bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of KN046 plus paclitaxel/cisplatin as first-line treatment for unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC).
Authors: Xu Jianming , Liu Rongrui , Zhang Yanqiao , Xu Nong , Fan Qingxia , Gao Shegan , Pan Hongming , Cai Mingquan , Yan Dong , Liang Qianqian , Wu Qiong , Guo Baohong , Qi Yakun , Xu Ting 
Published: June 2021

4062 Background: The prognosis of pts with advanced esophageal squamous cell carcinoma (ESCC) remains dismal clinically. Paclitaxel and cisplatin were used as the standard first-line regimen in ESCC for almost two decades. Recently, the combination of PD-1/PD-L1 pathway blockades with chemotherapy has shown synergistic efficacy in a few clinical trials. KN046 is the world's first dual immune checkpoint inhibitor, which can block PD-1/PD-L1 and CTLA-4 pathways at the same time. The purpose of this ongoing phase II trial (NCT03925870) in China was to evaluate the efficacy and safety of KN046 monotherapy or combined with chemotherapy for unresectable locally advanced, recurrent or metastatic ESCC. Methods: This trial included 3 cohorts, one of which enrolled systemic treatment naïve pts with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who have ECOG PS of 0-1. Eligible subjects were given paclitaxel (135-175mg/m2, iv, d1, q3w) and cisplatin (75mg/m2, iv, d2-4, q3w) plus KN046 (5mpk, iv, d1, q3w) for 4̃6 cycles during initial therapy. For those without progressive disease, maintenance treatment was administrated with KN046 monotherapy (5mpk, iv, q2w) until progression or unacceptable toxicity. Tumour response was assessed according to RECIST 1.1 every 6 weeks. The primary endpoint was investigator-assessed ORR. Secondary endpoints included DCR, safety, PK profile, and immunogenicity. Results: As of December 14, 2020, 15 pts were enrolled, all of them were male, 52.3% ≥60 years, 64% ECOG 1, 80% with distant metastasis. Median exposure time to KN046 was 11.4 wks and average KN046 treatment was 2.4 cycles. 12 pts were included in the efficacy analysis and 15 pts in the safety analysis. The overall response rate (ORR) and disease control rate (DCR) were 58.3% and 91.6%, respectively. 7 pts (58.3%) had partial response (PR) including one complete response of target lesion. 4 pts (33.3%) had stable disease (SD) with 3 pts showing more than 20% of tumor burden reduction. The overall incidence of KN046 related adverse events was 80.0%, with 13.3% Gr 3 or above TRAE. Infusion-related adverse events occurred during 7.8% and most were mild. Immune related adverse events（irAE）were seen in 53.3% and the most common Gr 3 irAE were nausea (n＝1, 6.7%) and rash (n＝1, 6.7%). Conclusions: KN046 plus paclitaxel/cisplatin demonstrated clinical efficacy and acceptable safety as first-line treatment, and might be a favorable option for pts with advanced ESCC. Clinical trial information: NCT03925870. Research Sponsor: Jiangsu Alphamab Biopharmaceuticals Co., Ltd. Clinical trial information: NCT03925870.
Update on overall survival (OS) of RESCUE: An open-label, phase 2 trial of camrelizumab (C) in combination with apatinib (A) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Zhang Yun , Xu Jianming , Shen Jie , Gu Shanzhi , Wu Lihua , Wu Jian , Shao Guoliang , Zhang Yanqiao , Xu Li , Yin Tao , Liu Jingfeng , Ren Zhenggang , Xiong Jianping , Mao Xianhai , Zhang Ling , Yang Jiayin , Li Lequn , Chen Xiaoming , Wang Zhiming , Wang Quanren 
Published: June 2021

4076 Background: C+A combination therapy displayed high objective response rate, disease control rate, and durable response with a manageable safety profile in patients (pts) with advanced HCC. Here we performed an updated analysis of OS to characterize the OS benefit of C+A in HCC pts. Methods: 70 pts in first-line cohort and 120 pts in second-line cohort were enrolled. Median OS and 2-year OS rate were evaluated via updated data (data cutoff, 3 January, 2021). Median time from enrollment to data cutoff of the total population (N = 190) was 29.1 months (range, 24.0-33.7). Results: OS events had occurred in 58.6% pts in first-line cohort and 60.0% pts in second-line cohort. The median OS was 20.1 months (95% CI, 14.9-NR) and 2-year OS rate was 43.3% (95% CI, 31.3-54.7) in first-line cohort. The median OS was 21.8 months (95% CI, 17.3-26.8) and 2-year OS rate was 44.6% (95% CI, 35.5-53.3) in second-line cohort. Conclusions: Long-term follow-up of C+A demonstrated remarkable survival benefit in advanced HCC pts, which further suggested that C+A is a promising combination therapy in advanced HCC pts. Clinical trial information: NCT03463876.
FOENIX-CCA2 quality of life data for futibatinib-treated intrahepatic cholangiocarcinoma (iCCA) patients with FGFR2 fusions/rearrangements.
Authors: Valle Juan W. , Hollebecque Antoine , Furuse Junji , Goyal Lipika , Meric-Bernstam Funda , Epstein Robert S. , Salimi Tehseen , Wacheck Volker , Liu Mei , Benhadji Karim A. , Bridgewater John A. 
Published: June 2021

4097 Background: In FOENIX-CCA2 (NCT02052778), a pivotal phase 2 study among iCCA patients (pts) with FGFR2 fusions/rearrangements, the highly selective, irreversible FGFR1–4 inhibitor futibatinib demonstrated a confirmed objective response rate of 41.7%, with a 9.7-month median duration of response. Adverse events were manageable with dosing modifications that did not adversely impact on response. We report outcomes for the preplanned analysis of Patient-Reported Outcomes (PROs) during futibatinib treatment as a secondary objective of FOENIX-CCA2. Methods: Pts enrolled in FOENIX-CCA2 had locally advanced/metastatic unresectable iCCA with FGFR2 fusions/rearrangements, ≥1 prior line of therapy (including gemcitabine/cisplatin) and ECOG PS 0-1. Pts received oral futibatinib 20 mg continuous QD dosing per 21-day cycle. PRO measures included EORTC-QLQ-C30 (1 global health, 5 functional, 9 symptom scales), EQ-5D-3L, and EQ visual analogue scale (VAS). PROs were collected at screening, cycles 2 and 4, every 3 cycles thereafter, and end of treatment. PRO data were evaluated up to cycle 13, the last visit before data were missing for >50% of the PRO population (PRO primary assessment time point). Results: 92/103 (89.3%) pts enrolled had PRO completion data at baseline and a minimum of 1 follow-up assessment (median age 58 y, 56.5% female), with 48 pts having PRO data at cycle 13. At baseline, mean (SD) EORTC QLQ-C30 global health status score was 70.1 (19.4) and EQ VAS score 71.7 (20.3). Mean EORTC QLQ-C30 global health status scores were maintained from baseline to cycle 13, corresponding to 9.0 months on treatment, with no clinically meaningful (≥10-point) changes in individual functional measures (Table). EORTC QLQ-C30 scores across individual symptom measures were also stable from baseline through cycle 13; only constipation showed an average of 10.0-point worsening at only cycle 4. Mean EQ VAS scores were sustained from baseline to cycle 13 (mean change ranging -1.8 to +4.8 across cycles), with values maintained within the population norm range from across 20 countries. Conclusions: Quality of life data from the phase 2 FOENIX-CCA2 trial show that physical, cognitive and emotional functioning, and overall health status were maintained among pts with advanced iCCA receiving futibatinib. Clinical trial information: NCT02052778. [Table: see text]
Clinical outcomes analysis of TP53-mutated advanced and metastatic biliary tract cancers.
Authors: Lee Sunyoung S. , Tran Cao Hop Sanderson , Tzeng Ching-Wei David , Metwalli Zeyad , Koay Eugene Jon , Ludmir Ethan B. , Chun Yun Shin , Chun Stephen G. , Javle Milind M. 
Published: June 2021

4106 Background: Advanced biliary tract cancers (BTC) are lethal cancers with limited treatment options and short survival. Median progression-free survival (mPFS) in the ABC-02 trial was 8.0 months with gemcitabine-cisplatin (GC) and 5.0 m with gemcitabine alone in the front-line setting. The ABC-06 trial showed mPFS of 4.0 m with second-line FOLFOX. TP53 mutation is known to be associated with poor prognosis in other cancers, but its impact on survival in advanced or metastatic BTC has not been detailed. Methods: Mutational profiles were obtained from a retrospective database collected via an institutional DNA/RNA sequencing panel, FoundationOne, or Guardant360. Out of 149 patients with TP53 mutations in BTC, 90 had advanced or metastatic BTC treated at a single institution between 2015 and 2021. These patients were not candidates for surgery, radiation, or liver-directed therapy. Results: Intrahepatic, hilar, distal, and gallbladder cancer diagnoses were confirmed in 66, 11, 10, and 3 patients. Median age was 63, with a male:female ratio of 1:1. Poorly, moderately, and well-differentiated adenocarcinomas were found in 62, 20, and 1 (not available in 7 patients). The most common TP53 mutations were R175H (n = 5) and R248Q (n = 4). Common co-mutated genes included KRAS (n = 15), ARID1A (n = 15), FGFR2 fusion (n = 14), IDH1 (n = 13), BAP1 (n = 10), CDKN2A (n = 9), and HER2 amplification (n = 8). Microsatellite unstable (MSI-H) tumors were found in 3 patients. The median tumor mutational burden was 2.5/Mb. Patients received front-line GC (n = 54), GC-nab-paclitaxel (GAP, n = 14), FOLFIRINOX (n = 3), and GC with targeted or trial therapy (n = 11, e.g. trastuzumab). mPFS with front-line therapy was 5.0 m (n = 90); it was 4.7 m with GC and 5.1 m with GAP. Patients who had co-mutated IDH1 or FGFR2 fusion had longer mPFS (9.5 and 6.9 m, respectively) than those who did not (n = 63, 3.7 m, p < 0.05) from front-line chemotherapy. mPFS after second-line FOLFOX (n = 17) and FOLFIRI (n = 10) was 2.1 and 1.9 m, respectively, and mPFS after third-line FOLFOX/FOLFIRI was 1.8 m (n = 8). The median overall survival (OS) of patients with co-mutated FGFR2, IDH1, or neither was 34.5, 22.0, and 13.1 m, respectively (p < 0.05). TP53-mutated BTC with mutations other than FGFR2/IDH1 did not show statistically significant difference in PFS or OS. Conclusions: Patients with TP53-mutated advanced BTC have shorter PFS than those without TP53 mutation in front and further-line settings. The presence of co-mutated FGFR2 or IDH1 is associated with improved PFS with chemotherapy (not FGFR/IDH1 inhibitors) and longer OS. Other co-mutations do not appear to have a survival benefit. It is crucial for clinicians to take into account the worse prognosis with TP53 mutation before starting front-line therapy in patients with advanced BTC and consider early clinical trial options.
Plasma biomarker study of lenvatinib in gastroenteropancreatic neuroendocrine tumors reveals Ang2 and FGF2 as predictors of treatment response: Results from the international phase II TALENT trial (GETNE 1509).
Authors: Capdevila Jaume , Jimenez-Valerio Gabriela , Martinez Alba , Hernando Jorge , Ibrahim Toni , Fazio Nicola , Lopez Carlos , Teule Alex , Valle Juan W. , Tafuto Salvatore , Custodio Ana B. , Reed Nicholas Simon , Raderer Markus , Grande Enrique , Garcia-Carbonero Rocio , Jiménez-Fonseca Paula , Alonso Vicente , Casanovas Oriol 
Published: June 2021

4113 Background: Predictive biomarkers of response to antiangiogenics currently remain elusive, with several molecules discovered but not fully validated nor clinically applied. TALENT trial is a multicenter prospective phase II study of lenvatinib, a VEGFR1-3 and FGFR1-4 multikinase inhibitor (MKI), in advanced G1/G2 neuroendocrine tumors (NETs) from pancreatic (panNETs) and gastrointestinal (giNETs) origins, which has reported the highest overall response rate (ORR) by central radiology assessment with a MKI in this setting. Here we report the plasma biomarker study. Methods: Proangiogenic profiling of plasma samples from patients included in the trial were analyzed by multiplex ELISA (custom made Quantibody Array, RayBiotech). Quantitative determinations of VEGF-A, FGF2, FGF4, Ang2, IL8, PlGF, VEGF-C, VEGF-D and VEGFR2 were obtained from 85 samples of sufficient quality (out of 111 patients included in the study). Association and prediction of response were evaluated for each biomarker and correlated with PFS, OS and ORR in all patients and the different subgroups included in the trial. Results: While none of the factors were able to discriminate PFS or OS in the whole population, a significant association of high-Ang2 and low-FGF2 to ORR was observed. Subgroup analysis confirmed this association in the two cohorts of patients, giNETs (p = 0.003) and panNETs (p = 0.024). In the panNET cohort, prior targeted therapy was mandatory. Prior sunitinib exposure was observed in 8 patients. Of the factors studied, Ang2 and VEGFR2 were significantly decreased in plasma from sunitinib-pretreated patients (-73% p = 0.022 and -62% p = 0.042 respectively). Furthermore, in these sunitinib-pretreated patients Ang-2 and VEGFR2 levels associated to ORR (p = 0.029 and p = 0.029 respectively) and were able to discriminate PFS (log rank p = 0.027 and 0.007 respectively). ROC curve analysis defined Ang2 and VEGFR2 plasma levels with optimal predictive power to be 415pg/ml and 1770pg/ml respectively (p = 0.021). Conclusions: Plasma proangiogenic profiling of TALENT patient samples unraveled high-Ang2 and low-FGF2 as predictive biomarkers of response to lenvatinib in both cohorts. In antiangiogenic-pretreated patients, Ang2 and VEGFR2 levels significantly predict response to treatment in panNETs. Importantly, current studies with MKIs should confirm the value of these markers for advanced NETs not only to predict response, but also to stablish sequential treatment options for these patients.
Baseline level and early on-treatment clearance of circulating mutant KRAS in metastatic pancreatic ductal adenocarcinoma treated with chemotherapy with or without immunotherapy.
Authors: Till Jacob E. , Abdalla Aseel , Bhagwat Neha , Black Taylor A. , Wang Zhuoyang , Yee Stephanie S. , Gherardini Pier Federico , Kitch Lacey J. , Selinsky Cheryl , Lyman Jaclyn Paige , LaVallee Theresa , Fisher George A. , Rahma Osama E. , Ko Andrew H. , Wainberg Zev A. , Wolff Robert A. , O'Reilly Eileen Mary , Vonderheide Robert H. , O'Hara Mark H. , Carpenter Erica L. 
Published: June 2021

4122 Background: Traditional imaging-guided therapeutic decision-making for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) may lag and, on occasion, be misleading. The concept of liquid biopsy-based molecular response holds promise for proximate and accurate therapy monitoring and assessment of emerging resistance to therapy. Here we investigate the association between baseline (pre-treatment) level and early, on-treatment changes in plasma circulating cell-free DNA (ccfDNA) mutant KRAS (ctKRAS) with progression-free survival (PFS) and overall survival (OS) in mPDAC. Methods: 189 plasma samples were analyzed from 123 total patients with mPDAC. An initial cohort included 54 patients treated at the University of Pennsylvania who received first-line standard of care (SOC) regimens and had a baseline plasma sample. Of these, 21 also had an on-therapy sample collected at ̃8 weeks. We also analyzed an independent cohort of 69 patients enrolled in the PRINCE trial (NCT03214250) who had a baseline sample, of which 45 also had an on-treatment sample at ̃8 weeks. PRINCE trial patients received gemcitabine/nab-paclitaxel with immunotherapy (I/O) agents (APX005M and/or nivolumab). ctKRAS variant allele fraction (VAF) was quantified by droplet digital PCR on pre-amplified ccfDNA. Baseline ctKRAS was dichotomized at 5% VAF. ctKRAS clearance was defined as detectable ctKRAS at baseline followed by ctKRAS becoming undetectable in the on-treatment sample. Results: Baseline ctKRAS (above/below 5% VAF) and ctKRAS clearance were associated with PFS and OS in both cohorts (Table). Further, in a multivariate cox regression model, ctKRAS clearance associated with improved PFS (HR 3.8, 1.4-10.9 or 3.6, 1.8-7.2) in both the SOC and I/O cohorts, respectively, and OS in the SOC cohort (HR 5.5, 1.5-20.8) after adjusting for baseline VAF. Conclusions: Baseline ctKRAS is significantly associated with OS and PFS in mPDAC in both independent cohorts. Further, early on-treatment ctKRAS clearance is strongly associated with improved PFS and OS, independent of baseline ctKRAS VAF. These data strongly support further investigation of ccfDNA as a biomarker of response and resistance to therapy.[Table: see text]
Local and systemic recurrence following total neoadjuvant therapy (TNT) and resection for borderline resectable and locally advanced pancreatic adenocarcinoma: Long-term follow up from two phase II studies.
Authors: Ryan Grace E. , Murphy Janet E. , Ulysse Christine A. , Yeap Beow Y. , Wo Jennifer Yon-Li , Weekes Colin D. , Clark Jeffrey William , Allen Jill N. , Blaszkowsky Lawrence Scott , Nipp Ryan David , Drapek Lorraine C. , Parikh Aparna Raj , Bolton Christine , Maruna Jacob , Ferrone Cristina R. , Qadan Motaz , Lillemoe Keith D. , Ryan David P. , Fernandez Del-Castillo Carlos , Hong Theodore S. 
Published: June 2021

4133 Background: With the advent of FOLFIRINOX, the management of pancreatic cancer has undergone a profound change. There has been a shift to TNT with FOLFIRINOX followed by radiation and an attempt at surgical resection. Recent trials of TNT have demonstrated an ability to resect locally advanced (LA) and borderline resectable disease. There is a lack of prospective data demonstrating local and systemic recurrence rates after TNT. Methods: Two previously reported prospective clinical trials (Murphy JE, et al, JAMA Oncol 2018, 2019) of total neoadjuvant therapy were conducted between 2012 and 2018 for borderline and LA disease (NCT01591733, NCT01821729). Patients received FOLFIRINOX for 8 cycles. Upon restaging, patients with resolution of vascular involvement received short-course chemoradiotherapy (5 Gy x 5 with protons or 3 Gy x 10 w photons) with capecitabine (N=34). Patients with persistent vascular involvement received long-course chemoradiotherapy with capecitabine (N=56). All patients were considered for resection after TNT except for those patients with metastatic or unresectable disease. Results: 97 eligible patients were enrolled and started treatment on the borderline resectable (n = 48) and locally advanced (n= 49) study. 90 patients completed therapy. 80 patients were taken to the operating room. 61 patients had R0 resection and 5 patients had R1 resection. The table shows the distribution of local recurrences, local recurrences and metastatic disease, and metastatic disease alone. With a median follow-up of 5.2 years (range: 2.4-6.0), of the 61 R0 patients, 22 patients remained alive and free of disease, 7 patients had a local recurrence, 4 patients had locoregional and metastatic recurrence, and 24 patients had a metastatic recurrence. 3 patients who underwent R0 resection died of unrelated causes. Median survival for patients undergoing R0 resection is 43.8 months. Conclusions: Total neoadjuvant therapy for locally advanced and borderline resectable pancreatic cancer is potentially curable and may change the pattern of spread.[Table: see text]
Impact of KRAS mutational status on outcomes in patients with pancreatic cancer (PDAC).
Authors: Ma Lucy Xiaolu , Jang Gun Ho , Zhang Amy , Denroche Robert Edward , Dodd Anna , Ramotar Stephanie , Hutchinson Shawn , Wang Yifan , Tehfe Mustapha , Ramjeesingh Ravi , Biagi James Joseph , Lam Bernard , Wilson Julie , Notta Faiyaz , Fischer Sandra , Grant Robert C , Zogopoulos George , Gallinger Steven , Knox Jennifer J. , O'Kane Grainne M. 
Published: June 2021

4142 Background: KRAS mutations (m) (KRASm) are present in over 90% of pancreatic adenocarcinomas (PDAC) with a predominance of G12 substitutions. KRAS wildtype (WT) PDAC relies on alternate oncogenic drivers, and the prognostic impact of these remains unknown. We evaluated alterations in WT PDAC and explored the impact of specific KRASm and WT status on survival. Methods: WGS and RNAseq were performed on 570 patients (pts) ascertained through our translational research program from 2012-2021, of which 443 were included for overall survival (OS) analyses. This included 176 pts with resected and 267 pts with advanced PDAC enrolled on the COMPASS trial (NCT02750657). The latter cohort underwent biopsies prior to treatment with first line gemcitabine-nab-paclitaxel or mFOLFIRINOX as per physician choice. The Kaplan-Meier and Cox proportional hazards methods were used to estimate OS. Results: KRAS WT PDAC (n = 52) represented 9% of pts, and these cases trended to be younger than pts with KRASm (median age 61 vs 65 years p = 0.1). In resected cases, the most common alterations in WT PDAC (n = 23) included GNASm (n = 6) and BRAFm/fusions (n = 5). In advanced WT PDAC (n = 27), alterations in BRAF (n = 11) and ERBB2/3/4 (n = 6) were most prevalent. Oncogenic fusions (NTRK, NRG1, BRAF/RAF, ROS1, others) were identified in 9 pts. The BRAF in-frame deletion p.486_491del represented the most common single variant in WT PDAC, with organoid profiling revealing sensitivity to both 3rd generation BRAF inhibitors and MEK inhibition. In resected PDAC, multivariable analyses documented higher stage (p = 0.043), lack of adjuvant chemotherapy (p < 0.001), and the KRAS G12D variant (p = 0.004) as poor prognostic variables. In advanced disease, neither WT PDAC nor KRAS specific alleles had an impact on prognosis (median OS WT = 8.5 mths, G12D = 8.2, G12V = 10.0, G12R = 12.0, others = 9.2, p = 0.73); the basal-like RNA subtype conferred inferior OS (p < 0.001). A targeted therapeutic approach following first line chemotherapy was undertaken in 10% of pts with advanced PDAC: MMRd (n = 1), homologous recombination deficiency (HRD) (n = 19), KRASG12C (n = 1), CDK4/6 amplification (n = 3), ERBB family alterations (n = 2), BRAF variants (n = 2). OS in this group was superior (14.7 vs 8.8 mths, p = 0.04), mainly driven by HRD-PDAC where KRASm were present in 89%. Conclusions: In our dataset, KRAS G12D is associated with inferior OS in resected PDAC, however KRAS mutational status was not prognostic in advanced disease. This suggests that improved OS in the WT PDAC population can only be achieved if there is accelerated access to targeted drugs for pts.