bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discontinuation of immunotherapy over 2 years for patients with non–small cell lung cancer (NSCLC): A search for predictors.
Authors: Cascetta Priscilla , Reni Anna , Facchinetti Francesco , Meyer May-Lucie , Riudavetz Mariona , Aldea Mihaela , Dall'Olio Filippo Gustavo , Marinello Arianna , Tagliamento Marco , Remon Masip Jordi , Besse Benjamin , Planchard David , Barlesi Fabrice , Derosa Lisa 
Published: June 2023

2661 Background: In advanced NSCLC, treatment completion at 24 months emerged in trials evaluating immune checkpoint inhibitors (ICI). Nevertheless, in clinical practice the question of the optimal treatment duration is under debate. Methods: We performed a retrospective study on advanced NSCLC treated with ICI (alone or with chemotherapy) at Gustave Roussy before 2021. Among patients still receiving ICI at 12 months, we analyzed the reasons for ICI discontinuation at 18 and 24 months. Results: Of the 682 patients treated with ICI (first-line for n=230, 33.7%), 159 (23.3%) received ICI for ≥ 12 months and 122 (17.9%) for ≥ 18 months. Between 18-24 months, 20 (57.1%) patients interrupted ICI for progressive disease (PD), 8 (22.8%) for toxicity and 7 (20.0%) after discussion with the patient. Out of the 88 (12.9%) patients who completed 2-years of ICI (median duration of treatment: 31.46 months, first-line for n=51), 22 (25.0%) patients discontinued ICI for PD and 40 (45.5%) without PD: 14 (15.9%) for toxicities, patient request or unknown causes and 26 (29.5%) for clinical decision before (n=16, 61.5%) or after (n=10, 38.5%) 30 months of treatment. Discontinuation according to phase III clinical trial design was supported by complete response (CR) by PET imaging +/- tissue biopsy of metabolically active lesions +/- ctDNA in 17 (65.4%) cases just before therapy discontinuation. After a median follow-up of 45.6 months since treatment discontinuation for these 26 patients, only two experienced PD at 4 and 6 months from ICI interruption, in both cases with no proof of CR at ICI discontinuation (p=0.111). The remaining 26 (29.5%) patients who continued ICI after 2 years, are on treatment based either on absence of CR at PET-CT +/- tissue biopsy of metabolically active lesions (n=20, 76.9%) or after discussion with the patients (n=6, 23.1%). After a median follow-up of 40.17 months from the of 24-months landmark, the median progression-free survival was unreached in both continuation and discontinuation groups. Conclusions: The patients who completed 2-years of ICI treatment usually continue to experience long‐term response after discontinuation. Considering that a subgroup of patients could still benefit from maintained ICI administration, PET imaging was considered to guide ICI cessation or continuation. Prospective studies specifically designed to investigate biomarkers of maintained responses or residual disease (imaging, ctDNA, multi-omics including microbiome) are required to establish the indication for ICI continuation or stop for each patient.
BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: Results from a first-in-human phase 1 study.
Authors: Zhang Li , Ma Yuxiang , Zhao Yuanyuan , Fang Wenfeng , Zhao Hongyun , Huang Yan , Yang Yunpeng , Chen Likun , Hou Xue , Zou Wen , Ding Muran , Yu Jing , Zhang Suoyu , Wang Junxian , Xiao Sa , Wang Hongwei , Zhu Hai , Olivo Martin Sebastian , Zhu Yi 
Published: June 2023

3001 Background: BL-B01D1 is a first-in-class novel ADC consisting of an EGFRxHER3 bispecific antibody linked to a novel TOP-I inhibitor payload via a cleavable linker. We now present safety/efficacy results from a FIH phase I study of BL-B01D1. Methods: This study included patients (pts) with locally advanced or metastatic solid tumors. For dose escalation (D-ESC, i3+3), BL-B01D1 was administered intravenously at doses of 0.27, 1.5, 3.0 mg/kg QW, 2.5, 3.0, 3.5mg/kg D1D8 Q3W or 4.5, 5.0, 6.0 mg/kg D1 Q3W. A subset of pts were enrolled into dose-expansion (D-EXP) at Q3W regimens. Results: As of Dec 31, 2022, 150 pts were enrolled and received at least one dose (D-ESC, n=25; D-EXP, n=125). DLTs were neutropenia, febrile neutropenia and thrombocytopenia at 3.0mg/kg QW and 3.5mg/kg D1D8 Q3W. The MTDs were determined to be 3.0mg/kg D1D8 Q3W and 6.0mg/kg D1 Q3W. D-EXP was carried out at 2.5, 3.0mg/kg D1D8 Q3W and 4.5, 5.0, 6.0 mg/kg D1 Q3W. 144 pts were enrolled across all Q3W dose levels (D-ESC and D-EXP), including 89 NSCLC, 7 SCLC, 27 nasopharyngeal cancer (NPC), 19 HNSCC and 2 others. Most common TRAEs (>10%, all grade / ≥ G3) were leukopenia (60%/30%), neutropenia (51%/34%), anemia (45%/15%), thrombocytopenia (44%/19%), alopecia (30%/0%), nausea (29%/<1%), vomiting (28%/0%), asthenia (21%/<1%), decreased appetite (22%/<1%), asthenia (21%/<1%), hypophagia (16%/0%), diarrhoea (15%/2%), mouth ulceration (15%/<1%), rash (13%/0%). No ILD was observed. 122 pts were evaluable for efficacy (at least 1 tumor assessment). PK and other details will be updated in the meeting. Conclusions: BL-B01D1 demonstrated encouraging efficacy in heavily pretreated metastatic/locally advanced solid tumors, especially in pts with EGFRm NSCLC. The safety profile showed adequate safety and tolerability. Clinical trial information: NCT05194982 . [Table: see text]
FUTURE-SUPER: A randomized, subtyping-based umbrella phase II trial for first-line treatment of metastatic triple-negative breast cancer.
Authors: Zhimin Shao , Fan Lei , Linxiaoxi Ma , Wu Songyang , Chen Li , Liu Xiyu , Zhang Wenjuan , Hu Xin , Jiang Yizhou , Wang Zhonghua , Li Huajun 
Published: June 2023

3011 Background: Triple-negative breast cancers (TNBCs) are heterogeneous in molecular drivers and immune traits. Our previous studies classified TNBCs into four subtypes (luminal androgen receptor, LAR; immunomodulatory, IM; basal-like immune-suppressed, BLIS; and mesenchymal-like, MES). The subtyping-based treatment strategy was proved clinically feasible, with promising efficacy (Cell Res 2021, NCT03805399) in patients with heavily pretreated metastatic TNBC (mTNBC). Here, we conducted FUTURE-SUPER, a multi-cohort, randomized trial to further evaluate the efficacy of subtyping-based therapy in the first-line treatment of mTNBC. Methods: Patients with untreated locally recurrent inoperable or mTNBC were enrolled. After categorization into 5 cohorts according to TNBC subtypes and genomic biomarkers, patients were randomly assigned (in a 1:1 ratio) to receive nab-paclitaxel (control group) or nab-paclitaxel plus subtyping-based treatment (subtyping-based group): pyrotinib (LAR-HER2 mut), everolimus (LAR- PI3K/AKTmut), camrelizumab and famitinib (IM), bevacizumab (BLIS/MES- PI3K/AKT WT), everolimus (MES- PI3K/AKT mut). The primary endpoint was progression-free survival (PFS). Secondary endpoints included PFS in each subtyping-based cohort, objective response rate (ORR), overall survival (OS) and safety. Results: Between July 29, 2020, and October 17, 2022, 139 patients were enrolled and randomly assigned. With a median follow-up of 18.5 mo (range, 3.5 to 30.3), 101 (72.7%) events of disease progression or death occurred. Median PFS was significantly longer in the subtyping-based group than in the control (11.3 mo vs 5.8 mo; hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.25 to 0.57; P<0.0001). Greater magnitude of PFS benefits were seen for the IM (median, 15.1 mo vs 6.5 mo; HR 0.37; 95% CI, 0.19 to 0.73), BLIS (median, 9.4 mo vs 3.9 mo; HR 0.41; 95% CI, 0.16 to 0.56) and LAR- PI3K/AKT mut (median, 19.1 mo vs 8.4 mo; HR 0.42; 95% CI, 0.12 to 1.53) subtypes. The ORR (measurable-disease population) was higher in the subtyping-based group than in the control group (80.0% [48/60] vs. 44.8% [26/58]; odds ratio, 0.20; 95% CI, 0.09 to 0.46). OS data were not mature. Most adverse events were of grade 1 or 2. Grade 3 and 4 toxicities were as expected, with neutropenia more frequently reported in the subtyping-based group (56.5% vs 26.1%). No treatment-related deaths were recorded. Further high-throughput biomarker analyses are ongoing. Conclusions: Subtyping-based precision treatment significantly prolonged PFS versus nab-paclitaxel in the first-line treatment of advanced TNBC, with manageable toxicities. Our findings highlight the profound clinical benefits with treatment optimization according to molecular/immunological subtypes in TNBC, outlining a direction for further exploration. Clinical trial information: NCT04395989 .
Tissue-agnostic efficacy of trastuzumab deruxtecan (T-DXd) in advanced solid tumors with HER2 amplification identified by plasma cell-free DNA (cfDNA) testing: Results from a phase 2 basket trial (HERALD/EPOC1806).
Authors: Taniguchi Hiroya , Yagisawa Masataka , Satoh Taroh , Kadowaki Shigenori , Sunakawa Yu , Nishina Tomohiro , Komatsu Yoshito , Esaki Taito , Sakai Daisuke , Doi Ayako , Kajiwara Takeshi , Ono Hiromi , Asano Masatoshi , Hirano Nami , Odegaard Justin Iver , Fujii Satoshi , Nomura Shogo , Sato Akihiro , Yoshino Takayuki , Nakamura Yoshiaki 
Published: June 2023

3014 Background: HER2 ( ERBB2) gene amplification (amp) is a potential therapeutic target beyond breast and gastric cancers. HER2 amp can be detected in plasma cfDNA which may be an alternative to tissue biopsy. HERALD/EPOC1806 was a multicenter, investigator-initiated phase 2 trial of T-DXd for patients with HER2-amplified advanced solid tumors identified by cfDNA testing. Methods: We enrolled adults with advanced solid tumors harboring HER2 amp detected by next-generation sequencing of cfDNA (Guardant360) in the GOZILA study (UMIN000029315). We excluded breast or gastric cancer patients with HER2 overexpression (IHC 3+ or IHC 2+/ISH+). Patients received T-DXd 5.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR). Results: From December 2019 to January 2022, 4,734 patients were screened by cfDNA in the GOZILA study. Among 252 with HER2 amp, 62 with 16 cancer types were enrolled in HERALD. Median baseline plasma HER2 copy number (CN) was 8.55 (range, 2.4–73.9). All patients but 3 (all with salivary gland cancer) received prior anti-cancer therapy (median, 3 lines; range, 0–8). At a median follow-up of 8.9 months (data cut-off: July 17, 2022), the confirmed ORR was 56.5% (95% CI, 43.3–69.0%), statistically higher than the threshold value of 5%. Responses were observed for 13 cancer types, including KRAS-mutant colorectal (1/3), PIK3CA-mutant endometrial (5/6), and tissue HER2-negative gastric cancers (1/2). Plasma HER2 CN above vs. below the baseline median value did not impact response (ORR: 58.1% vs. 54.8%); however, the clearance vs. persistence of HER2 amp in cfDNA on Cycle 2 Day 1 corresponded to higher response (ORR: 88.0% vs. 22.7%). ORR by independent review was 58.1% (95% CI, 44.8–70.5%), and the disease control rate was 90.3% (95% CI, 80.1–96.4%). Median progression-free survival was 7.0 (95% CI, 4.9–9.7) months, and the median duration of response was 8.8 months (95% CI, 5.8–11.2). Most adverse events were mild to moderate. Interstitial lung diseases occurred in 16 patients (25.8%, G1/G2/G3; 14/1/1). Conclusions: T-DXd achieved a high ORR, durable response with a manageable safety profile in patients with advanced solid tumors and HER2 amp detected in cfDNA. Clinical trial information: JapicCTI-194707 .[Table: see text]
A novel genetic marker of fluoropyrimidine-induced cardiovascular toxicity.
Authors: Palles Claire , Lucas Marie , Watts Katie , Galavotti Sara , Chin Ik Shin , Campbell Cameron , Briggs Sarah E W , Jaeger Emma , Church David , Taylor Karen , Bliss Judith , Fisher David , Madi Ayman , Cameron David A. , Maughan Timothy S. , Tomlinson Ian , Iveson Timothy , Kerr David James , Kerr Rachel , Cheadle Jeremy 
Published: June 2023

3028 Background: Fluoropyrimidine (FP) based adjuvant chemotherapy (5-Fluorouracil and Capecitabine) increases survival of patients with colorectal and breast cancers. However, 1-5 % of patients experience cardiovascular toxicity, which is not explained by variants in the gene encoding dihydropyrimidine dehydrogenase. Methods: We sought genetic determinants of FP-induced cardiovascular toxicity by performing a genome wide association study of NCI-CTCAE graded cardiovascular toxicity using samples from the QUASAR 2 trial (n=759 patients with colorectal cancer (CRC)). Validation studies (n= 5438 patients with CRC and 1478 patients with breast cancer) were performed in the SCOT, COIN and TACT2 trials. The most commonly reported symptoms were chest pain, angina and arrhythmias with 6 patients experiencing myocardial infarctions. Results: rs4904753, mapping to an intron of D-glutamate cyclase (DGLUCY) was genome wide significant in QUASAR 2 (P =4.38 x 10-16) and validated in SCOT, COIN and TACT2 (P<0.0002 in all studies. rs4904753 was associated with levels of expression of DGLUCY in multiple tissues including the atrial appendage. Under a recessive model, 45.3% (61/137) of patients with cardiac toxicity as compared to 10.2% (691/6786) of controls carried both minor alleles (meta-analysis: OR=7.72, 95% CI 5.31-11.22, P=1.03 x 10-26). Conclusions: The sensitivity, specificity, positive predictive value and negative predictive values of testing for two copies of the toxicity associated allele of rs4904753 were 48%, 90%, 8% and 99% respectively. Clinical implementation of testing for this variant has the potential to identify almost half of those at risk of FP-induced cardiovascular toxicity with high specificity, thereby enabling changes to their clinical management. [Table: see text]
First report of tumor-informed circulating tumor DNA in fibrolamellar carcinoma in adolescents and young adults: 51 patients.
Authors: McKenna Elise , Kent Paul , Tasse Jordan C , Schadde Erik , Fisher Oliver M , Humar Abhinav , Kato Tom , Ellison Jessica , Yamashiro Darrell , Cornelius Albert 
Published: June 2023

3034 Background: Fibrolamellar Carcinoma (FLC) is an extremely rare form of primary liver cancer (50-200 cases/year), unrelated to hepatocellular carcinoma. The only established standard of care is surgery. However, recurrence is at least 80%, even with R0 surgery, suggesting that FLC is best thought of as a systemic disease instead of a surgical disease. Systemic therapies in retrospective studies of more than 25 show immunotherapy and chemotherapy combinations have promise. Circulating “tumor-informed” tumor DNA (ctDNA) is a tool for tracking microscopic systemic disease, serving as a marker of systemic involvement, has shown success in management of other cancers. FLC has never been studied using this technology. Our retrospective study of 51 patients over a 2.5-year period is the first attempt to understand if ctDNA can be helpful in the management of FLC. Methods: All patients consented to blood draws on a 1-3 monthly basis, according to the company (Signatera) protocol. All patients had regular imaging reviewed by the FibroFighters Foundation National Tumor Board. Complete response (CR), Partial response (PR) (> 30% decrease), Progressive Disease (PD) (> 20% increase), and Stable Disease (SD) (neither PD/PR/CR) were recorded according RECIST 1.1. The imaging closest in time to the blood draw was used for correlation purposes. “Negative” is defined as a value = 0.00. “Positive” is defined as a value > 0.00. Results: Fifty-one FLC patients (26M, 25F, median age 23, range 10-56), 92% stage (III/IV), consented to ctDNA “blood biopsies,” (n=226 samples, mean 4.4/patient, range 1-11). Negative values correlated with no evidence of disease (NED) on imaging 78% of the time, positive values with disease 94% [PPV/NPV/sens/spec of 0.78/0.94/0.93/0.81]. NPV and sens increased to almost 100% with a ctDNA threshold of > 1.0 at the expense of a lower PPV and spec. However, consecutive negative ctDNA values correlated with radiologic NED 86% [PPV/NPV/sens/spec = 0.86/0.84/0.77/0.91] without a single PD in this cohort (n=64). A “downward trend or slope” on consecutive values predicted Objective Response (CR+PR) and Disease Control (CR+PR+SD) at 68% and 96% [PPV/NPV/sens/spec of 0.68/0.49/0.36/0.78 and 0.96/0.26/0.36/0.94, respectively], while an “upward trend” performed less well to predict relapse [PPV/NPV/sens/spec = 0.54/0.98/0.94/0.81]. Conclusions: In this first exploration of 51 young FLC patients, and 226 tissue-informed cell free ctDNA data points, “Positive” and “Negative” values overall performed well for predicting RECIST 1.1 “disease” or “NED” respectively, especially for consecutive values of zero, where no progressions were observed in 64 distinct FLC scenarios. A downward trend or “slope” performed better than an upward trend to predict objective response (PR+CR) versus relapse (PD).
Early detection of lung cancer using small RNAs.
Authors: Sharma Amita , Sikosek Tobias , Horos Rastislav , Rajakumar Timothy , Tikk Kaja , Schumann Christian , Walterspacher Stephan , Christopoulos Petros , Schuler Martin H. , Darwiche Kaid , Taube Christian , Hegedus Balazs , Rabe Klaus , Rieger-Christ Kimberly M. , Jacobnson Francine , Aigner Clemens , Bankier Alexander A. , Reck Martin , Steinkraus Bruno 
Published: June 2023

3035 Background: Low-dose computed tomography (LDCT) screening can significantly reduce lung cancer mortality. However, annual screening is limited by low adherence in the USA and still not broadly implemented in Europe. As a result, <10% of lung cancers are detected through existing programs. Thus, there is great need for additional diagnostic modalities, such as a blood test that could be deployed in the primary care setting. Methods: We prospectively recruited 1,189 patients meeting the 2013 USPSTF screening criteria for lung cancer and collected stabilized whole blood. Ultra-deep small RNA sequencing was performed with a method to remove highly abundant erythroid RNAs, opening bandwidth for the detection of less abundant species originating from plasma or the immune cellular compartment. We utilized 100 random data splits to train and evaluate logistic regression classifiers using small RNA expression, discovered an 18-small RNA feature consensus signature (miLung), and validated this in an independent cohort (246 patients). Blood cell sorting and tumor tissue sequencing were performed to deconvolve small RNAs into their source of origin. Results: We generated diagnostic models and report a median ROC AUC of 0.86 (95% CI 0.84-0.86) in the discovery cohort, and generalized performance of 0.84 in the validation cohort. Diagnostic performance increased stage-dependently from 0.73 (95% CI 0.71-0.76) for Stage I to 0.90 (95% CI 0.89-0.90) for Stage IV. We identified a tumor-shed, plasma-bound ribosomal RNA fragment of the L1 stalk as a dominant predictor of lung cancer. The fragment is decreased following surgery with curative intent. In additional experiments, dried blood spot collection and sequencing revealed that small RNA analysis could potentially be conducted via home-sampling. Conclusions: These data suggest the potential of a small RNA-based blood test as a viable alternative to LDCT screening for early detection of smoking-associated lung cancer. Clinical trial information: NCT03452514 . [Table: see text]
Outcomes in participants with a false positive multi-cancer early detection (MCED) test: Results from >4 years follow-up from DETECT-A, the first large, prospective, interventional MCED study.
Authors: Lennon Anne Marie , Buchanan Adam H , Rego Seema P , Choudhry Omair A , Elias Paul Z , Sadler Jennifer R , Cohen Joshua D , Douville Christopher B , Honushefsky Ashley M , Klein Alison , Salvati Zachary M , Sheridan Kathleen , Tomasetti Cristian , Wagner Eric S , Walter Carroll N , Fishman Elliot K. , Kinzler Kenneth W. , Vogelstein Bert , Beer Tomasz M. , Papadopoulos Nickolas 
Published: June 2023

3039 Background: Recommended standard of care (SOC) early detection tests are solely available for four cancer types and fewer than 20% of incident cancers in the US are being diagnosed as a result of screening. Advances in detection of tumor-derived analytes in the blood are enabling the development of MCED tests that may expand early cancer detection. While MCED tests are being designed with high specificity, false positive (FP) results remain a concern for clinicians and patients alike, as no long-term outcomes of individuals with a FP MCED test have been reported. DETECT-A was the first prospective interventional clinical trial to evaluate an MCED blood test. The test used was an early version of CancerSEEK, evaluated in 9,911 women without history of cancer ( Science, 369:6499, 2020). This prospectively planned analysis evaluates cancer incidence among DETECT-A participants with FP results, with the intention of providing key long-term data on test effectiveness. Methods: This analysis included 98 DETECT-A participants with FP results, where a FP was defined as a positive CancerSEEK result with subsequent PET-CT and clinical evaluation with no evidence of cancer within 1 year of the initial CancerSEEK test. Sixty-three of 98 participants had no follow-up procedure performed after imaging, and 35 subjects had noninvasive/minimally invasive follow-up procedures performed. Electronic medical records were analyzed from January 2020 through November 2022 for cancer diagnosis, treatment, remission, recurrence, and mortality. Results: Ninety-six of 98 participants with a FP result remained free of cancer with a median follow-up of 4.3 years (IQR: 3.9-4.9) from the initial CancerSEEK test. One stage I breast cancer and one stage III ovarian cancer were diagnosed 2.7 and 2.9 years respectively from the initial CancerSEEK test. Conclusions: Patients with a negative PET-CT and initial clinical evaluation after a positive CancerSEEK test had low (<1% per year) risk for cancer in the ensuing four years after the initial CancerSEEK test. If confirmed, this result should prove reassuring to clinicians and to patients who have no evidence of cancer on comprehensive imaging following a positive MCED test. Further, these results provide preliminary support for the recommendation that patients who participate in MCED testing and receive a FP result can safely return to routine care after comprehensive anatomic and functional imaging and clinical evaluation reveal no suspicion of cancer.