bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final report and long-term outcomes: Phase I trial of a HER2 intracellular plasmid-based vaccine in HER2+ advanced stage breast cancer.
Authors: Disis Mary L. , Dang Yushe , Coveler Andrew L. , Higgins Doreen , Childs Jennifer , Salazar Lupe G 
Published: June 2021

2619 Background: Vaccination with the intracellular domain (ICD) of HER2 in pre-clinical models is both immunogenic and protective against the development of mammary tumors. This study (NCT00436254) was designed to examine the safety and optimal immunogenic dose of a DNA-based vaccine encoding the HER2 ICD in subjects with HER2+ breast cancer. Methods: Sixty-six patients with stage III or IV HER2 + breast cancer in remission or with stable bone only disease were enrolled into three vaccine arms: 1 (10mcg dose of plasmid), 2 (100mcg) and 3 (500mcg). Vaccines were administered i.d. monthly for three immunizations. Endpoints included safety and optimal dose. HER2 specific IFN-gamma immune responses were evaluated and DNA persistence at the vaccine site was assessed. Toxicity and clinical outcomes were followed for 10 years. Results: The majority of vaccine-related toxicity was grade 1 (89%) and grade 2 (11%) and was not significantly different between the three dose arms. All Arms developed HER2 ICD immunity after vaccination, however, patients in Arm 2 and Arm 3 had significantly better immune responses (of higher magnitude and at most time points) than patients in Arm 1 (p=0.003 and p<0.001, respectively) after adjusting for baseline factors. At 60 weeks, the number of patients who maintained the greatest fold-difference in HER2 ICD immune responses from their baseline was highest in Arm 2 (73%) when compared to Arm 1 (47%) and Arm 3 (45%). Associations between ICD responses and plasmid DNA persistence at the vaccine site were estimated via linear regression models. HER ICD immunity after the end of immunizations, relative to baseline, was significantly lower in patients with DNA persistence at week 16 compared to those without persistence (p=0.02). Patients at the highest dose demonstrated the greatest incidence of plasmid persistence (92%) as compared to 33% in Arm 1 and 10% in Arm 2. The median time of follow-up was 118.6 months (Arm 1), 99.7 months (Arm 2), and 73.5 months (Arm 3). The median OS and PFS has not been reached in any Arm and did not differ with respect to treatment arm (Log-rank p-value 0.36 for OS, and 0.63 for PFS). However, we observed a separation of Kaplan-Meier curves for OS from about 40 months and curves for PFS from about 30 months, and the separation maintained until the end of the study for Arm 2 versus Arm 1 and Arm 3. One patient in Arm 2 developed lymphocytic colitis 2.2 years from enrollment deemed possibly related to vaccination. Conclusions: An intermediate dose (100mcg) of vaccine was immunogenic and associated with persistence of immunity at 60 weeks. A randomized phase II trial of the HER2 ICD plasmid-based vaccine in the neoadjuvant setting is in development. Clinical trial information: NCT00436254.
Real world experience with standalone immunotherapy regimens: Immune-related adverse events, healthcare utilization and cost among patients with commercial or Medicare Advantage insurance.
Authors: Gunturu Krishna Soujanya , Pham Timothy , Shambhu Sonali , Fisch Michael Jordan , Barron John , Debono David Joseph 
Published: June 2021

2625 Background: Immunotherapy is a fast growing class of cancer therapy. We evaluated the rates of immune-related adverse events (irAEs), healthcare utilization, and costs up to 1 year post-index among patients using monotherapy (PD-1/PD-L1 inhibitor) and combination therapy (PD-1/PD-L1 with CTLA-4 inhibitors). Methods: We reviewed claims from the HealthCore Integrated Research Database (HIRD), which contains commercially insured/Medicare Advantage members and captures clinical, utilization, and cost measures. We analyzed both the monotherapy (M) and combination therapy (C) cohorts focusing on members with ≥ 6 months of baseline continuous medical and pharmacy coverage. Descriptive and multi-variate analyses were performed. Results: The C cohort had 904 and M had 9,084 patients, with mean ages of 58 and 64 years, respectively. Prominent cancer types were melanoma for C and lung for M. The most common incident irAEs (%) for C vs. M were: endocrinopathies (27.7, 14.7), hepatitis (17.1, 7.7), nephritis (21.0, 14.0), neuropathy (6.6, 7.0), followed by colitis, dermatitis, and myocarditis. After adjustment, C therapy showed greater risk of all-cause inpatient admissions (OR 2.27, 95% CI 1.93, 2.66), all-cause emergency department (ED) visits (OR 1.55, 95% CI 1.33, 1.81) and irAE-related visits (See table). Mean adjusted all-cause cost difference for C vs M was +$43,747 (95% CI $38,440, $49,427). In age ≥65 subset, 222 received C and 4,208 received M. C therapy patients had more irAE-related hospitalizations (45.3% vs. 57.7%, p=0.0004). Costs were similar to the main cohort. Conclusions: C therapy showed greater incident irAE rates, increased utilization and medical costs compared to M therapy. Limitations include less precise ascertainment of irAEs in claims data and generalizability only to those with commercial or Medicare Advantage insurance. Our study highlights the increased toxicity and cost tradeoffs involved in choosing combination immunotherapy over monotherapy.[Table: see text]
BOS172738, a highly potent and selective RET inhibitor, for the treatment of RET-altered tumors including RET-fusion+ NSCLC and RET-mutant MTC: Phase 1 study results.
Authors: Schoffski Patrick , Cho Byoung Chul , Italiano Antoine , Loong Herbert H. F. , Massard Christophe , Medina Rodriguez Laura , Shih Jin-Yuan , Subbiah Vivek , Verlingue Loic , Andreas Karen , Basson Craig T. , Clawson Alicia , Ho Peter T.C. , Knight Shelley , Scheuber Anita , Keegan Mitchell 
Published: June 2021

3008 Background: RET (REarranged during Transfection) gene alterations (mutations and fusions) leading to constitutive kinase activity are identified as drivers of disease progression in multiple tumor types, including non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). BOS172738 is an investigational, potent, selective oral RET kinase inhibitor. This next-generation inhibitor was designed with nanomolar potency against RET and >300-fold selectivity against vascular endothelial growth factor receptor 2, to maximize the potential therapeutic window. Methods: NCT03780517 is a phase 1 study consisting of a dose-escalation and dose-expansion phase. During the escalation, 67 patients with RET-altered advanced solid tumors received once-daily oral doses of BOS172738 (10-150 mg). Intra-patient dose escalation was allowed as was over-accrual to dose levels deemed to be safe. Study endpoints were safety (CTCAE v. 4.03), tolerability and confirmed overall response rate (ORR; RECIST 1.1). The data cutoff was Dec. 11, 2020. Results: BOS172738 exhibited a favorable safety profile (n=67) for long-term administration with most treatment-emergent adverse events (TEAEs) classified as grade ≤2 and deemed unrelated to drug. The most common TEAEs were creatinine phosphokinase (CPK) increase (54%), dyspnea (34%), facial edema, aspartate aminotransferase elevation, anemia (25% each), neutropenia, diarrhea (22% each), fatigue (21%), and constipation (20%). BOS172738 was not associated with hypertension or significant hepatoxicity. BOS172738 demonstrated broad anti-tumor activity with an investigator-assessed ORR of 33% (n=18/54), a NSCLC ORR of 33% (n=10/30), MTC ORR of 44% (n=7/16, including 1 complete response) and one patient with RET fusion+ pancreatic cancer reported a partial response. Responders included patients with brain metastases with one patient whose brain lesion decreased by 43%. The median duration of response has not been reached. Many patients remain on study, including the longest of 659 days, at data cutoff. BOS172738 exhibited dose-dependent exposure (AUC, Cmax), rapid absorption (median Tmax 1 to 4.5 h), and an extended half-life (approximately 65 hours) maximizing target coverage. Conclusions: BOS172738 is a highly potent and selective RET inhibitor with a differentiated safety profile and clinical activity against RET-altered tumors, including patients with brain metastases. BOS172738 continues to be evaluated in patients with NSCLC, MTC, and in patients previously treated with other selective RET inhibitors. Clinical trial information: NCT03780517.
Racial and ethnic disparities among participants in precision oncology clinical studies.
Authors: Aldrighetti Christopher M. , Niemierko Andrzej , Van Allen Eliezer Mendel , Willers Henning , Kamran Sophia C. 
Published: June 2021

3014 Background: Precision medicine has revolutionized oncologic care in the United States (US) in the past two decades. While the US cancer population is rapidly diversifying, enrollment of a diverse patient population into clinical trials lags behind. In particular, it is unclear whether minority patients are adequately represented in precision oncology trials. Herein, we report racial/ethnic representation in precision oncology studies spanning four common cancer types (breast, lung, prostate, colorectal cancers). Methods: Completed US clinical studies incorporating precision medicine objectives based on a set of 12 precision oncology search terms (including tumor biomarker, whole exome sequencing, tumor mutation testing, gene expression signatures, tumor microarray, tumor genomics, et cetera) were identified from Clinicaltrials.gov. Studies were reviewed for reporting race/ethnicity for inclusion in the analysis. The Surveillance, Epidemiology, and End Results (SEER) database was used to determine incidence of race/ethnicity in the US cancer population, correlated with disease site and median year of enrollment for each trial. The difference in incidence (D-I) was defined as the median absolute difference in study racial enrollment and SEER incidence, with a negative value corresponding to underrepresentation. Wilcoxon signed-rank test was used to compare median D-I to a value of 0 by racial/ethnic subgroups. Results: Overall, 156 studies were identified; 40.3 and 27.5% studies enrolling from 2000 through 2020 met the inclusion criteria for racial and ethnic subgroups reporting, respectively. Of 4,418 total enrollees, 82.5% were White, 10.5% Black, 3.8% Asian, and 0.4% American Indian/Alaskan Native (AIAN). Ethnically, 6.4% were Hispanic. The D-I was +2.2% for Whites (interquartile range (IQR) = -43.7% to 25.4%; P < 0.013), -0.74% AIAN (IQR = -0.8% to +5.9%; P < 0.001), -2.5% Asians (IQR = -4.1% to 30.4%; P < 0.152), -4.6% Blacks (IQR = -20.1% to +45.0%; P < 0.001), and -8.1% Hispanics (IQR = -14.8% to + 29.6%; P < 0.001). By disease site, Blacks were significantly underrepresented proportional to their cancer incidence among prostate (D-I of -11.8%, p = 0.009) and lung studies (D-I of -5.9%, p = 0.013), while prostate studies significantly overrepresented Whites (D-I +14.0%, p = 0.005). Lung studies overrepresented Asians (D-I +0.49%) consistent with the prominent role of targetable oncogene drivers in this population. Conclusions: Results demonstrate an underrepresentation of minority racial groups and an overrepresentation of Whites in precision oncology studies. Increased emphasis on equitable enrollment onto these studies is critical, as resulting precision Omic conclusions are used to stratify populations and personalize treatments. A continued lack of diversity among enrollees may further leave behind vulnerable minority populations in the era of precision oncology.
Liquid biopsy testing: Impact on treatment assignment and survival in a community-based oncology practice—A real-world experience.
Authors: Choucair Khalil , Mattar Bassam Ibrahim , Truong Quoc Van , Koeneke Travis Lee , Truong Phu Van , Dakhil Christopher , Cannon Michael W. , Page Seth Joel , Deutsch Jeremy Michael , Carlson Eric A. , Moore Dennis Frederic , Nabbout Nassim H. , Kallail K. James , Dakhil Shaker R. , Reddy Pavan S. 
Published: June 2021

3027 Background: Liquid biopsy is a promising, rapid and minimally invasive genetic test examining circulating tumor DNA. It offers a significant potential in selecting signal-matched therapeutic options. Methods: A retrospective chart review was conducted on adult patients with advanced solid cancer whose tumors were tested with the Guardant 360® (Guardant Health) assay between December 2018 and 2019. A follow-up analysis (censor date: 01/06/2021) was carried to assess the actual impact of testing results on treatment assignment and survival. Results: A total of 178 patients underwent testing. Mean age at diagnosis was 65 years. Median (m) Karnofsky Performance Scale was 90% and the majority of patients (89.9%) had ≥ stage III-B disease. Lung (LCa; 50.56%), breast (BCa; 17.42%) and colorectal (CRCa; 7.87%) cancers were the most common cancer types. A positive test was reported in 140/178 patients (78.7%); of those, 105/140 (75%) had an actionable mutation, either with an FDA-approved target-matched therapy (n = 32/105; 30.5%) or with a therapy outside current FDA indication (n = 73/105; 69.5%). In patients with no actionable mutation (n = 35/140; 25%), 85.7% (n = 30/35) had a signal-based clinical trial opportunity. The actual overall signal-based matching rate was 17.8% (24/135; vs. 82.2% no-match rate). Within candidates for FDA-approved treatment, 50% (16/32) received targeted therapy while only 6.9% (5/73) were treated with targeted agents outside current FDA indication: mean matching score (number of matched drugs/number of actionable mutations) was 0.6 (range: 0.33-2) and 0.8 (range: 0.17-2), respectively. Only 10% (3/30) were referred to signal-based clinical trials. Survival analysis of LCa, BCa and CRCa patients with actionable mutations who actually received any therapy (n = 66) revealed post-testing survival advantage for target-matched therapy (n = 22) compared to unmatched therapy (n = 44): overall survival (OS) was longer in the matched cohort (mOS: 13.3 months; 95% CI: 11.8-14.8 vs. 10.7 months; 95% CI: 9-12.4 in unmatched) but did not reach statistical significance ( P = 0.09). Progression free survival (PFS) was significantly longer in patients who received matched therapy (mPFS: 11.3 months; 95% CI: 9.9-12.7 vs. mPFS: 6.8 months; 95% CI: 5.1-8.5 in unmatched; P < 0.05). Conclusions: Implementation of liquid biopsy testing is feasible in community practice and impacts therapeutic choices in patients with advanced malignancies. Receipt of liquid biopsy-generated signal-matched precision therapies conferred added survival benefit compared to unmatched therapy. Larger sample size studies are needed to validate these findings.
Blood-based tumor mutational burden from circulating tumor DNA (ctDNA) across advanced solid malignancies using a commercially available liquid biopsy assay.
Authors: Drusbosky Leylah , Bilen Mehmet Asim , Azzi Georges , Barata Pedro C. , Boland Patrick M , Bryce Alan Haruo , Chae Young Kwang , Force Jeremy Meyer , Gutierrez Martin , Kasi Pashtoon Murtaza , Dada Hiba I. , Weipert Caroline , Hensel Chuck , Kiedrowski Lesli A. , Lee Che-Yu , Lefterova Martina , Gandara David R. 
Published: June 2021

3040 Background: Pembrolizumab was recently FDA approved across solid tumors for TMB scores ≥ 10mut/Mb as assessed by next-generation sequencing (NGS) of tissue (tTMB). A prior study of advanced cancer patients treated with immunotherapy found that higher somatic TMB, as defined by the 80th percentile in each histology, was associated with better overall survival. Previously, bTMB assessed by ctDNA from patients with newly diagnosed advanced NSCLC at a score of 16 mut/MB correlated with a tTMB score of 10 mut/MB. TMB levels vary by cancer type, line of treatment, and therapy received; the distribution of bTMB scores across solid tumor types has not been well characterized. Here we report the distribution of bTMB scores in patients with advanced malignancies. Methods: We queried 5,610 samples from patients with different cancer types undergoing clinical cell-free DNA testing (Guardant360; Redwood City, CA) and assessed bTMB scores from October 2020 - January 2021. bTMB score was derived via a previously described computational algorithm examining the total number of synonymous and non-synonymous SNVs and indels across a 1.0MB genomic footprint. We assessed the success rate of bTMB evaluation, overlap with microsatellite instability (MSI) status, and defined the distribution of bTMB levels across indications in this dataset. Results: bTMB score was successfully assessed in 4,275/5,610 (76.3%) samples (Table). The majority of samples (58%) were tested at disease progression as compared to initial diagnosis (42%). The median turnaround time from sample receipt to clinical reporting was 11 days and decreased to 9 days over the course of the study. For the majority of cancer types the 80th percentile TMB was ≥ 16 mut/MB tissue equivalency. Conclusions: Our analysis demonstrates the feasibility of measuring bTMB using a commercially available liquid biopsy assay. bTMB scores trended higher than tTMB previously reported in these cancer types, reflecting the ability of ctDNA to better capture tumor heterogeneity. cfDNA may allow for exploration of bTMB evolution throughout treatment. TMB should be interpreted in the context of disease, treatment, and method; these data establish a pan-cancer benchmark for bTMB which will serve as a resource for further studies.[Table: see text]
Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer.
Authors: Skorupan Nebojsa , Ahmad Mehwish Iqra , Pegna Guillaume Joe , Peer Cody J. , Trepel Jane B. , Lee Min-Jung , Lee Sunmin , Rastogi Shraddha , Sato Nahoko , Figg William Douglas , Hassan Raffit , FitzGerald David JP , Pastan Ira , Alewine Christine 
Published: June 2021

3051 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload to tumors. Previous clinical trials demonstrated that almost all patients formed anti-drug-antibodies (ADAs) to LMB-100 that made administration beyond cycle 2 ineffective. Tofacitinib is an oral JAK inhibitor that prevented formation of ADAs against a closely related immunotoxin in pre-clinical studies. The primary objective of the dose escalation cohort was assessment of safety and tolerability of LMB-100 given with tofacitinib to patients with mesothelin-expressing solid tumors. The primary objective of the expansion cohort was to determine whether co-administration of tofacitinib delays formation of neutralizing LMB-100 ADAs. Methods: Patients (n = 13) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 mcg/kg) and co-treated with oral tofacitinib for the first 10 days of the cycle (10 mg BID). Results: Dose level 1 of LMB-100 was started at 100 mcg/kg one dose level below the single agent MTD. Dose escalation to 140 mcg/kg (dose level 2) resulted in DLTs in 2 of the 3 patients treated: grade 3 cardiac toxicity and grade 4 hyponatremia, both attributed to capillary leak syndrome. Ultimately, 7 patients were treated at dose level 1 without DLTs and 100 mcg/kg was chosen as the LMB-100 dose for the expansion cohort. The last of 6 patients treated in the expansion cohort developed grade 4 pericardial effusion leading to early closure of the study for toxicity. No objective responses were seen. Of the 8 patients who received two cycles of treatment at MTD, 4 met prespecified criteria for ADA prevention, and 2 patients who went on to receive cycle 3 had detectable LMB-100 plasma drug levels after administration. Conclusions: LMB-100 was unable to be co-administered safely with tofacitinib. ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence. Clinical trial information: NCT04034238.
RNA sequencing effectively identifies gene fusions undetected by DNA sequencing in lung adenocarcinomas.
Authors: Zhao Ruiying , Han Yuchen , Xiang Chan , Chen Shengnan , Zhao Jikai , Guo Lianying , Yu Anbo , Shao Jinchen , Zhu Lei , Tian Yue , Yang Fan , Shao Lin , Li Xuejing , Zhang Lu 
Published: June 2021

3052 Background: Next-generation sequencing of DNA, which can provide valid information for clinical therapeutic decision-making, has been widely used in the management of lung cancer especially adenocarcinoma. However, due to its technical limitations for detecting certain alterations such as gene rearrangement, the DNA-based sequencing (DNA-seq) may miss the actionable alteration in some cases, who would have benefited from targeted therapy. The study aimed to evaluate the capability of RNA sequencing (RNA-seq) in identifying DNA-seq undetectable gene alterations in lung adenocarcinomas. Methods: A total of 219 lung adenocarcinomas, which had no driver alteration detected by DNA-seq (OncoScreen Plus, Burning Rock Biotech) and had a max AF ≥5%, underwent capture-based RNA-seq using a custom panel (OncoRNA, Burning Rock Biotech) spanning full transcripts of 115 genes commonly involved in cancer genomic rearrangements. Furthermore, an independent cohort of 100 DNA-seq driver–negative lung adenocarcinomas were also subjected to RNA-seq with the same panel. Results: In the discovery cohort, 166/219 samples (75.8%) generated qualified RNA-seq data for subsequent analyses. RNA-seq identified 44 previously undetected alterations (26.5%), including 40 gene fusions (24.1%), 1 MET exon14 skipping variant ( METex14, 0.6%) and 3 other alternative splicing variants (1.8%). Among them, 14 (8.4%) were potential actionable alterations, consisting of METex14 and in-frame fusions containing functional domain of the driver gene (4 ROS1 fusions, 3 BRAF fusions, 2 NRG1 fusions, 2 EGFR fusions, 1 ALK fusion and 1 MET fusion). In the validation cohort, 69/100 samples (69.0%) generated qualified data. RNA-seq identified 22 DNA-seq undetected alterations (31.9%), with 7 of them being potential actionable fusions (10.1%). ROS1 fusion remained as the most common actionable alteration (n = 3), followed by ALK fusion (n = 2), EGFR fusion (n = 1) and MET fusion (n = 1). Further analyses of the two datasets revealed that lacking sufficient coverage spanning the rearrangement breakpoint in the DNA-seq panel mainly accounted for the failure of DNA-seq on detecting these fusions. This can be improved by increasing the corresponding probe coverage in the DNA-seq panel. In addition, complex genomic rearrangement at DNA level and the presence of repetitive sequence in the intronic region spanning or adjacent to the breakpoint might lead to missed calling of canonical fusions by DNA-seq. Conclusions: Targeted RNA-seq can effectively identify genomic rearrangements that are undetectable by DNA-seq and provide lung adenocarcinoma patients with more opportunities for targeted therapy. Therefore, it should be recommended for all patients, in whom DNA-seq fails to detect driver alteration.