with oxaliplatin) or modified XELOX (mXELOX) in the first-setting of G/GEJ cancer cohorts. This study is registered on ClinicalTrials.gov (NCT03852251). Methods: Pts with unresectable advanced G/GEJ adenocarcinoma and no prior systemic therapy, regardless of PD-L1 status were enrolled, excluding known HER2-positive pts. Enrolled patients received AK104 (4 mg/kg, 6 mg/kg, 10 mg/kg, Q2W or 10 mg/kg, 15mg/kg Q3W) + chemo (mXELOX Q2W or XELOX Q3W). The primary endpoint was objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Results: As of 13 Aug 2021, 96 pts were enrolled with median age 62.7 years (range: 29–75), 70.8% male, 62.5% ECOG PS 1, 44.8% liver metastasis. The median follow-up was 9.95 months (range, 0.4-26.8). 88 patients (92%) had at least one post-baseline tumor evaluation. The ORR was 65.9% (58/88) with 2 (2.3%) complete responses and 56 (63.6%) partial responses. The disease control rate (DCR) was 92.0% (81/88). The median duration of response (DoR) was 6.93 months (95%CI, 4.60 to 11.20). The median PFS was 7.10 months (95%CI, 5.55 to 10.48). The median OS was 17.41 months (95%CI, 12.35 to NE). In pts with PD-L1 CPS≥1 vs CPS＜1, median OS was 17.41 months and 14.65 months, respectively. Treatment-related adverse events (TRAEs) occurred in 97.9% of pts, and the most frequent were platelet count decreased (60.4%), white blood cell count decreased (58.3%), neutrophil count decreased (56.3%), anaemia (47.9%), nausea (30.2%), vomiting (30.2%), aspartate aminotransferase increased (30.2%). Grade ≥3 TRAEs occurred in 62.5% pts. No new safety signals were identified. Conclusions: AK104 in combination with mXELOX/XELOX showed promising activity and manageable safety in previously untreated pts with advanced G/GEJ adenocarcinoma. AK104 + chemo represents a potential new first-line treatment option for these pts. A phase III study of AK104 combined with chemo as first-line therapy for G/GEJ cancer is underway. Clinical trial information: NCT03852251.
Productivity loss outcomes and indirect costs among patients (Pts) with cholangiocarcinoma (CCA).
Authors: Teschemaker Anna , Thiel Ellen , Park Julie , Parasuraman Shreekant 
Published: January 2022

392 Background: CCA pts, often diagnosed at older age with advanced disease, face poor prognoses and economic burden. Despite increasing CCA incidence in working age pts, little is known on financial impact on working pts. This study describes the impact of CCA on productivity loss and indirect costs due to workplace absence, short-term disability (STD), and long-term disability (LTD). Methods: Retrospective claims data from IBM MarketScan Commercial and Health and Productivity Management (HPM) databases between 7/1/2010 to 12/31/2019 were used. Eligible pts were ≥18 years, had ≥1 non-ruleout claim for CCA ( ICD-9/ -10: intrahepatic [iCCA]: 155.1/C221; extrahepatic [eCCA]: 156.1, 156.9/C240, C249) in the index period (1/1/2011 – 12/31/2019), and had ≥6 months of continuous medical and pharmacy benefit enrollment before and ≥1 month of follow-up and full-time employee eligibility after index date. Productivity loss as absenteeism, STD, and LTD among iCCA and eCCA was reported per pt per month (PPPM) for a work month of 21 days. Absenteeism was defined as absence days for illness; STD and LTD were defined as days on disability leave. Indirect cost was estimated using wage equivalent to median hourly wage rate and salary replacement rate of 70% from US Bureau of Labor and Statistics. Results: A total of 1065 CCA pts (iCCA, n=624 [58.6%]; eCCA, n=380 [35.7%]) were identified. The number of productivity benefit–eligible pts for analysis in absenteeism, STD, and LTD were 107, 617, and 549, respectively. Across cohorts, mean age ranged from 51.9 to 53.9 years; >60% were men. Mean (SD) follow-up time (days) was 725.0 (730.4) for absenteeism, 639.7 (587.0) for STD, and 614.4 (583.2) for LTD. The most notable comorbidities across cohorts were moderate/severe liver disease (58–63%) and pain (67–71%). Among pts with productivity claims, more CCA-related absences and higher related indirect costs were observed in iCCA than eCCA pts. The trend in all-cause disability outcomes of STD, LTD, and related costs was less clear between iCCA and eCCA pts; however, medical costs were higher in iCCA pts. Conclusions: CCA pts had high productivity loss and indirect costs, which is pt costs due to days missed from work in addition to medical costs; iCCA pts incurred substantially more absences, related indirect costs, and medical costs than eCCA pts.[Table: see text]
Patient report outcomes: Financial toxicity in cholangiocarcinoma.
Authors: Keilson Jessica M. , Lindsey Stacie , Bachini Melinda , Medin Caroline , Berk Alexandra , Cornew Sophia , Maithel Shishir K. 
Published: January 2022

394 Background: While surgery is the only curative option for cholangiocarcinoma (CCA), it is amenable only in a minority of patients and has high recurrence rates. Numerous experimental and targeted therapies are under investigation; however, objective health-related quality of life (HRQoL) data for patients receiving these therapies are currently not available. Methods: Pts engaged in the Cholangiocarcinoma Foundation completed two validated HRQoL surveys: Functional Assessment of Cancer Therapy (FACT)-Hepatobiliary and COmprehensive Score for financial Toxicity (COST). Subscales (Physical Well-Being, PWB; Social Well-Being, SWB; Emotional Well-Being, EWB; Functional Well-Being, FWB; Hepatobiliary Cancer Subscale, HCS; Financial Toxicity Scale, FTS) and composite scores (FACT-Hep, composite for PWB, SWB, EWB, FWB, HCS) were calculated according to the FACIT-Manual, with higher values indicating improved HRQoL. Results: 208pts completed the surveys. 75% (n = 156) had intrahepatic CCA, 57% (n = 119) underwent resection, of which 48% (n = 56) had disease recurrence. 22% (n = 45) enrolled in a clinical trial and 80% (n = 167) underwent molecular profiling, of which 29% (n = 48) received targeted therapy. While pts enrolled in a clinical trial reported similar HRQoL compared to those not enrolled in a clinical trial, they also reported lower FTS (effect size 0.33, p = 0.05), suggesting higher financial burden. Pts who received targeted therapy reported equivalent HRQoL and lower FTS compared to those who did not (effect size 0.43, p = 0.01). Conclusions: Our data suggest that enrollment in a clinical trial does not affect a patient’s physical, emotional, social, or functional well-being. However, despite these treatments being paid for through trial enrollment, patients still report higher financial burden. This is also seen among patients who received targeted therapy. For patients with CCA, clinical trials and personalized therapy are mainly offered late in the advanced disease setting, at which point a significant financial toll has already been endured. Further, they are often only available at large academic centers, creating a physical barrier to access. These findings underscore the need to increase clinical trial availability and eliminate physical and financial barriers that threaten access and utilization of personalized and progressive therapies.[Table: see text]
Multi-target blood test to improve the performance of hepatocellular carcinoma surveillance programs: A modeling-based virtual trial.
Authors: Chhatwal Jagpreet , Samur Sumeyye , Yang Ju Dong , Roberts Lewis R. , Nguyen Mindie , Ozbay A. Burak , Ayer Turgay , Parikh Neehar , Singal Amit G. 
Published: January 2022

405 Background: Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer mortality in the United States. Although clinical guidelines recommend ultrasound (U/S), with or without the serum biomarker alpha fetoprotein (AFP) for HCC surveillance in at-risk patients, only 24% of patients adhere to surveillance and only one-third of HCCs are detected before developing symptoms. A multi-target HCC blood-based test (mt-HBT) was recently shown to have promising sensitivity for early HCC detection and may help improve surveillance adherence given its blood-based nature. Our objective was to evaluate the comparative clinical effectiveness of mt-HBT with the current standard-of-care surveillance strategy in patients with cirrhosis. Methods: We simulated a virtual trial by developing a microsimulation model of the natural history of HCC in patients with compensated (Child Pugh A) cirrhosis over a 30-year horizon. To inform model parameters, we used published data on tumor progression, competing risks of mortality, and real-world HCC surveillance adherence. Test performance characteristics were informed by a network meta-analysis. We simulated the life course of 51-year-old patients with cirrhosis and compared no surveillance with biannual surveillance using (1) AFP only, (2) U/S only, (3) U/S+AFP, (4) mt-HBT, and (5) mt-HBT with improved adherence. We assumed a blood-based test—without U/S—would improve surveillance adherence by 10% compared with current adherence (̃4% absolute improvement). Results: Per 100,000 cirrhosis patients, mt-HBT detected 6,220 more early-stage HCC than no surveillance, 2,250 (+57%) more than AFP, 1080 (+21%) more than U/S, and 200 (-3%) less than U/S+AFP. mt-HBT with improved adherence detected 210 (+3%) more early-stage HCC than U/S+AFP (Table). The remaining HCC cases were either symptomatic or the patients died per other competing causes prior to detection. The number of screening tests needed to detect one HCC were 296 for AFP, 287 for U/S, 253 for U/S+AFP, 254 for mt-HBT and 262 for mt-HBT with improved adherence. The number of diagnostic MRI/CT needed to detect one HCC were 40 for AFP, 38 for U/S, 45 for U/S+AFP, 37 for mt-HBT, and 38 for mt-HBT with improved adherence. Conclusions: mt-HBT detects more early-HCC cases than U/S and similar number of early-HCC cases with U/S+AFP. By decreasing surveillance barriers and increasing adherence, mt-HBT could improve early HCC detection and could be promising option for HCC surveillance in patients with cirrhosis. [Table: see text]
A phase Ib, multicenter, open-label study to assess the safety, tolerability, and preliminary efficacy of sintilimab plus IBI310 (anti-CTLA4 mAb) in patients with advanced hepatocellular carcinoma.
Authors: Zhou Jian , Shi Ying-Hong , Liu Baorui , Jia Wei-Dong , Gu Shanzhi , Qin Yanru , Liu Ying , Han Zhengxiang 
Published: January 2022

421 Background: Immune checkpoint inhibitors (ICI) targeting PD-1/L1 or in combination with CTLA-4 have shown therapeutic benefit in patients with advanced hepatocellular carcinoma (aHCC). This study aimed to evaluate the safety, tolerability, and preliminary efficacy of IBI310, an anti-CTLA-4 monoclonal antibody (mAb), combined with sintilimab, in patients with aHCC who failed or intolerant to previous systemic therapy. Methods: Three cohorts were pre-designed to explore recommended dose of IBI310 in de-escalation order: sintilimab 200 mg plus IBI310 3, 2 or 1 mg/kg every 3 week (q3w). Patients will receive the combined treatment up to 4 cycles, followed by sintilimab 200 mg q3w up to 24 months. Primary endpoint was safety. Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), progress free survival (PFS) and overall survival (OS) by RECISTv1.1 per investigators. Results: 9 subjects were initially treated with sintilimab 200 mg plus IBI310 3 mg/kg q3w without predefined adverse event (AE) observed. 3 mg/kg was determined as recommended dose of IBI310 and no subject was assigned to other cohorts. As of the data cut-off of August 30, 29 subjects were enrolled (median age 51.4 years, 86.2% male, 96.6% BCLC C, 24.1% ICI treated). The average treatment cycles of IBI310 and sintilimab were 2.8 and 5.7. The most frequent treatment related adverse events (TRAEs) of any grade were alanine transaminase increases (34.5%), aspartate transaminase increases (34.5%), thrombopenia (24.1%), and lipase increases (24.1%). Grade ≥3 TRAEs occurred in 34.5% of subjects (including one grade 5 immune-mediated pneumonitis). Dose interruption and discontinuation rates due to AE were 55.2% and 6.9%. With a median follow-up of 9.89 months, investigator confirmed ORR and DCR were 17.2% (all partial response, including one anti-PD1 mAb failed) and 72.4%. The median PFS was 3.9 months (95% CI: 2.6, NR) and median OS not reached (95% CI: 11.4, NR). The 6-month PFS and OS rates were 45.8% (95%CI 25.2%, 64.2%) and 93.1% (95%CI 75.1%, 98.2%) respectively. 6 patients remain on treatment at cutoff date. Conclusions: The combination of sintilimab and IBI310 shows promising efficacy and managable safety profile in aHCC patients. Our results are comparable to that have been published in the same setting. This regimen is currently being evaluated in phase II study. Clinical trial information: NCT04401813.
Cyclin dependent kinase 9 inhibition as a potential treatment for hepatocellular carcinoma.
Authors: Shao Yu Yun , Hsu Hung-Wei , Wo Rita Robin , Wang Han-Yu , Cheng Ann-Lii , Hsu Chih-Hung 
Published: January 2022

425 Background: Composite cyclin dependent kinase (CDK) inhibition has shown potential as a treatment for hepatocellular carcinoma (HCC) in preclinical studies. We tested whether the specific inhibition of CDK9 was effective against HCC. Methods: The effects of two specific CDK9 inhibitors, BAY1143572 and AZD4573, on cell viability and apoptosis in HCC cell lines were examined. We tested the in vivo efficacy of CDK9 inhibition in mouse xenograft models of HuH7 human HCC cells and in an orthotopic model of BNL mouse HCC cells. Overexpression and knockdown of CDK9 were performed to confirm the efficacy of CDK9 inhibition. Results: Both BAY1143572 and AZD4573 exhibited potent antiproliferative activities in HCC cell lines including HuH7, HLE, and HepG2, regardless of the levels of c-myc expression while inhibiting the downstream signals of CDK9, such as the phosphorylation of RNA polymerase II. These 2 CDK9 inhibitors induced apoptosis in HCC cells and reduced the expression of antiapoptotic proteins such as myeloid cell leukemia-1, survivin, BimEL, and the X-linked inhibitor of apoptosis protein. Reduction of CDK9 expression through siRNA knockdown also reduced the phosphorylation of RNA polymerase II and the colony formations of HuH7 and HLE cells. In the xenograft studies, mice receiving either CDK9 inhibitor exhibited a significantly lower tumor growth rate than did the mice receiving vehicles. In the orthotopic model, the HCC growth in mice receiving BAY1143572 also tended to be slower than that in the control group. Overexpression of CDK9 in HuH7 cells reduced the efficacy of both CDK9 inhibitors. Conclusions: We demonstrated the in vitro and in vivo activity of CDK9 inhibition on multiple HCC cell lines. Our data support further clinical development of CDK9 inhibitors as a treatment for HCC.
Sintilimab plus lenvatinib as conversion therapy in patients with unresectable locally intermediate to advanced hepatocellular carcinoma: A single-arm, single-center, open-label, phase 2 study.
Authors: Wang Lijun , Wang Hongwei , Cui Yong , Jin Kemin , Liu Wei , Wang Kun , Xing Baocai 
Published: January 2022

449 Background: Most patients (pts) with hepatocellular carcinomas (HCC) are diagnosed at intermediate to advanced stages, at which they have missed the opportunity for curative resection. Combining a PD-1 inhibitor with tyrosine kinase inhibitors (TKIs)has achieved a high response rate for advanced HCC in first- and second-line settings. This study aimed to explore the efficacy and safety of conversion therapy with sintilimab (PD-1 inhibitor) plus Lenvatinib (TKI) in pts with unresectable locally intermediate advanced HCC. Methods: This was a phase 2, single-arm study (NCT04042805). Eligible pts were adults who were newly diagnosed with HCC, not amenable to curative resection, no extrahepatic metastasis, with an ECOG PS 0-1 and Child-Pugh class A/B. Pts received 12mg or 8mg oral Lenvatinib daily plus 200mg intravenous sintilimab every 3 weeks until disease progression or unacceptable toxicity, followed by multidisciplinary assessment and potential hepatectomy. The primary endpoint was tumor objective response rate (ORR) RECIST version 1.1. Secondary endpoints included conversion resection rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Between August 1, 2019, and September 1, 2021, 26 pts were enrolled with a median age of 60 years (range, 30-78). The study population was predominantly male (92%), and 92% were HBV-positive. Patients were classified as BCLC stage B (46%) and stage C (54%). Twenty-six pts were evaluable for response, with an ORR of 35% (95%CI, 0.15-0.54) and a DCR of 92% (95%CI, 0.81-0.99). Seven (27%) pts received hepatectomy, and 1 (4%) patient received radical ablation and stereotactic radiotherapy. With a median follow-up of 9 months (range, 2-24), the median PFS and OS were not reached. All pts were evaluable for toxicity, and 20 (77%) pts had at least one treatment-related AE (TRAE). TRAEs occurring in ≥20% of pts were hypothyroidism (38%), proteinuria (31%), and hypertension (23%). Five pts had grade 3 TRAEs. Conclusions: In view of the encouraging response rate observed and the acceptable safety profile, the lenvatinib plus sintilimab regimen may achieve a favorable conversion rate and be a feasible conversion therapy for patients with unresectable locally intermediate to advanced HCC. Clinical trial information: NCT04042805.
Galectin-9 expression and decreased survival in advanced biliary tract cancers.
Authors: Keilson Jessica M. , Ruggieri Amanda , Hammons Jacklyn , Chen Helen X. , Sharon Elad , Yarchoan Mark , Azad Nilofer Saba , Medin Caroline , Henry Curtis , Robinson Brian , Maithel Shishir K. , Lesinski Gregory B. 
Published: January 2022

465 Background: Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies often refractory to chemotherapeutic or targeted therapies, carrying an overall poor prognosis and high mortality. Identifying prognostic biomarkers and effective therapeutic targets for this disease therefore remains a high priority. T-cell immunoglobulin mucin domain-containing protein 3 (TIM-3), a negative regulatory immune checkpoint receptor, is known to induce immune tolerance and inhibit T-cell antitumor immunity. Its ligand, galectin-9 (Gal-9), has been shown to play a paradoxical role in tumorigenesis in a number of disease states. However, the role of Gal-9 in the setting of BTCs is not completely understood. Methods: We examined expression patterns of total cellular Gal-9 and TIM-3 in a panel of human BTC cell lines with diverse molecular profiles via immunoblot. Soluble Gal-9 (sGal-9) was measured by enzyme-linked immunoassay (ELISA). Tetrazolium-based MTT assay was utilized to evaluate cell viability following Ab-mediated Gal-9 neutralization. Pre-treatment peripheral blood was obtained from patients with metastatic BTCs enrolled in a randomized phase II clinical trial (NCI10139) and sGal-9 levels were measured. ROC curve analysis was employed to identify an optimal concentration cut-point value. Kaplan-Meier models were used to assess the association between sGal-9 levels and overall survival. Results: Human BTC cells demonstrate detectable and differential expression levels of total Gal-9 and TIM-3 proteins in vitro, with greater expression among intrahepatic cell lines (HUCCT-1, HUH28, SNU478). TIM-3 expression was not detected among extrahepatic (MzChA-1) and gallbladder cancer (WITT) cell lines. sGal-9 is secreted at variable levels between cell lines and its neutralization does not affect viability. Pre-treatment peripheral blood was obtained from 73 patients with metastatic BTCs (53% (n = 39) intrahepatic cholangiocarcinoma, 22% (n = 16) extrahepatic cholangiocarcinoma, 25% (n = 18) gallbladder cancer). There was no significant difference in sGal-9 levels between disease sites (p = 0.08). Patients were dichotomized by low and high sGal-9 levels. High baseline plasma levels of sGal-9 were associated with worse overall survival among patients with advanced BTCs (p = 0.03). Conclusions: Biliary tract cancer cells differentially express galectin-9 and its ligand, TIM-3, in vitro. Higher plasma levels of soluble galectin-9 are associated with worse overall survival, suggesting galectin-9 expression may be related to a more aggressive disease state. Additional work is needed to better inform the mechanistic role of the galectin-9/TIM-3 axis on disease progression and how best to leverage this pathway as a therapeutic target in the management of biliary tract cancers.