bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMUNIB trial (AIO-HEP-0218/ass): A single-arm, phase II study evaluating safety and efficacy of immunotherapy nivolumab in combination with lenvatinib in advanced-stage hepatocellular carcinoma (HCC).
Authors: Vogel Arndt , Siegler Gabriele Margareta , Siebler Jurgen , Lindig Udo , Schultheiß Michael , Müller Tobias , Simon Henry , Jöckel Christiane , Mueller Daniel Wilhelm , Al-Batran Salah-Eddin , Saborowski Anna , De Toni Enrico N 
Published: June 2022

4107 Background: The field of systemic options in HCC therapy has significantly evolved in recent years, and first line options now include sorafenib, lenvatinib and bevacizumab plus atezolizumab. Nivolumab is a recombinant human IgG4 mAb targeting PD-1 with clinically meaningful activity in about 15-20% of HCC patients, but the confirmatory phase III trial Checkmate 459 failed to demonstrate superiority over sorafenib. VEGF signaling is not only a driver of tumor angiogenesis, but also contributes to the formation of an immunosuppressive microenvironment. Combinations of anti-angiogenic multikinase inhibitors, specifically lenvatinib, and PD-1/PD-L1 inhibitors have demonstrated remarkable antitumor activity and manageable toxicity in several tumor types, including HCC. We therefore aimed to evaluate the efficacy of nivolumab in combination with lenvatinib as first line treatment in patients with advanced HCC. Methods: This investigator-initiated single-armed phase II trial (NCT03841201) recruited 50 patients (pts) at 8 sites in Germany between 07/2019 and 05/2021. Primary endpoints were objective response rate (ORR) according to investigator assessed RECIST 1.1 and safety/tolerability. Secondary endpoints included ORR according to iRECIST, time to progression (TTP), progression free survival (PFS) and overall survival (OS). Recruitment of the trial was completed in 05/2021. At the time of analysis, 4 patients remained on treatment. Results: 50 pts (24 BCLC B, 24 BCLC C, 2 not evaluable) were enrolled and received at least one dose of the combination treatment. ORR by RECIST 1.1 was 28% (CR: 6.0%, PR: 22.0%, SD: 46.0%, PD: 12.0%). Median PFS was 9.0 mo (26 events). Median TTP was 11.5 mo (0.69 at 6 mo, 0.45 at 12 mo, 0.36 at 18 mo) and median OS was 27.1 mo (8 events). 45 (91.8%) pts experienced at least one TRAE, of which 29 pts (59.1%) encountered at least one TRAE ≥ grade 3. 17 (34.7%) pts had one or more SAE related to the study medication, whereof 15 pts (30.6%) experienced at least one treatment related SAE ≥ grade 3. Conclusions: No new safety signals were observed for the combination of nivolumab and lenvatinib. Although the study failed to reach its prespecified ORR of at least 40%, the high activity in all efficacy endpoints with a mOS of 27.1 mo supports the further investigation of the combination in HCC. Clinical trial information: NCT03841201.
Pembrolizumab monotherapy for previously untreated advanced hepatocellular carcinoma (aHCC): 3-year follow-up of the phase 2 KEYNOTE-224 study.
Authors: Borbath Ivan , Van Laethem Jean-Luc , Karwal Mark , Verslype Chris , Van Vlierberghe Hans , Kardosh Adel , Bergamo Francesca , Stål Per , Sarker Debashis , Palmer Daniel H. , Edeline Julien , Cattan Stéphane , Kudo Masatoshi , Cheng Ann-Lii , Ogasawara Sadahisa , Siegel Abby B. , Hatogai Ken , Wang Anran , Vogel Arndt 
Published: June 2022

4109 Background: Pembrolizumab monotherapy showed durable antitumor activity and a manageable safety profile in patients with sorafenib-treated (cohort 1) and treatment-naive (cohort 2) aHCC in the open-label, phase 2 KEYNOTE-224 (NCT02702414) study. Longer term data from KEYNOTE-224 after ̃3 years of follow-up for patients with treatment-naive aHCC are reported. Methods: Eligible patients in cohort 2 had histologically, cytologically, or radiologically confirmed aHCC, Barcelona Clinic Liver Cancer stage C or B not amenable or refractory to locoregional therapy and not amenable to curative treatment, Child-Pugh A liver function, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and ECOG PS 0 or 1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (̃2 years). Primary end point was ORR assessed per RECIST v1.1 by BICR. Secondary end points included DOR, DCR, TTP, and PFS, all assessed per RECIST v1.1 by BICR, OS, and safety/tolerability. Results: All 51 patients enrolled in cohort 2 received ≥1 dose of pembrolizumab. Median follow-up, defined as the time from first dose to the data cutoff (October 1, 2021), was 35 months (range, 31-37). ORR was 16% (95% CI, 7-29). Median DOR was not reached (NR; range, 3 to 24+ months); 58% of responders were estimated to have a response duration ≥18 months. Best overall response was 8 (16%) PRs, 21 (41%) SDs, and 17 (33%) PDs; no CRs were observed and response was not evaluable for 2 patients (4%) and not assessed for 3 patients (6%). DCR was 57% (95% CI, 42-71). ORR was generally consistent among patients with a viral and nonviral etiology for HCC, although sample sizes were small. The median TTP was 4 months (95% CI, 3-9). Median PFS was 4 months (95% CI, 2-8). Estimated PFS rate at 24 months was 15%. Median OS was 17 months (95% CI, 8-23). Estimated OS rate at 24 months was 34%. No new or unexpected adverse events (AEs) occurred. Treatment-related AEs were reported in 28 patients (55%; grade 3-5, 8 [16%]). Conclusions: Updated results from cohort 2 of the KEYNOTE-224 study continued to demonstrate durable antitumor activity, promising OS, and manageable safety for pembrolizumab monotherapy in patients with aHCC and no prior systemic therapy. These data, together with recent positive results from KEYNOTE-394, underscore the broad applicability of pembrolizumab in patients with aHCC both as monotherapy and in combination with other therapies. Clinical trial information: NCT02702414.
Early detection of hepatocellular carcinoma using cfDNA signatures from cirrhotic patients with nodules.
Authors: Fan Rong , Chen Lei , Wang Yingchao , Wei Weiwei , Qian Yunsong , Du Lutao , Fan Xiaotang , Yu Yanlong , Jiang Guoqing , Huang Yangqing , Bai Honglian , Gao Yanhang , Wang Chunying , Deng Guohong , Zhang Qingzheng , Wang Chuanxin , Liu Jingfeng , Wang Hongyang , Hou Jinlin 
Published: June 2022

4113 Background: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Early detection of HCC patients is related to favorable survival. Nodules in liver cirrhosis (LC) are at higher risk of developing into HCC. There is an urgent clinical need for development of an accurate and affordable non-invasive method for early HCC diagnosis among LC patients with nodules. Methods: We have previously shown that the genome-wide HIFI (5-Hydroxymethylcytosine/motIf/ Fragmentation/nucleosome footprInt) method held a solid diagnostic value in differentiating HCC from LC. In this study, we leverage this knowledge to diagnose early HCC (BCLC 0/A) in cirrhotic nodules using copy number variation (CNV) to replace 5-Hydroxymethylcytosine to simplify NGS protocol and decrease cost. The updated method generates a score that reflects the presence of tumor-derived cfDNA in 10 ml blood via low coverage (2x) whole-genome sequencing (WGS). We applied it in a retrospective cohort (validation set 1, n = 171) and a prospective cohort (validation set 2, n = 156), both of which involved patients with newly diagnosed early stage HCC (BCLC 0/A) as well as individuals with cirrhotic nodules. Results: The updated method showed excellent performance for early HCC detection both in the validation set 1 (84 HCC and 87 cirrhotic nodules; AUC: 0.951, 82.1% sensitivity at 90.8% specificity) and validation set 2 (71 HCC and 85 cirrhotic nodules; AUC: 0.958, 81.7% sensitivity at 91.8% specificity) (Table). The AUC values for distinguishing early HCC from cirrhotic nodules could reach 0.951 (80.9% sensitivity at 91.0% specificity) and 0.947 (74.7% sensitivity at 92.1% specificity) among patients with AFP < 400 μg/L and those with nodular size < = 2 cm, respectively. More importantly, our model also maintained consistent performance in detecting very early stage HCC (BCLC 0) with AUC of 0.941 (74.7% sensitivity at 91.3% specificity). Conclusions: These findings provide an accurate, affordable, excellent clinical potential model integrating four cfDNA molecular signatures for detecting early stage HCC from cirrhotic nodules using low-coverage WGS of plasma cfDNA samples. [Table: see text]
Socioeconomic factors associated with a late-stage pancreatic cancer diagnosis: An analysis of the national cancer database.
Authors: Gallegos Jillian Marie , Verplancke Kiana , Taylor Alexandra , McMahon Kevin , Silberstein Peter T. , Dahl Mary Elizabeth 
Published: June 2022

4135 Background: Pancreatic cancer is an aggressive, lethal cancer that is the 4th leading cause of cancer death in the United States. It is often asymptomatic until later stages, thus it is critical to assess the socioeconomic factors associated with diagnosis at early vs. late stages. Using the National Cancer Database, we aim to identify associations between socioeconomic factors of patients that present with early stage (0-I) pancreatic cancer in comparison to late-stage disease (stage IV) at diagnosis. Methods: In this study, 256,822 patients from the National Cancer Database who were diagnosed with NCDB Analytic Stage Group stage 0-I and stage IV pancreatic cancer were analyzed based on age, race, sex, ethnicity, insurance type, income, geographic location, education and Charlson-Deyo score. Demographic factors of patients that presented with early and late-stage disease were analyzed using chi square and multivariate analysis. All patients included in the study were diagnosed with pancreatic cancer between 2004 and 2018. Results: We identified significant ( P <0.05) associations between race, sex, insurance status, education, income, and geographic location with diagnosis of advanced-stage disease. A greater percentage of males were diagnosed with late-stage cancer than early-stage (52.8% vs 47.9%). Females were more likely to have an earlier-stage diagnosis and were 15% less likely to have late-stage diagnosis than males (p < 0.001 and 95% CI = 0.839-0.875). African Americans were 10% more likely to have a late-stage diagnosis than Caucasians (p < 0.001 and 95% CI = 1.069-1.144). For insurance status, private and Medicaid insurance had higher percentages of late-stage diagnosis than early-stages, and all types of insurance had lower rates of late-stage diagnosis than patients without insurance (p < 0.001). Patients from a zip-code associated with < $38,000 median household income and zip-codes with lower levels of high school diplomas had higher rates of late-stage diagnosis (p < 0.025). Conclusions: Factors associated with increased likelihood of pancreatic cancer presentation at advanced stage compared to early stage include race, sex, insurance status, education, median income, comorbidity score, and geographic location.
Phase I dose escalation and expansion study of defactinib, pembrolizumab, and gemcitabine in patients with advanced treatment-refractory pancreatic cancer.
Authors: wang-gillam Andrea , Lim Kian-Huat , McWilliams Robert R. , Suresh Rama , Lockhart A. Craig , Brown Amberly , Herndon John , Pedersen Katrina Sophia , Tan Benjamin R. , Boice Nicolas , Abdiannia Mina , Gao Feng , Yoon Harry H. , Zhu Mojun , Trikalinos Nikolaos A. , Ratner Lee , Aranha Olivia , Hawkins William G. , Herzog Brett , DeNardo David G. 
Published: June 2022

4146 Background: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse models. Defactinib is a highly potent oral FAK inhibitor shown to have a tolerable safety profile. We evaluated the safety and recommended phase 2 dose (RP2D) of defactinib in combination with pembrolizumab and gemcitabine for PDAC patients. Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In 3x3 dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a RP2D. In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had treatment response or stable disease (SD) on standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and post-treatment tumor biopsies were performed to evaluate changes in tumor immunity. Results: The triple drug combination was well-tolerated with no dose-limiting toxicities. Among 17 treated patients with refractory PDAC, the disease control rate (DCR) was 58.8% with one partial response (PR) and nine SDs and the median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 9.1 months, respectively. Among the evaluable patients in the maintenance cohort, DCR was 63.6% with one PR and six SD. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS were 5.0 months and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated, had promising preliminary efficacy, and showed increased infiltrative T lymphocytes in post-treatment tumor biopsies. Incorporation of a more potent chemotherapy backbone should be considered to achieve better clinical response in future trial design. Clinical trial information: NCT02546531.
Cabozantinib (C) in combination with atezolizumab (A) in urothelial carcinoma (UC): Results from Cohorts 3, 4, 5 of the COSMIC-021 study.
Authors: Pal Sumanta K. , Agarwal Neeraj , Singh Parminder , Necchi Andrea , McGregor Bradley Alexander , Hauke Ralph J. , Powles Thomas , Suárez Cristina , Van Herpen Carla M.L.- , Vaishampayan Ulka N. , Sudhagoni Ramu , Curran Dominic , Andrianova Lana , Loriot Yohann 
Published: June 2022

4504 Background: C, a multitargeted receptor tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment that may enhance response to immune checkpoint inhibitors (ICIs). COSMIC-021, a multicenter phase 1b study, is evaluating C + A (anti‒PD-L1 therapy) in various solid tumors (NCT03170960). C + A demonstrated encouraging clinical activity in cohort 2 of COSMIC-021 in patients (pts) with UC previously treated with platinum-containing chemotherapy (chemo) (Pal S et al. ASCO 2020. Abstract 5013). Outcomes of C + A from 3 other UC cohorts (C3, C4, C5) are presented. Methods: Pts with inoperable locally advanced/metastatic UC with transitional cell histology and ECOG PS 0‒1 were eligible. Pts enrolled in C3 and C4 had no prior therapy and were cisplatin-based chemo ineligible (C3) or eligible (C4). C5 enrolled pts with one prior ICI and no prior VEGFR-TKI therapy. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for first year and Q12W thereafter. The primary endpoint is objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints: safety, duration of response (DOR), PFS, and OS. Results: Thirty pts each were enrolled in C3 and C4, and 31 in C5. Baseline characteristics for C3, C4, and C5, respectively: median age, 74 y, 66 y, 68 y; male, 67%, 73%, 55%; ECOG PS 1, 63%, 57%, 74%; lung/liver metastasis; 33%/17%, 40%/20%, 58%/23%; ≥3 tumor sites, 30%, 43%, 45%; bladder as primary site, 67%, 70%, 71%. As of Nov 30, 2021, the median follow-up for C3, C4, and C5 was 27.9, 19.1, and 32.9 mo, respectively, with 1, 6, and 1 pts on treatment. C + A demonstrated clinical benefit across all cohorts (Table). Most common treatment-related adverse events (TRAEs) of any grade across C3, C4, and C5, respectively, were diarrhea (43%, 33%, 35%), nausea (27%, 17%, 26%), fatigue (27%, 27%, 48%), and decreased appetite (33%, 27%, 39%); grade 3/4 TRAEs occurred in 63%, 43%, and 45%, and there was no grade 5 TRAE. Conclusions: C + A demonstrated encouraging clinical activity with manageable toxicity in inoperable locally advanced/metastatic UC as first-line systemic therapy in cisplatin-based chemo eligible/ineligible pts and as second- or later line in pts who received prior ICI. Clinical trial information: NCT03170960. [Table: see text]
A phase 1b/2 study of batiraxcept (AVB-S6-500) in combination with cabozantinib in patients with advanced or metastatic clear cell renal cell (ccRCC) carcinoma who have received front-line treatment (NCT04300140).
Authors: Shah Neil J. , Beckermann Katy , Vogelzang Nicholas J. , Mao Shifeng S. , Ornstein Moshe Chaim , Hammers Hans J. , Gao Xin , McDermott David F. , Haas Naomi B. , Yan Hongxia , Esquibel Vanessa , Rangwala Reshma A. , Campbell Matthew T 
Published: June 2022

4511 Background: AXL is up-regulated by hypoxia-inducible factor-1 signaling in both VHL-deficient and hypoxic tumor cells and plays a critical role in the metastatic phenotype of ccRCC. Batiraxcept is a recombinant fusion protein containing an extracellular region of human AXL combined with the human immunoglobulin G1 heavy chain (Fc), demonstrating highly potent, specific AXL inhibition. Methods: Batiraxcept at doses of 15 and 20 mg/kg, plus cabozantinib 60 mg daily, was evaluated using a 3+3 dose escalation study design. The primary objective was safety; secondary and exploratory objectives included identification of the recommended phase 2 dose (RP2D), overall response rate (ORR), and duration of response (DOR). Correlation of serum soluble AXL (sAXL)/GAS6 with ORR was evaluated. Key eligibility criteria include previously treated (2L+) ccRCC patients; prior treatment with cabozantanib was not allowed. sAXL/GAS6 was evaluated at baseline. Results: Data as of 4-February-2022, Phase 1b enrolled 26 patients, 16 patients treated with 15 mg/kg and 10 patients with 20 mg/kg dose of batiraxcept. Baseline characteristics: median age 60 (40-81); male 22 (85%); median prior line of therapy 1 (1-5); IMDC risk group of favorable 6 (23%); prior VEGF inhibitor 15 (58%); 100% with prior immunotherapy. At median follow up of 4.9 months, 92% (n=24) patients remained on the study. No dose limiting toxicities were observed at either 15 mg/kg or 20 mg/kg dose. Batiraxcept and cabozantinib related adverse events (AEs) occurred in 17 subjects (65%). Most common related AE include decreased appetite 31% (n=8), diarrhea and fatigue 23% (n=6). Grade 3 related AEs occurred in 4 patients (15%) including diarrhea, thromboembolism, hypertension, small bowel obstruction, and thrombocytopenia (n=1, 4% each) being most common. No grade 4 or 5 related AEs were observed. The ORR was 46% (n=12, partial response [PR]; Table). No patients had primary progressive disease. Among the patients who had baseline sAXL/GAS6 ratio of ≥ 2.3, the ORR was 67% (12/18). Regardless of baseline sAXL/GAS6 ratio, 3-month DOR was 100%; and 6-month progression free survival was 79%. Batiraxcept PK levels were similar across both doses and GAS6 levels suppressed through the dosing period. Conclusions: Batiraxcept plus cabozantinib is well tolerated. The RP2D of batiraxcept was identified as 15 mg/kg. Early efficacy signals were observed including 100% DOR at 3 months. Baseline sAXL/GAS6 may serve as a potential biomarker to enrich the population. Clinical trial information: NCT04300140. [Table: see text]
Landscape analysis of urothelial carcinoma (UC) by telomerase reverse transcriptase (TERT) alterations.
Authors: Stewart Tyler F. , Dosset Magalie , Brodskiy Pavel , Xiu Joanne , Rezazadeh Arash , Mar Nataliya , Darabi Sourat , Demeure Michael J. , Barata Pedro C. , Geynisman Daniel M. , Ghatalia Pooja , Joshi Monika , Ramamurthy Chethan , Nabhan Chadi , Heath Elisabeth I. , Carter Hannah , Zanetti Maurizio , McKay Rana R. 
Published: June 2022

4524 Background: TERT is a catalytic subunit of telomerase, the unique enzyme that confers immortality to cells and is expressed in >90% of cancer cells. Mutations in the TERT promoter region (pTERTmut) are the most prevalent noncoding mutations in cancer. Recent data suggest pTERTmut are associated with improved outcomes in patients with UC treated with immune checkpoint inhibitors. We evaluated the molecular and immune landscape of UC with and without pTERTmut. Methods: UC tissue samples were analyzed for DNA alterations (NextSeq, 592 Genes; NovaSeq, WES) and mRNA expression (NovaSeq, WTS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). PD-L1 expression was assessed by immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). MSI/MMR was tested by fragment analysis, IHC and NGS. TMB-H was based on a cut-off of > 10 mut/MB. We compared alterations between samples with and without detected pathogenic pTERTmut. Significance was determined by Mann–Whitney U, X2, and Fischer-Exact and p adjusted for multiple comparisons (q) was < 0.05 using Benjamini-Hochberg. Results: Overall, 1686 UC samples were analyzed, 1166 from primary lesions and 499 from a lymph node or metastatic site. pTERTmut was present in 68% of primary and 61% of metastatic tumors, and correlated with modest increase of TERT expression (1.18 fold, p=0.015). pTERTmut was associated with less frequent alterations in TP53, KMT2D, CCND1, MYC, KEAP1 and less MSI/dMMR. By contrast, pTERTmut was associated with more frequent alterations in ARID1A, TSC1, PIK3CA and TMB-H (all q<0.05). Over 41% of pTERTmut were TMB-H. TERTp mutations were not associated with FGFR alterations. The frequency of co-occurring mutations was similar by specimen site. In evaluating the immune landscape (Table), pTERTmut was associated with higher expression of PD-L1 (IHC, mRNA), PD-L2 (mRNA) and TIM3 (mRNA) in tumors from primary sites (all p and q<0.05), but not in metastatic sites. Investigation of tumor-associated immune cells demonstrated that pTERTmut correlated with higher percentage of M1-macrophages and CD8+ T cells in primary tumors, and was inversely-correlated with NK cells in metastatic sites (all q<0.05). Conclusions: This is the largest analysis looking at the molecular and immune landscape of pTERTmut UC tumors. We observed differential patterns of DNA alterations and tumor immune microenvironment based on pTERTmut status. Further work is needed to understand differences in these molecular cohorts and the association of these data with clinical outcomes. [Table: see text]