bluuebunny/crossref_metadata_2025_split huggingface dataset:
Downstaging locally advanced hepatocellular carcinoma with selective internal radiation therapy.
Authors: Hoang Marjorie , Chow Pierce K. H. 
Published: January 2023

536 Background: Locally advanced HCC (beyond BCLC A, including PVT but without extra-hepatic metastases) that are unresectable because of inadequate future liver remnant may be downstaged by selective internal radiation therapy (SIRT) with Yttrium-90 to subsequently receive interval surgical resection. We hypothesized that HCC that required downstaging before resection will have some disparity in overall survival (OS) and recurrence-free survival (RFS) compared to HCCs that were resected upfront. Methods: We reviewed all patients who underwent surgical resection for HCC between 1st January 2000 and 31st December 2019 and identified those that had locally advanced HCC and were downstaged with Y90-SIRT and referred for consideration of surgical resection. OS and RFS of patients resected upfront for early and locally advanced HCC and those resected after downstaging were obtained using the Kaplan Meier method and compared using Log-rank (Mantel-Cox) test after propensity score matching. Results: 1141 patients had surgical resection for HCC within the study period. 245 patients were excluded for other primary cancers or metastatic disease at diagnosis. 875 were resected upfront (473 early, 402 locally advanced) and 23 locally advanced HCC were downstaged with SIRT before resection. Locally advanced HCC patients downstaged with Y90 before resection have significantly better OS and RFS than locally advanced HCC with upfront resection (5-year OS of 69.0% versus 47.5% p = 0.048; 5-year RFS of 53.5% vs 27.0%, p = 0.047) and similar OS and RFS with resected early HCC (5-year OS of 69.0% versus 62.6% p=0.475; 5-year RFS of 53.5% vs 39.0%, p = 0.736). Conclusions: In addition to downstaging HCC to resection, Y90-SIRT also produces a change in tumour biology that favours better prognosis. A randomised controlled trial to the role of SIRT as neoadjuvant therapy in locally advanced HCC is justified and can potentially change practice.
Gunagratinib, a highly selective irreversible FGFR inhibitor, in patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR pathway alterations: A phase IIa dose-expansion study.
Authors: Guo Ye , Yuan Chunwang , Ding Weimin , Gao Yi , Zhu Xu , Ying Jieer , Sun Meili , Zhang Jingdong , Zhuang Zhixiang , Huang Yangqing , Deng Lichun , Chen Ping , Bai Yuxian , Niu Zuoxing , Li Wei , Yin Xiaoyu , Xu Aibing , Cheng Yufeng , Li Jin 
Published: January 2023

572 Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR 1, 2, 3 and 4 activities irreversibly by covalent binding. Here we present data from an ongoing phase IIa dose-expansion study (ICP-CL-00301 NCT03758664) of gunagratinib in patients with cholangiocarcinoma (CCA). Methods: Eligible participants were aged 18-75 years, had locally advanced or metastatic CCA with FGFR2 fusions or rearrangements, and had disease progression after ≥1 prior treatment or intolerant of prior treatment. Patients received oral gunagratinib 20 mg QD (21-day cycle) until disease progression, intolerance, withdrawal of consent, or death. Radiological tumor evaluation was done at baseline and every 6 weeks until disease progression. Primary endpoint was objective response rate (ORR). Results: As of September 5, 2022, 18 CCA patients were enrolled and received 20 mg gunagratinib. The median age of the patients was 52.0 with 44.4% male and ECOG between 0-2. Median follow-up was 5.57 months. Among the 17 patients who have completed at least one tumor assessment, 9 patients had confirmed partial response (PR) and 7 patients had stable disease (SD). The ORR was 52.9% (9/17). The disease control rate (DCR) was 94.1% (16/17). The median progression free survival (mPFS) was 6.93 months (95% CI, 5.42–not reached) (not mature at cutoff). Among the 17 patients with safety data, 16 (94.1%) patients experienced at least one treatment-emergent adverse event (TEAE). Grade 3 or higher TEAEs occurred in 35.3% of patients. Five serious TEAE were reported with only one serious treatment-related adverse event (TRAE). Discontinuation rate due to TRAEs was 0%. There were no treatment-related deaths. Conclusions: The study data demonstrated that gunagratinib is safe and well-tolerated in previously treated patients with locally advanced or metastatic CCA harboring FGFR2 gene fusions or rearrangements. The response rate in such a patient group is high comparing to other approved FGFR inhibitors. Gunagratinib is a promising second-generation FGFR inhibitor with potential for the treatment of multiple indications with FGF/FGFR pathway abnormalities. Clinical trial information: NCT03758664 . [Table: see text]
Phase II study of cobolimab in combination with dostarlimab for the treatment of advanced hepatocellular carcinoma.
Authors: Acoba Jared David , Rho Young , Fukaya Erin 
Published: January 2023

580 Background: Immunotherapy is the backbone of hepatocellular cancer (HCC) systemic treatments. Preclinical studies have shown that the combination of anti-TIM-3 antibody and anti-PD-1 antibody is more effective than either therapy alone. Early clinical experience shows that the combination of cobolimab (anti-TIM-3) and dostarlimab (anti-PD-1) can be safely administered. Herein we report an interim update to this phase II, single arm study of cobolimab and dostarlimab in patients with untreated advanced HCC. We hypothesize that this combination immune checkpoint inhibitor therapy will increase the overall response rate (ORR) of patients from 20% (historical control) to 35%. Methods: In total, 42 patients with histologically confirmed, Barcelona Clinic Liver cancer (BCLC) stage B or C HCC will be enrolled on to this trial. Patients receive cobolimab 300 mg and dostarlimab 500 mg on day 1 of each 21-day cycle for up to two years or until disease progression, unacceptable toxicity, or patient withdrawal. CT or MRI is performed every 9 weeks to assess clinical response. The primary objective is to assess ORR. Results: At the cutoff date of September 1, 2022, 16 patients had been enrolled and received at least one dose of cobolimab and dostarlimab. The median age was 68 years (range 44 – 84); most were male (n=15); 5 were White, 5 Native Hawaiian, 4 Asian, and 2 other races. 3 patients had stage BCLC B and 13 had stage BCLC C disease; 1 had Hep B and 5 had Hep C; and 14 were Child Pugh A and 2 Child Pugh B. This interim analysis for efficacy includes 13 patients who had at least one post-baseline tumor assessment (or clinical progression or died). Complete response was seen in 1 patient, partial response in 5 patients (ORR 46%), stable disease in 3 patients (23%), and disease progression in 4 patients (31%). Of the 7 patients with an elevated AFP at baseline, 4 (57%) had a decrease in AFP level by greater than 50%. There was one grade 4 treatment-related adverse event (AE) of neutropenia. Grade 1/2 AEs included pruritus, rash, fatigue, hypothyroidism, and elevated AST and ALT. Conclusions: Interim results indicate that the combination of cobolimab and dostarlimab has acceptable safety with encouraging clinical activity as first line treatment in patient with advanced HCC. To our knowledge, this is the first report of clinically meaningful efficacy of a TIM-3 antibody in combination with a PD-1 antibody in patients with HCC. Clinical trial information: NCT03680508 .
Management (mgmt) of futibatinib-associated adverse events (AEs) in patients (pts) with advanced cancers: Results of a pooled analysis.
Authors: Meric-Bernstam Funda , Hollebecque Antoine , Furuse Junji , Oh Do-Youn , Bridgewater John A. , Shimura Masashi , Anderson Bailey , Hangai Nanae , Wacheck Volker , Goyal Lipika 
Published: January 2023

586 Background: Futibatinib, a covalently binding FGFR1–4 inhibitor, showed a 42% objective response rate with a 9.7 mo median duration of response in pts with advanced intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions/rearrangements in the phase 2 FOENIX-CCA2 trial. Futibatinib treatment (tx) was safe and tolerable with a predictable and manageable side effect profile. This pooled retrospective analysis examined mgmt of futibatinib-associated AEs in pts with advanced tumors, including iCCA. Methods: Pts from a global phase 1/2 study (NCT02052778) and a Japanese phase 1 study (JapicCTI-142552) who received futibatinib 20 mg QD (recommended dose) were included. Futibatinib dose modifications and supportive medications (meds) for AE mgmt were analyzed for futibatinib-associated AEs of clinical interest (group terms: hyperphosphatemia, hepatic AEs, retinal disorders, nail disorders, rash, palmar plantar erythrodysesthesia [PPE], cataract). The Kaplan-Meier method was used for time-to-resolution (TTR) analysis. Results: As of October 1, 2020, 318 pts with advanced solid tumors (60% CCA; 98% with ≥1 prior tx) had received ≥1 futibatinib 20 mg QD dose (median tx duration, 3.6 mo). Table includes incidence and mgmt of key AEs of clinical interest. Hyperphosphatemia was the most frequent cause of futibatinib dose modifications; 85% and 30% of pts with hyperphosphatemia received phosphate binders and/or phosphaturic agents, respectively, with no obvious TTR differences. Other common supportive meds included analgesics (in 55% of pts with nail disorders; 71% with PPE) and corticosteroids (37% of pts with rash). Retinal disorders occurred in 8% of pts (all grade [gr] 1-2 and resolved). Cataract, a late-onset AE on continued tx, occurred in 12 (4%; 4 [1%] gr ≥3) pts, leading to dose modifications in 3 pts. One pt underwent cataract surgery and resumed futibatinib tx the next day. Discontinuations due to tx-related AEs were rare (2.5%) and included 1 pt each with retinal detachment, onycholysis, and cataract. Conclusions: This analysis of AE mgmt showed a consistent and manageable safety profile for futibatinib in pts with pretreated advanced tumors. Commonly observed AEs with futibatinib were well managed with dose adjustments and supportive meds and rarely led to tx discontinuation. Clinical trial information: NCT02052778 /JapicCTI-142552. [Table: see text]
Analysis of the impact of eliminating bolus 5-fluorouracil in metastatic colorectal cancer.
Authors: Peng Chengwei , Saffo Saad , Shusterman Michael , Becker Daniel Jacob , Berlin Jordan , Oberstein Paul Eliezer , Nagar Anil , Yu Shun 
Published: January 2023

59 Background: 5-Fluorouracil (5-FU) is a component of first-line treatment regimens for metastatic colorectal cancer (mCRC). Historically, 5-FU is administered as a bolus followed by an infusion. However, the bolus dose adds substantial toxicity and is often withheld in patients with limited functional status or high-risk comorbidities, but its impact on treatment outcomes remains unclear. Small studies suggest that it may be omitted. The aim of this study was to determine whether omission of the 5-FU bolus is associated with a difference in overall survival (OS). Methods: An electronic health record-derived national multicenter oncology database from Flatiron Health was queried to select patients with mCRC who received a first-line 5-FU-containing regimen. Demographics, relevant labs, treatment details, and survival outcomes were collected. Propensity score (PrS) matching and OS analysis were performed incorporating age, race, sex, ECOG score, combination drug regimen, and baseline creatinine and bilirubin. Variables with p < 0.10 in univariable Cox proportional hazards models were included in the multivariable analysis. Results: We included 9741 patients with mCRC who received 5-FU-based regimens. All individuals received a 5-FU infusion, and 7901 (81%) also received a 5-FU bolus. Among our entire cohort, 43% were female, 23% were > 70 years, 66% were white, and 89% had ECOG ≤ 1. Over a median follow-up time of 19 months, 5847 patients (60%) died. In the unmatched univariable (HR 0.94, 95% CI 0.88-1.00, p = 0.06) and multivariable (aHR 0.85, 95% CI 0.93-1.06, p = 0.85) analyses, there was no association between the use of bolus 5-FU and OS. A number of factors were associated with an increased risk of death, including older age, high ECOG scores, and elevated bilirubin or creatinine levels. Similarly, in our PrS-matched dataset (n = 6126), the use of a 5-FU bolus was not associated with OS (HR 0.98; 95% CI 0.91-1.06; p = 0.64). Conclusions: The findings of our PrS-matched multicenter cohort study indicate that, after adjusting for host and treatment factors, 5-FU bolus dosing was not associated with an overall survival benefit among patients with mCRC. These results suggest that, in mCRC, the addition of a 5-FU bolus does not appear to add efficacy to regimens utilizing infusional 5-FU. Future work is necessary to determine the role of bolus dosing in the adjuvant setting and its impact on other clinically-relevant outcomes.
Correlation of high serum interleukin-6 with clinical outcome and T cell response in patients with unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.
Authors: Chon Hongjae , Kim Chan , Yang Hannah , Cheon Jaekyung , Ha Yeonjung , Lee Sung Hwan , Kang Beodeul , Kim Ilhwan , Kim Hyeyeong , Lee Won Suk , Jung Sanghoon , Gaillard Vince 
Published: January 2023

596 Background: We elucidated the clinical and immunologic implications of serum interleukin (IL)-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (Discovery cohort: 84 patients from three centers; Validation cohort: 81 patients from one center). Baseline blood samples were analyzed using a flow cytometric bead array. The tumor immune microenvironment was analyzed using RNA sequencing. Results: In the Discovery cohort, clinical benefit (CB) was defined as a complete or partial response or stable disease for ≥ 6 months. Among various blood-based biomarkers, the serum IL-6 level was significantly higher in patients without CB than in those with CB (mean 11.56 vs. 5.05 pg/mL, P=0.02). The optimal cutoff value for high IL-6 was determined as 18.49 pg/mL using maximally selected rank statistics, and 15.2% of patients were identified to have high IL-6 levels at baseline. In both the Discovery and Validation cohorts, patients with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev compared with that of patients with low IL-6 levels. In the multivariable Cox regression analysis, the clinical implication of high IL-6 levels persisted even after adjustment for various confounding factors. Patients with high IL-6 levels showed reduced interferon-γ and tumor necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and CD8+ T-cell proliferation. Finally, patients with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumor microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment.
Effect of early antibiotic exposure on survival of patients receiving atezolizumab plus bevacizumab but not sorafenib for unresectable HCC: A sub-analysis of the phase III IMbrave150 study.
Authors: Fulgenzi Claudia A.M. , Murphy Cian , D'Alessio Antonio , Scheiner Bernhard , Pinter Matthias , Cortellini Alessio , Pinato David J. James 
Published: January 2023

597 Background: The combination of atezolizumab plus bevacizumab (A+B) is the standard of care for patients (pts) with unresectable/advanced hepatocellular carcinoma (HCC). Emerging evidence suggest a detrimental role of early antibiotics (ATB) exposure in immunotherapy recipients. However, it is unclear whether ATB affect outcomes of pts receiving A+B. Methods: We conducted a patient-level analysis of subjects receiving either A+B or Sorafenib (Sor) within the IMbrave150 trial to assess the impact of early ATB exposure (ATB+, i.e. +/-30 from treatment initiation) on overall (OS) and progression-free survival (PFS). Differences in median (m) OS and mPFS were estimated by the Kaplan-Meier method. Cox proportional regression models were used to assess the prognostic impact of ATB+ adjusting for race, age, baseline AFP, baseline ALBI grade, continent of origin and neutrophil-to-lymphocyte ratio, a measure of systemic inflammation. Results: Data of 420 IMbrave150 participants were made available by Vivli. Among them, 278 received A+B and 142 Sor. Most pts were of ECOG performance status 0 (65%); 47% had extrahepatic spread, 40% had macrovascular invasion and 35% had AFP>400 ng/mL. Viral aetiology (39% HBV and 24% HCV) was the most common risk factor for HCC. Overall, 60 pts in the A+B arm (21.5%) and 31 (21.8%) in the Sor group were ATB+. Baseline characteristics were well balanced across ATB groups, except for region of origin, with a higher proportion of Asian pts in ATB+ (60% vs 45%; p=0.01). After a median follow-up of 10.38 months (95%CI:8.6-12.5), OS and PFS rates at 12 months were 72.3% and 9.7% in A+B; 64.8%, and 1.4% in Sor, respectively. ATB+ exposure was associated with increased risk of death both in univariate (HR 1.67; 95%CI 1.04-2.69) and multivariate models (HR 1.62; 95%CI 1.40-1.89) in the A+B (p for interaction <0.001), but not in the Sor arm (univariate HR 0.63; 95%CI 0.32-1.25; multivariate HR 0.70; 95%CI 0.31-1.60). Similarly, the risk of progression was increased for ATB+ pts in the A+B arm (univariate HR 1.68; 95%CI 1.03-2.71; multivariate HR 1.59; 95%CI 1.40-1.81), but not in the Sor arm (univariate HR 0.51;95%CI 0.26-1.01; multivariate HR 0.53; 95%CI 0.21-1.30) with positive p for interaction (p=0.002). Objective response rate (ORR) according to RECIST v.1.1 did not differ between ATB+ (28.0%) and ATB- (30.0%) in A+B (p=0.68). Conclusions: In a post-hoc sub-analysis of IMbrave150 we demonstrate for the first time the negative impact of early antibiotics exposure on outcomes of patients receiving A+B but not in those treated with Sor. Prospective translational studies should evaluate the role of ATB-mediated gut dysbiosis as a proposed mechanism underlying the adverse outcome in immunotherapy-recipients.
Use of FOLFOXIRI plus bevacizumab in metastatic colorectal cancer (mCRC): An age-stratified analysis.
Authors: Vassilev Zdravko , Fan Xiaozhou , Ostojic Helene , Xu Julie , Barzi Afsaneh 
Published: January 2023

64 Background: As the incidence of early-onset mCRC continues to rise, evidence is emerging for the use of more aggressive treatment in the front-line setting in patients aged < 50 years (yrs). Although the superior efficacy of the multiagent chemotherapy FOLFOXIRI+bevacizumab (triplet+bev) over doublet regimens (FOLFOX or FOLFIRI+bev) is well documented, it is commonly associated with increased toxicity. Contemporary data are needed on triplet+bev use by age group in the US, which may help tailor treatment in patients with early-onset mCRC. Methods: This was a retrospective, observational cohort study using Optum Oncology Electronic Health Records data between 2010 and 2021. Use of triplet+bev and subsequent treatments were reported by age group (18–49, 50–64, ≥65 yrs) among newly diagnosed patients with mCRC. Baseline demographic and clinical characteristics data for patients receiving triplet+bev and regorafenib as a subsequent treatment were collected. Results: Among 36,053 eligible patients with mCRC diagnosed between 2010 and 2021, 13.8% were aged 18–49 yrs, 36.4% 50–64 yrs, and 49.8% ≥65 yrs at the time of diagnosis. The proportion of patients receiving triplet+bev was higher in age groups 18–49 yrs (4.0%) and 50–64 yrs (3.4%) vs ≥65 yrs (1.5%). Between 2010 and 2020, the proportion of patients receiving triplet+bev changed from 1.5% to 4.2% in age group 18–49 yrs, from 3.1% to 2.6% in 50–64 yrs, and from 1.1% to 1.2% in ≥65 yrs. Over a median 20-month follow-up period, 58.0% of patients in age groups 18–49 and 50–64 yrs, and 53.7% of patients in age group ≥65 yrs, received a new treatment after triplet+bev. In the overall cohort, the most common new treatment after triplet+bev was regorafenib (20.7%), received by 18.2% of patients in age group 18–49 yrs, 22.7% in 50–64 yrs, and 19.2% in ≥65 yrs. Other new subsequent treatments in the overall cohort included trifluridine/tipiracil (17.1%) and cetuximab (16.3%), with a similar trend seen among all age groups. Across age groups, triplet+bev recipients were more likely to be male, obese, resident in the Midwest or Northeast, and have distant metastases, and less likely to have colorectal surgical resection prior to mCRC diagnosis. Patients in age group 18–49 yrs subsequently receiving regorafenib were more likely to be obese and less likely to have Charlson Comorbidity Index ≥3, distant metastases, and colorectal surgical resection before mCRC diagnosis vs those who did not receive regorafenib. Conclusions: Our study shows that, recently, triplet+bev use has increased in patients with mCRC, particularly in those aged < 50 yrs. Chemotherapy-free treatments may be an option for these patients beyond the first-line setting. While regorafenib is typically used in third or later lines, these real-world data suggest it is often a preferred option following triplet+bev treatment.
The tumor mutation burden in gastro-entero-pancreatic-neuroendocrine tumors.
Authors: Jeong Sun Young , Kim Seung Tae , Jang Jae Yeon 
Published: January 2023

654 Background: Neuroendocrine tumors (NET) are rare tumors with limited treatment options. Tumor mutation burden (TMB) has been known as a novel biomarker in various tumor types. However, there has been little study of the role of TMB-high in gastro-entero-pancreatic (GEP)-NETs. Methods: We analyzed 31 metastatic GEP-NET patients who were newly diagnosed between 2013 to 2022. Next-generation sequencing (NGS) including TMB analysis, as a routine clinical practice was performed. The TruSight Oncology 500 assay from Illumina was used as a cancer panel. Results: Among a total of 31 patients, the median TMB was 4.7 mutation/Mb (3.10-6.3). Primary origin was stomach in 4 (12.9%), small bowel in 2 (6.5%), rectum in 7 (22.6%), pancreas in 21 (38.7%), bile duct in 1 (3.2%), gall bladder in 4 (12.9%), liver in 1 (3.2%) patient. 17 (54.8%) patients were diagnosed with well-differentiated NET with grade 1 in 3 (9.7%), and grade 2 in 14 (45.2%) patients. Grade 3 NET (neuroendocrine carcinoma) was confirmed in 14 (45.2%) patients. The median number of metastases was 2.7 (1.0-4.0). The most common metastatic site was the liver (26 patients, 83.9%). All tumors were classified as type of micro-satellite stable (MSS). Only one patient had the tumor with high TMB (266.4 mutation/Mb). This tumor was classified as the grade 3 neuroendocrine carcinoma and the primary tumor site was pancreas. Conclusions: This analysis revealed that the GEP-NETs were generally considered as tumor-type of low TMB. However, uncommonly, GEP-NET with high-TMB could be found. For the precision medicine, the NGS test is needed as a routine clinical practice in this tumor type.