bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomised phase III trial of the hypoxia modifier nimorazole added to radiotherapy with benefit assessed in hypoxic head and neck cancers determined using a gene signature (NIMRAD).
Authors: Thomson David , Slevin Nick , Baines Helen , Betts Guy , Bolton Steve , Evans Mererid , Garcez Kate , Irlam Joely , Lee Lip , Melillo Nicola , Mistry Hitesh , More Elisabet , Nutting Christopher , Price James , Ryder David , Schipani Stefano , Sen Mehmet , Yang Huiqi , West Catharine ,   on behalf of the NIMRAD Investigators
Published: June 2023

6006 Background: Tumour hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the addition of nimorazole to definitive radiotherapy (RT). Methods: NIMRAD was a phase III, multi-centre, placebo-controlled, double-blind trial in patients with HNSCC unsuitable for concurrent platinum chemotherapy or cetuximab with definitive RT (NCT01950689). Patients were randomized 1:1 to receive nimorazole (1.2 g/m2 daily, prior to RT) + RT (65 Gy in 30 fractions over 6 weeks) or placebo (taken via the same schedule) + RT. The primary endpoint was loco-regional control (freedom from loco-regional progression, FFLRP) in patients with hypoxic tumours, defined as greater than or equal to the median hypoxia score of the first 50 patients analysed (≥0.079), using a validated 26-gene signature. The planned sample size was 340 patients allowing for signature generation in 85%, assumed HR 0.50 for nimorazole effectiveness in the hypoxic group, and requiring 66 loco-regional failures to have 80% power in a two-tail log-rank test at the 5% significance level. Results: 338 patients were randomised by 19 UK centres from May 2014 to May 2019, with a median follow-up of 3.1 years (95%CI 2.9-3.4). Hypoxia scores were available for 286 (85%). The median patient age was 73 years (range 44-88); and clinical factors were balanced between the arms, both for the whole population and hypoxic group (Table). There were 36 (25.9%) loco-regional failures in the hypoxic group, where nimorazole + RT did not improve FFLRP (adjusted HR 0.72; 95% CI 0.36-1.44; p=0.35), or overall survival (adjusted HR 0.96; 0.53-1.72; p=0.88) compared with placebo + RT. Similarly, nimorazole + RT did not improve FFLRP or OS in the whole population. In total (n=338), 73% of patients allocated nimorazole adhered to the drug for ≥50% of RT fractions. Nimorazole + RT caused more acute nausea compared with placebo + RT (CTCAE v4.0 G1+2: 56.6% vs 42.4%, G3: 10.1% vs 5.3%, respectively; p=0.003), with no differences in other early or late toxicities. Conclusions: Addition of the hypoxia modifier nimorazole to RT for locally advanced HNSCC in older and less fit patients did not improve loco-regional control or survival. Clinical trial information: NCT01950689 . [Table: see text]
Final overall survival analysis of JUPITER-02: A phase 3 study of toripalimab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC).
Authors: Mai Hai-Qiang , Chen Qiu-Yan , Chen Dong-Ping , Hu Chaosu , Yang Kunyu , Wen Jiyu , Li Jin-Gao , Shi Yingrui , Jin Feng , Xu Ruilian , Pan Jian-ji , Qu Shenhong , Li Ping , Hu Chunhong , Liu Yi-Chun , Jiang Yi , He Xia , Wang Hung-Ming , Lim Darren Wan-Teck , Xu Rui-Hua ,   Coherus Biosciences and Shanghai Junshi Biosciences
Published: June 2023

6009 Background: There are currently no FDA-approved IO therapies for NPC. Toripalimab in combination with Gemcitabine-Cisplatin (GP) chemotherapy had shown significant improvement over chemotherapy alone in progression-free survival (PFS) as first-line treatment for recurrent or metastatic (r/m) NPC at the interim PFS analysis of JUPITER-02 (NCT03581786) study. The final overall survival (OS) analysis results are summarized here. Methods: Patients with r/m NPC (n = 289) were randomized (1:1) to receive toripalimab 240 mg (n = 146) or placebo (n = 143) in combination with GP once every 3 weeks (Q3W) for up to 6 cycles, followed by monotherapy with toripalimab or placebo Q3W until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors were ECOG performance score (0 vs. 1) and extent of disease (recurrent vs. primary metastatic) at enrollment. The primary endpoint was PFS by an independent review committee. Secondary endpoints included OS and safety. Results: By the cutoff date of Nov 18, 2022, when 133 events were reached for the final OS analysis, the median survival follow up was 30.1 months. A significant improvement in OS was observed for the toripalimab arm over the placebo arm: HR = 0.63 (95% CI: 0.45-0.89), two-sided p = 0.0083. The median OS was not reached in the toripalimab arm and was 33.7 months in the placebo arm. The 2-year and 3-year OS rates were 78.0% vs. 65.1%, and 64.5% vs. 49.2% respectively. A consistent effect on OS, favoring the toripalimab arm, was observed in nearly all subgroups, including PD-L1 high and PD-L1 low expression subgroups. No new safety signals were identified in the toripalimab arm since the interim report. The incidence of Grade ≥3 adverse events (AEs) (89.7% vs 90.2%) and fatal AEs (3.4% vs 2.8%) were similar between two arms. However, AEs leading to discontinuation of toripalimab/placebo (11.6% vs 4.9%), immune-related (irAEs) (54.1% vs. 21.7%) and Grade ≥3 irAEs (9.6% vs. 1.4%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as 1st-line treatment for r/m NPC provided clinically important and highly significant OS advantage over GP alone with a manageable safety profile. These results support the use of toripalimab with GP chemotherapy as the new standard care for this population. Clinical trial information: NCT03581786 .
Circulating tumor DNA (ctDNA) monitoring in patients with breast cancer receiving neoadjuvant palbociclib and endocrine therapy: A secondary analysis of the NeoRHEA phase 2 study.
Authors: Stanciu Alexandra , Papagiannis Andreas , Pipinikas Christodoulos , Campbell Nathan , Brandão Mariana , Cailleux Frederic , Agostinetto Elisa , Ameye Lieveke , Paesmans Marianne , Besse-Hammer Tatiana , Awada Ahmad , Piccart-Gebhart Martine J. , Sotiriou Christos , Neven Patrick , Duhoux Francois P. , Rosenfeld Nitzan , Vuylsteke Peter , Ignatiadis Michail 
Published: June 2023

601 Background: Personalized circulating tumor DNA (ctDNA) assays are being evaluated in early breast cancer (BC). We investigated the value of ctDNA monitoring in the NeoRHEA study. Methods: NeoRhea (NCT03065621) is a single arm phase 2 study in which patients with estrogen receptor (ER)+/HER2- early breast cancer were treated with neoadjuvant palbociclib + endocrine therapy (ET) for 4 months. Plasma samples were collected at four timepoints: pre-treatment (BL), after the first treatment cycle (C1D28), before surgery (Surgery) and one month post Surgery (End of Study). ctDNA detection was evaluated using the personalized RaDaR assay. Whole-exome sequencing (WES) was performed on BL tumor biopsies followed by a personalized assay development using tumor, plasma and normal DNA in order to track up to 48-patient specific somatic variants in plasma cell-free DNA (cfDNA) using next generation sequencing. Associations between ctDNA detection and BL clinical-pathological characteristics, cell cycle arrest (CCCA) defined as Ki67 ≤2.7% at surgery, residual cancer burden (RCB) rate and breast cancer free survival (BCFS) were investigated. Results: Of 100 patients enrolled, 78 patients and 302 plasma samples were successfully profiled by the RaDaR assay. The number of variants targeted by the assay ranged between 7-48 (median = 25). The median estimated variant allele fraction for ctDNA positive samples was 0.02% (range 0.0009%-0.91%). A total of 42/76 patients were ctDNA positive at BL, 4/76 at C1D28, 4/75 at Surgery and 0/75 at End of Study. Out of 78 patients, 68% were postmenopausal, 78 % had cT2 and 69% cN0 tumors, 20% had multifocal/multicentric tumors, 18% had histological grade 3 tumors, 76% had CCCA (Ki67 not available in 20 patients) and 34% RCB 3 at surgery. ctDNA detection at BL was higher in histological grade 3 tumors (p = 0.03), lower in multifocal/multicentric tumors (p = 0.01), higher in RCB III tumors, (p = 0.01) but was not associated with CCCA. With a median follow-up of 3.8 years (range 1-5 years), 4 patients developed distant and one patient locoregional recurrences. ctDNA detection after one month of treatment (logrank p = 0.02), but not at baseline (p = 0.59) nor at surgery (p = 0.67) was associated with worse BCFS. Conclusions: Detection of ctDNA in early-stage breast cancer is challenging. Our data suggests association of ctDNA detection with some pathological and clinical variables. Independent validation is needed. Clinical trial information: NCT03065621 .
Neoadjuvant nivolumab alone or in combination with relatlimab or ipilimumab in resectable head and neck squamous cell carcinoma (HNSCC).
Authors: Ferris Robert L. , Gooding William E. , Chiosea Simion I. , Duvvuri Umamaheswar , Kim Seungwon , Kubik Mark , Sridharan Shaum , Fenton Moon Jung , Skinner Heath Devin , Kelly Zahra Rahman , Li Housaiyin , Vujanovic Lazar , Zandberg Dan Paul 
Published: June 2023

6018 Background: PD-1 inhibition using nivolumab (nivo) monotherapy is modestly effective in metastatic HNSCC. Neoadjuvant trials using nivo may permit development of more effective combinations in surgically resectable HNSCC. We evaluated combinations with nivo plus additional immune checkpoints, CTLA-4 (ipilimumab, ipi) and LAG-3 (relatlimab, rela). Methods: Phase II randomized trial of neoadjuvant nivo alone (240 mg q2 weeks), or with ipi (1 mg/kg q3 weeks) or rela (160 mg q4 weeks) for 4 weeks prior to surgery. Response was scored using RECIST and standard pathologic response criteria. Patients were stratified by p16, PD-L1, and LAG-3, with staining assessed by immunohistochemistry. Freshly digested tumors were subjected to single cell RNA sequencing (scRNAseq) for T cell receptors and gene pathways to identify biomarkers of response or progression. The Cochran-Armitage trend test was used to explore associations with increasing pathological response efficacy. Results: 41 patients (pts) have been enrolled, with 33 evaluable for this analysis. Of these 33, median age is 63 (32-81), primary site oral cavity (n=25), oropharynx (n=5, 3 HPV), larynx (n=3), clinical T2 (n = 5), T3 (n = 12), T4 (n = 13), and cN0/1 (n = 22), cN2 (n = 9), and PD-L1 CPS > 1 (n=25). There were no serious study drug-related AEs or unexpected surgical delays/complications. Pathologic response (Table) was more frequent with nivo/rela (11/13) vs. nivo/ipi (6/10) or nivo (4/10). Partial (>50%) or major (>90%) pathologic responses were more frequent and deeper in the combination arms. Minor (<50%) pathologic responses were more frequent with nivo/rela, and similar between nivo/ipi and nivo. There was no association between RECIST response, PD-L1, or LAG3 and pathologic response. Combined PD-L1 and LAG3 expression was not associated with pathologic response in the nivo/rela arm, however more patients with combined positivity had a >50% response (4 vs. 0). Expansion of CD8+ T cells, as well as expanded proportion of CD8+ CXCL13+ T cells in responder tumors were identified in post-treatment specimens using scRNAseq. Conclusions: Neoadjuvant nivo/ipi or nivo/rela combinations were safe and associated with promising pathologic responses compared to nivo monotherapy. Anti-tumor CD8+ T cell populations and targetable pathways are emerging in responder patients. The trial continues to enroll and further evaluation of this strategy is warranted. Clinical trial information: NCT04080804 . [Table: see text]
Influence of widely targeted quantitative lipidomics on plasma lipid predictors and pathway dysregulation for nasopharyngeal carcinoma.
Authors: Chen Xi , Guo Xiang , Lv Xing 
Published: June 2023

6030 Background: Dysregulation of lipid metabolism is closely associated with cancer progression. We aimed to establish a prognostic model to predict distant metastasis-free survival (DMFS) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC), based on widely targeted quantitative lipidomics. Methods: We measured and quantified the plasma lipid profiles of 179 patients with NPC using widely targeted quantitative lipidomics. Then, patients were randomly split into the training (125 patients, 69.8%) and validation (54 patients, 30.2%) sets. To identify distant metastasis-associated lipids, univariate Cox regression was applied to the training set ( p< 0.05). We employed a deep survival method called DeepSurv to develop our proposed model based on significant lipid species ( p< 0.01) and clinical biomarkers to predict DMFS. Concordance index and receiver operating curve analyses were performed to assess model effectiveness. We also explored the potential role of lipid alterations in the prognosis of NPC. Results: A total of 665 plasma endogenous lipid species consisting of 27 lipid classes and subclasses from 179 patients with NPC were annotated in lipidomics analysis. Forty lipids were recognized as distant metastasis-associated ( p< 0.05) by univariate Cox regression. The concordance indices of our proposed model were 0.764 (95% confidence interval (CI), 0.682–0.846) and 0.760 (95% CI, 0.649–0.871) in the training and validation sets, respectively. We also calculated the C-index values of the baseline survival model based only on clinical biomarkers, with 0.718 (95% CI, 0.591–0.845) and 0.672 (95% CI, 0.511–0.833) being detected in the training and validation sets, respectively, indicating the outstanding predictive performance of lipid biomarkers. High-risk patients had poorer 5-year DMFS compared with low-risk patients (Hazard ratio, 26.18; 95% CI, 3.52–194.80; p< 0.0001). Moreover, the six lipids were significantly correlated with immunity- and inflammation-associated biomarkers and were mainly enriched in metabolic pathways. Conclusions: Widely targeted quantitative lipidomics reveals plasma lipid predictors and pathway dysregulation for locoregionally advanced NPC, the prognostic model based on that demonstrated superior performance in predicting metastasis in NPC patients.
A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody.
Authors: Koyama Taiji , Kiyota Naomi , Imamura Yoshinori , Boku Shogen , Shibata Nobuhiro , Satake Hironaga , Tanaka Kaoru , Hayashi Hidetoshi , Iwae Shigemichi , Onoe Takuma , Asada Yukinori , Yamazaki Tomoko , Nose Taku , Ohata Shinya , Kimbara Shiro , Nagatani Yoshiaki , Minami Hironobu 
Published: June 2023

6032 Background: An important unmet need in treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based chemotherapy and anti-PD-1 antibody (PD-1 Ab). Recent retrospective studies suggest that previous treatment with Immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. This phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab (PTX+bwCmab) for patients with R/M-HNSCC previously treated with both platinum and PD-1 Ab. Methods: This is a single-arm, multicenter phase II trial. Key eligibility criteria were R/M-HNSCC; previous treatment with both platinum-based chemotherapy and PD-1 Ab; ECOG performance status 0 or 1; measurable disease per RECIST v1.1; and adequate organ function. PTX+bwCmab consisted of weekly paclitaxel 100 mg/m2 (days 1, 8, 15) and biweekly cetuximab 500 mg/m2 (days 1, 15) with a cycle of 28 days. Primary endpoint was objective response rate (ORR). We set a null hypothesis of 10% and alternative of 30% with a one-sided alfa of 0.05 and power of 90%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (CTCAE v5.0). Binominal confidence intervals (CIs) for ORR and DCR were estimated by the exact method. Time-to-event analyses were calculated by the Kaplan-Meier method with 95% CIs. Results: Between August 2020 and August 2022, 35 patients were enrolled, of whom 32 were evaluable for response. ORR was 68.7% (95% CI: 49.9-83.8), which met the prespecified criteria for the primary endpoint of ORR. With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.7 and 13.4 months, respectively. DCR was 93.7% (95% CI: 79.1-99.2). The most common AEs of any grade were skin rash (65%), peripheral nerve neuropathy (45%), neutropenia (40%), fatigue (40%) and paronychia (37%). Grade 3 and 4 adverse events included neutropenia (34%), mucositis (8%), pneumonitis (8%) and febrile neutropenia (5%). These AEs were manageable and no treatment-related death within 30 days was observed. Conclusions: PTX+bwCmab showed highly encouraging efficacy and tolerability in RM-HNSCC patients previously treated with both platinum and PD-1 Ab. Although preliminary, these results suggest that this is a promising treatment option for this hitherto untreatable patient group. Further evaluation is warranted. Clinical trial information: jRCTs051200040 .
Phase I/IIa clinical trial of a small molecule EBNA1 inhibitor, VK-2019, in patients with Epstein Barr virus–positive nasopharyngeal cancer with pharmacokinetic and pharmacodynamic correlative studies.
Authors: Colevas A. Dimitrios Dimitrios , Rudek Michelle A. , Even Caroline , Lee Victor Ho-Fun , Gillison Maura L. , Khan Saad A. , Lu Rong , Winters Elizabeth , Biedermann Savanna , Lai Steven , Messick Troy 
Published: June 2023

6035 Background: Epstein-Barr Virus (EBV) is associated with a diverse collection of malignancies, including nasopharyngeal carcinoma (NPC). One viral-encoded protein, EBNA1, is consistently expressed in all known EBV-associated malignancies and is critical for the replication and maintenance of the EBV genome in latently infected cells. VK-2019 is a first-in-class, orally bioavailable EBNA1 inhibitor that blocks latent replication and proliferation in preclinical studies. Methods: We conducted a Phase I/IIa clinical trial of VK-2019 as a single therapeutic agent in patients with advanced (recurrent or metastatic) NPC. An accelerated titration design allowed dose escalation to proceed rapidly from 60 mg/day to 1800 mg/day. Blood samples for detailed pharmacokinetic analyses were collected after the first and multiple doses. In addition, tumor biopsies were collected from 2 patients at the 1800 mg/day dose level at baseline and during treatment and analyzed for EBV copy number and viral and cellular gene expression. Results: A total of 22 advanced NPC patients were enrolled. VK-2019 was well tolerated with mostly grade 1-3 adverse events being reported. VK-2019 is rapidly absorbed with a biphasic distribution and a terminal T1/2 of ~12h after single or multiple doses. Cmax and AUC increases with dose escalation through 920 mg with large variability at 1800mg. Accumulation has been observed with multiple doses up to 460mg. Based on preclinical efficacy models, target exposures are at or above expected activity levels for patients at least on the 920 mg daily dose and above. A partial response ( > 30% decrease in tumor size) was observed for one patient. Preliminary results from biopsies from 2 patients show decreases in EBV copy number and viral gene expression (LMP2 and gp150). We also observed decreases in EBER-positive cells in one patient. Conclusions: In this study, VK-2019 was well tolerated, exhibiting an excellent safety profile and exposure above in vitro efficacy. An MTD has not been yet established. Preliminary results indicate a decrease in EBV copy number and viral gene expression in latently infected tumor cells in some patients. Alternate dose schedules are justified to determine the clinical efficacy of an EBNA1 inhibitor in patients with advanced NPC. Funded by NCI, R01-CA235633 and Cullinan Oncology. Clinical trial information: NCT04925544 .
Platinum/taxane/pembrolizumab vs platinum/5FU/pembrolizumab in patients with recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC).
Authors: Sun Lova , Cohen Roger B. , Colevas A. Dimitrios Dimitrios 
Published: June 2023

6039 Background: Pembrolizumab +/- chemotherapy is standard of care for patients (pts) with r/m HNSCC. Despite approval of platinum/5FU/pembrolizumab based upon the KN-048 study, a taxane is often substituted for 5FU due to ease of administration and tolerability. No studies have directly compared these approaches. We describe nationwide patterns of taxane vs 5FU chemoimmunotherapy in r/m HNSCC and compare survival and time on treatment between the two. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, and included pts treated with frontline pembrolizumab plus platinum-based chemotherapy (either taxane or 5FU) for r/m HNSCC. Demographic, cancer, and clinical outcomes were summarized. Categorical variables were compared using Pearson’s chi-square test; continuous variables were compared using T-test. Overall survival (OS) was estimated using Kaplan Meier methodology, and compared using log-rank test. Multivariable Cox regression for overall survival adjusting for age, sex, race, year of diagnosis, ECOG performance status (PS), smoking history, primary tumor site, PD-L1, HPV status, cisplatin use, socioeconomic status, insurance, and practice type was performed, with multiple imputation by chained equations for missing variables. Results: Of 444 pts, 321 (72%) received 5FU and 123 (28%) received taxane (108 paclitaxel, 15 docetaxel). Use of cisplatin rather than carboplatin was higher in the 5FU group than the taxane group (16.8% vs 4.9%, p=0.001). Taxane use was higher in academic vs community practices (50.7% vs 23.9%, p<0.001); within community sites, Northeast states had highest taxane use (27.5%) and Western states had lowest taxane use (16.7%). Pts with Medicare or Medicaid were more likely to receive taxane (35.5%) vs commercial (23.6%) or other (26.7%) insurance. OS did not differ between taxane and 5FU groups (mOS 12.7 vs 13.5 months, p=0.743). On multivariable Cox regression, HR for death associated with taxane vs 5FU was 1.01 (95%CI 0.73-1.41). HPV positive status was associated with improved survival (HR 0.58, 95%CI 0.40-0.83). PS>1 (HR 1.38, 95%CI 0.96-1.98) and cisplatin use (HR 1.37, 95%CI 0.95-1.98) showed non-significant trends towards worse survival. Taxane-treated pts received more treatment cycles (mean 11.3 vs 8.8 cycles, p=0.015) and were on treatment slightly longer (mean 6.9 vs 6.0 months, p=0.289) than 5FU-treated pts. Conclusions: In US pts with r/m HNSCC undergoing chemoimmunotherapy, rates of taxane vs 5FU use vary by academic setting, geographic region, and insurance status. There was no difference in survival between 5FU and taxane, and taxane-treated pts received more cycles of therapy. Platinum-taxane appears to be a non-inferior alternative to platinum-5FU with pembrolizumab for r/m HNSCC, and should be allowed in clinical trials.