bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients (Pts) with advanced hepatocellular carcinoma (aHCC): Long-term results from CheckMate 040.
Authors: El-Khoueiry Anthony B. , Yau Thomas , Kang Yoon-Koo , Kim Tae-You , Santoro Armando , Sangro Bruno , Melero Ignacio , Kudo Masatoshi , Hou Ming-Mo , Matilla Ana , Tovoli Francesco , Knox Jennifer J. , He Aiwu Ruth , El-Rayes Bassel F. , Acosta-Rivera Mirelis , Lim Ho Yeong , Memaj Arteid , Sama Ashwin Reddy , Hsu Chiun 
Published: January 2021

269 Background: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) followed by NIVO 240 mg Q2W is approved in the US for sorafenib-treated pts with aHCC based on initial results from CheckMate 040 (NCT01658878), which reported objective response rate (ORR) of 32% and median overall survival (mOS) of 22.8 months (mo).1 We present 44-mo long-term follow-up results from the CheckMate 040 NIVO+IPI cohort. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Safety and tolerability, ORR (blinded independent central review per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS were assessed. Data cutoff was May 26, 2020. Results: 148 pts were randomized. Minimum follow-up was 44 mo. mOS remained at 22.2 mo in arm A, 12.5 mo in arm B, and 12.7 mo in arm C; 36-mo OS rates were 42%, 26%, and 30%, respectively. Durable responses were achieved across treatment arms, with DOR approaching 4 years in some cases. DCR was higher in arm A than arms B and C. In all arms, responses were observed regardless of baseline programmed death ligand 1 expression ( < 1% or ≥ 1%) or baseline alpha-fetoprotein level ( < 400 µg/L or ≥ 400 µg/L). Pts with hepatitis B or C virus (HBV or HCV) etiology had higher ORR than uninfected pts in arms B (29% vs 43% vs 9%) and C (31% vs 42% vs 0%). ORR was independent of etiology in arm A (HBV, 32%; HCV, 29%; uninfected, 31%). Additional efficacy data are in the table. There were no additional discontinuations due to treatment-related adverse events or immune-mediated adverse events (IMAEs) since the primary analysis. IMAEs were reported more frequently in arm A than arms B and C; the most common were rash, hepatitis, and adrenal insufficiency. Most IMAEs were reversible and resolved when treated using established algorithms. Conclusions: At a minimum follow-up of 44 mo, second-line NIVO1+IPI3 continued to demonstrate clinically meaningful responses and long-term survival benefit in aHCC. The safety profile was manageable and no new safety signals were identified with longer follow-up. Clinical trial information: NCT01658878. [Table: see text]
Efficacy and safety of lenvatinib in the real-world treatment of hepatocellular carcinoma: Results from a Canadian multicenter database (HCC CHORD).
Authors: Amaro Carla Pires , Allen Michael J , Knox Jennifer J. , Tsang Erica S , Lim Howard John , Lee-Ying Richard M. , Qian Jessica , Meyers Brandon M. , Thawer Alia , Al-Saadi Sulaiman Mohammed Saif , Hsu Tina , Ramjeesingh Ravi , Karachiwala Hatim , Abedin Tasnima , Tam Vincent C. ,   HCC CHORD Consortium
Published: January 2021

275 Background: The REFLECT trial establishedlenvatinib (LEN) as a first-line treatment option for hepatocellular carcinoma (HCC). Compared to sorafenib (S), LEN has a higher objective response rate (ORR) and progression-free survival (PFS) with a slightly different toxicity profile. The aim of this study was to gather data regarding the efficacy and safety of LEN when used in the real-world treatment of HCC. To our knowledge, this is the first study to examine LEN use in HCC patients treated outside of Asia. Methods: HCC patients treated with LEN from 10 cancer centers in the Canadian provinces of British Columbia, Alberta, Ontario and Nova Scotia between July 2018 to July 2020 were included. Overall survival (OS), PFS, disease control rate (DCR) and ORR were retrospectively analyzed and compared across first- and second-to-fourth line use of LEN. ORR was determined radiographically according to the treating physician´s opinion in clinical notes and not RECIST 1.1 or mRECIST. Toxicities were also examined. Results: A total of 220 patients were included in this analysis. Median age was 67 years, 80% were men and 25.5% East Asian. The most frequent causes of liver disease were hepatitis C (37%) and B (26%). 62% of patients received any localized treatment before LEN, of those 26% had TACE, 15% TARE and 7.7% had liver transplant. Before starting LEN 29% of patients were ECOG 0 and 59% were ECOG 1. Most patients were Child-Pugh A (81%) and BCLC stage C (75.5%). Main portal vein invasion was present in 14% of the patients. Median follow-up was 4.5 months. A total of 173 patients (79%) received LEN as first line therapy and 47 patients (21%) were treated in second-to-fourth line. Of patients receiving LEN in first line, 22 (13%) started treatment with S, but switched to LEN before progression due to poor tolerance of S. ORR, DCR, PFS and OS are shown in the table. Toxicities occurred in 86% of patients and led to dose reductions in 76 (35%) patients and drug discontinuation in 53 (24%) patients. The most common side effects were fatigue (59%), hypertension (41%), decreased appetite (25%) and diarrhea (22%). Conclusions: Outcomes of HCC patients treated in Canada with LEN in the first line are comparable to those demonstrated in the REFLECT trial, despite the inclusion of Child-Pugh B and ECOG >1 patients. LEN use in second or later lines also showed similar outcomes, although more conclusions are difficult to draw due to the small numbers. LEN appears to be effective and safe in real world practice outside of Asia in first- and second-to-fourth line treatment of HCC. [Table: see text]
Anlotinib plus TQB2450 in patients with advanced refractory biliary tract cancer (BTC): An open-label, dose-escalating, and dose-expansion cohort of phase Ib trial.
Authors: Zhou Jun , Gong Jifang , Cao Yanshuo , Peng Zhi , Yuan Jiajia , Wang Xicheng , LU Ming , Shen Lin 
Published: January 2021

292 Background: Anti-angiogenic agents have been clinically investigated in combination with anti-PD-1/L1 mAbs due to their immuno-modulatory effects. Anlotinib (A), a potent oral multi-target tyrosine kinase inhibitor, has anti-angiogenic properties and anti-tumor efficacy with a favorable toxicity profile. The combination of A and TQB2450 (T), an anti-PD-L1 mAb, exhibited superior tumor growth suppression compared to either monotherapy in murine models. This ongoing phase 1b study cohort is aimed to assess the safety and efficacy of A+T in pts with advanced BTC. Methods: In this study cohort, patients (pts) with previously treated, advanced BTC were enrolled. A 3+3 dose escalation was used to determine the maximum tolerated dose (MTD) and a recommended phase 2 dose (RP2D) in a dose-escalating stage. Additional pts were enrolled in a dose-expansion stage to further establish the safety and determine the preliminary efficacy. Oral A of 10 and 12 mg was administered once daily for 14 days on / 7 days off with intravenous T of 1200 mg every 3 weeks. The primary endpoint was dose-limiting toxicity (DLT) during first cycle (first 3 weeks) to estimate the MTD, RP2D and overall response rate (ORR). Tumor response was assessed according to RECIST version 1.1 and iRECIST. The Secondary endpoints were progression-free survival (PFS), disease control rate (DCR) and safety. Results:25 pts were enrolled (8 with intrahepatic cholangiocarcinoma [IHCC]; 8 with extrahepatic cholangiocarcinoma [EHCC]; 9 with gall bladder cancer [GBC]) until August 2020. Median number of prior lines of therapy was 1 (range 1-5). During dose-escalation, no DLT was observed and 12 mg anlotinib was determined as RP2D for expansion. Among 24 evaluable pts (with at least once tumor assessment), 3 had achieved complete response (CR) and 7 had partial response (PR), which were all treated by 12 mg anlotinib plus TQB2450, 8 had stable disease (SD) and 6 had progression disease (PD). ORR was 41.67% and DCR was 75%. 10 pts were still on treatment. The median PFS was 240 days (95% CI, 83~NR).Treatment-related adverse events (TRAEs) occurred in 83.3% of pts (G3/4 in 16.7% [4/24], and leading to treatment discontinuation in 4.2% [1/24]). The most common TRAEs were hypertension (33.3%), decreased white blood cell counts (25.0%), increased TBIL (20.8%), decreased neutrophil counts (20.8%), increased DBIL (12.5%), and increased IBIL (12.5%). Conclusions: A+T had a manageable safety profile and encouraging antitumor efficacy in pts with previously treated, advanced BTC. No unexpected AEs were identified beyond the established safety profile for each agent. Clinical trial information: NCT03996408.
Use of yttrium-90 (Y90) glass microspheres (TheraSphere) as neoadjuvant to transplantation/resection in hepatocellular carcinoma: Analyses from the LEGACY study.
Authors: Lewandowski Robert , Johnson Guy E. , Kim Edward , Riaz Ahsun , Bishay Vivian , Padia Siddharth , Salem Riad 
Published: January 2021

300 Background: The objective of the LEGACY study was to assess the Objective Response Rate (ORR) and Duration of Response (DoR) following treatment with Yttrium-90 (Y90) glass microspheres in patients with unresectable solitary hepatocellular carcinoma (HCC). The objective of the analyses presented here are to evaluate ORR, DoR, and Overall Survival (OS) by transplant/resection status and to compare these outcomes with patients who did not go on to transplantation/resection after receiving treatment with Y90. Methods: LEGACY is a single-arm, multicenter, retrospective study of patients with unresectable HCC who received treatment with Y90 glass microspheres (TheraSphere) at one of three sites in the United States. LEGACY included all consecutive eligible patients who received treatment between January 2014 and December 2017 and met the eligibility criteria (Child-Pugh A; ECOG score of 0 or 1; BCLC A or C; and a solitary tumor > 2 and ≤8 cm). Primary efficacy endpoints included ORR and DoR. ORR included patients who achieved either a complete response or partial response based on localized mRECIST; response was assessed via blinded, independent, central review. Secondary endpoints include OS and number and type of subsequent treatments, including transplantation and resection. Results: Among all 162 patients enrolled in LEGACY, ORR was 72.2% (117/162; 95% CI = 64.9%, 78.5%); the majority of patients experienced DoR ≥ 6 months (89/117, 76.1%, 95% CI = 67.6%, 82.9%). Median follow-up time for all 162 patients enrolled in LEGACY was 29.9 months by reverse Kaplan-Meier analysis; 3-year OS was 86.6%. For 45/162 (27.8%) of patients, Y90 treatment served as neoadjuvant therapy; 34 went on to transplantation (21.0%) and 11 (6.8%) went on to resection. For neoadjuvant treatment, ORR was 80.0% (36/45, 95% CI = 66.2, 89.1), DoR ≥ 6 months was 30.6% (11/45, 95% CI = 18.0, 46.9), and 3-year OS was 92.8% (95% CI = 74.2, 98.2). Of these 45 patients, 35 patients achieved complete response (CR), 1 achieved partial response (PR), and 9/45 (20.0%) were deemed not evaluable as they underwent surgery prior to the 6-month mark and did not have imaging assessments post-Day 46. These nine patients were censored, lowering the DoR; however, histopathology revealed that 7/9 (77.8%) achieved complete pathologic necrosis, 1/9 (11.1%) had extensive pathologic necrosis, and 1 (11.1%) had partial pathologic necrosis. For the 117/162 (72.2%) patients who did not go on to surgical treatment, ORR was 91.5% (107/117, 95% CI = 85.0, 95.3), DoR ≥ 6 months was 72.9% (78/117, 95% CI = 63.8, 80.4), and 3-year OS was 83.5% (95% CI = 72.2, 90.5). Conclusions: Treatment of solitary unresectable HCC with Y90 glass microspheres provides strong ORR, DoR, and OS both as neoadjuvant therapy to transplantation/resection and as treatment in non-surgical candidates.
Phase II study of anlotinib plus sintlimab as second-line treatment for patients with advanced biliary tract cancers.
Authors: Zong Hong , Zhong Qian , Zhao Ruihua , Jin Shuiling , Zhou Chuang , Zhang Xiaojian , Shi Jianxiang , Qiao Shishi , Han Jinming , Jiang Miao 
Published: January 2021

307 Background: Gemcitabine combined with cisplatin (GP) has been established as the standard first-line treatment in patients with unresectable biliary tract cancers (BTC), a heterogeneous group of rare and aggressive malignancies arising from the epithelium of the biliary duct system. Nevertheless, there has been no approved standard of care for second-line treatment. In this study, we explored the efficacy and safety of the combination of anlotinib and sintlimab as a novel second-line regimen in BTC. Methods: In this phase II trial, patients with advanced BCT, who experienced progression after first-line chemotherapy, received anlotinib (12 mg, PO, D1-14, Q3W) combined with sintlimab (200 mg, iv, D1, Q3W) until disease progression or unacceptable toxicity. The primary endpoint was OS, and the secondary endpoints included ORR, PFS, DCR, and safety. The exploratory endpoint was the correlation of clinical outcomes with biomarkers. Results: From Aug 2019 to Sep 2020, 17 patients were enrolled. 9(52.9%) were men, and the median age was 59(43-69) years. Nine patients were diagnosed with ICC, 2 with ECC, and 6 with GBC. 15 patients were assessable for response. At a median follow-up of 8.76 months (95%CI: 3.60-13.94 months), the primary endpoint OS has not been reached, the median PFS was 6.50 months (95%CI: 3.60-9.40 months). ORR was 40.00%, and DCR was 86.67%. The incidence of treatment-related adverse events (TRAEs) was 70.60%, and the most common grade 1-2 AEs were hypertension (70.60%), diarrhea (17.65%), and hypothyroidism (17.65%). Conclusions: Anlotinib plus sintlimab demonstrates significant clinical activity and acceptable toxicity in patients with advanced BTC who failed first-line chemotherapy. Clinical trial information: ChiCTR1900022003.
Evaluation of neratinib (N), pembrolizumab (P), everolimus (E), and nivolumab (V) in patients (pts) with fibrolamellar carcinoma (FLC).
Authors: Abou-Alfa Ghassan K. , Meyer Tim , Zhang Jie , Sherrin Scott , Yaqubie Amin , Clemens O’Neill Alison , Xu Feng , Eli Lisa D , Harding James J. , O'Reilly Eileen Mary , Lalani Alshad S. , Bryce Richard , Gordan John Dozier 
Published: January 2021

310 Background: FLC, a rare liver cancer of young adults, has no effective systemic therapies. Surgical resection is used extensively with non-curative intent. FLC is associated with a DNAJB1- PRKACA chimeric transcript that produces a fusion protein with retained kinase activity and increased expression of several oncogenic signaling pathways including, but not limited to, HER2 ( ERBB2). Methods: N (240 mg oral daily) was studied in FLC pts in the SUMMIT study (NCT01953926); and later under compassionate use for N-based combinations (combo): P (2 mg/kg q3w), E (7.5 mg daily), and V (240 mg q2w) in doublet or triplet regimens. Eligible pts: ≥12y; histologically confirmed FLC; adequate organ function; any number of prior therapies. Primary endpoint: objective response rate (ORR; RECIST v1.1). Secondary endpoints: duration of response; clinical benefit rate (CBR); safety (CTCAE v4.0); somatic and germline sequencing (MSK IMPACT). Results: As of 03-Sep-2020, 15 pretreated pts received N in SUMMIT (confirmed ORR 0%; CBR 13%). Efficacy data for 5 pts from SUMMIT and 2 more pts receiving combo under compassionate use (4 male, 3 female, median age 26 years, median 0 [range 0–4] prior systemic therapies) are in shown in the table. The most common adverse events (AE) with single-agent N (n = 5) were diarrhea (grade 1 80%; grade 2 20%) and nausea (grade 1 60%); other AEs were grade ≤1 in ≤20% of pts. Conclusions: N monotherapy had limited benefit as a single agent in FLC pts. Several case studies evaluating N-based combo with checkpoint inhibitors administered under compassionate use demonstrated that NP led to 1 PR, and the triplet of NPE to prolonged SD. These are case-limited observations but are critical and worth evaluating further in upcoming clinical trials given the continued lack of a standard of care therapy for pts with FLC. Clinical trial information: NCT01953926. [Table: see text]
Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma: A phase Ib/II study.
Authors: Borad Mitesh J. , Bai Li-Yuan , Chen Ming-Huang , Hubbard Joleen M. , Mody Kabir , Rha Sun Young , Richards Donald A. , Davis S. Lindsey , Soong John , Huang Chi-En C-E , Tse Emmett , Ahn Daniel H. , Chang Heung-Moon , Yen Chia-Jui , Oh Do-Youn , Park Joon Oh , Hsu Chiun , Becerra Carlos Roberto , Chen Jen-Shi , Chen Yen-Yang 
Published: January 2021

312 Background: Silmitasertib (CX-4945), an oral small molecule inhibitor of casein kinase 2 (CK2), has exhibited preclinical antitumor activity and strong synergism with gemcitabine + cisplatin. We investigated the safety and efficacy of silmitasertib in combination with gemcitabine + cisplatin in patients with unresectable cholangiocarcinoma (CCA). Methods: S4-13-001 is a multicenter, open-label, phase Ib/II study of silmitasertib in combination with gemcitabine + cisplatin in patients with locally advanced or metastatic CCA. The phase Ib portion included dose-escalation, expansion, and exploratory cohorts of silmitasertib with doses ranging from 200 to 1000 mg bid (6 days for the escalation/expansion cohorts and 10 and 21 days’ continuous dosing for the exploratory cohorts). In the phase II portion patients received silmitasertib 1000 mg bid for 10 days in combination with gemcitabine + cisplatin on days 1 & 8 over a 21-day cycle. In this interim analysis, we present findings from the combined population of patients from the phase Ib and II portions of the study. Response to treatment was assessed by RECIST v1.1 every 6 weeks. Primary efficacy outcome measure was progression-free survival (PFS). ClinicalTrials.gov (NCT02128282). Results: A total of 87 patients were enrolled and received silmitasertib in the phase Ib (n=50) and phase II (n=37) portions of the study. Of these, 55 patients were evaluable for efficacy with details as follows: median PFS 11.1 (95% CI 7.6–14.7) months; median overall survival (OS) 17.4 (95% CI 13.4–25.7) months; overall response rate (ORR) 32.1%; and disease control rate (DCR) 79.3%. Almost all patients (79/87; 90.8%) evaluable for safety reported ≥1 treatment-related adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib were diarrhea (65.5%), nausea (50.6%), vomiting (33.3%), fatigue (31.0%), and anemia (21.8%). The most common grade ≥3 TEAEs were diarrhea (13.8%), neutropenia (11.5%), nausea (9.2%), anemia (8.0%), and thrombocytopenia (8.0%). Eleven patients (12.6%) discontinued treatment due to TEAEs. Conclusions: Silmitasertib in combination with gemcitabine + cisplatin yields promising preliminary evidence of efficacy in patients with locally advanced or metastatic CCA. Based on these data a randomized phase III trial is planned. Clinical trial information: NCT02128282.
Comprehensive genomic profiling (CGP) utilizing cell-free DNA (cfDNA) in patients (pts) with pancreatic ductal adenocarcinoma (PDAC).
Authors: George Ben , Haberberger James , Ferguson Naomi L , Gjoerup Ole , McGregor Kimberly , Hendifar Andrew Eugene , Laheru Daniel A. , Weekes Colin D. , Ross Jeffrey S. , Hemmerich Amanda 
Published: January 2021

421 Background: PDAC has a propensity for early systemic dissemination and most pts with primary tumors radiographically confined to the pancreas harbor micro-metastases. cfDNA based CGP offers a non-invasive mechanism to identify actionable genomic targets in PDAC and account for serial clonal evolution in response to therapeutic selection pressure. We interrogated the Foundation Medicine database to characterize cfDNA based CGP in pts with PDAC. Methods: We performed a retrospective analysis of pts with PDAC who underwent cfDNA based CGP between May 2016 and February 2020. cfDNA based CGP was done utilizing either the FoundationOne Liquid (F1-Liquid) or the Foundation-ACT (F-ACT) testing platform. Samples were interrogated for exonic and select intronic regions of cancer-related genes for both F1-Liquid (Exons: 70 genes; Select Introns: 7 genes) and F-ACT (Exons: 59 genes; Select Introns: 6 genes). Variant zygosity and somatic/germline status (SGZ) for short variant mutations was computationally predicted without matched normal tissue using an investigational method. A Gaussian Mixture Model (GMM) was used to identify latent molecular classes in samples harboring somatic, pathogenic variants (n=613); the Bayesian Information Criteria (BIC) was used for model selection. Results: We identified 1,009 pts with cfDNA based CGP - median age was 65, 55% were male, and median cfDNA concentration was 24 ng/µL. cfDNA yield had an influence on the detection of somatic alterations (p <0.001). 613/1009 (60.8%) of pts had at least one somatic alteration detected on cfDNA based CGP. TP53 (53.7%), KRAS (40.3%) and CDKN2A (6.5%) were the most frequently altered genes (Table1). Homologous Recombination DNA Damage Repair (HR-DDR) gene alterations [somatic and/or germline BRCA2, ATM, and CHEK2 alterations], were detected in 12.3% (124/1009) pts – 11.4% (46/403) in KRAS mutated pts and 12.9% (78/606) in KRAS wildtype (WT) pts. Fusions were detected only in KRAS WT pts (1.5%, 6/403). Pts with cfDNA based CGP could be classified into 4 latent classes – class 1 ( KRAS - 100%, TP53 - 100% and CDKN2A – 33.3%), class 2 ( KRAS - 65.7%), class 3 ( KRAS – 68.2%, CDKN2A/B – 7.7% ) and class 4 ( KRAS – 38.5%, TP53 - 26.7%). Conclusions: The putative role of cfDNA based CGP in monitoring therapeutic response and clonal evolution in pts with PDAC may be predicated on cfDNA yield. In clinical scenarios where pre-treatment tissue availability is limited, cfDNA based CGP may be have utility in leveraging the predictive value of somatic and/or germline HR-DDR gene alterations. The prognostic and/or predictive relevance of the four latent classes needs validation in clinically annotated data sets. [Table: see text]