bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extended progression-free survival and long-term safety of nirogacestat in patients with desmoid tumors.
Authors: O'Sullivan Coyne Geraldine Helen , Kummar Shivaani , Steinberg Seth M. , Hogu Murielle , Takebe Naoko , Shah Amisha , Doroshow James H. , Chen Alice P. 
Published: June 2022

11545 Background: Desmoid tumors are rare, locally invasive, soft-tissue neoplasms that can cause significant morbidity and frequently recur despite surgery or radiation. The ongoing phase II trial of nirogacestat, a gamma-secretase inhibitor, in patients (pts) with recurrent, refractory desmoid tumors (NCT01981551), has reported disease stabilization and multiple partial responses as assessed by RECIST criteria (Kummar JCO 2017). Herein, we report long-term outcomes, tolerability, and safety of this study. Methods: A total of 17 pts enrolled in this open label, single arm, phase II study, completing accrual in 2014. Pts received 150 mg nirogacestat orally twice a day in continuous 3-week cycles. Objective treatment response was defined by RECIST 1.1 at cycle 1 and every 6 cycles thereafter using CT (affected area) per the primary study objective; optional MRI assessment was concurrently performed. Yearly CT scans of the chest, abdomen, and pelvis were performed on pts starting in 2016. Results: As of Dec. 31, 2021, 4/17 (23%) pts remain on nirogacestat treatment for over 7 years. The objective response rate has not changed since the 2017 publication [31.25% (5/16 evaluable patients), with an exact two-sided Clopper-Pearson 95% confidence interval of 11.0-58.7%], but the observed extended progression-free survival (PFS) is notable; no RECIST disease progression has been observed for any of the 16 evaluable patients at any point on study. Median time on treatment was 4.14 years (range: 0.17-7.99 years). Most common adverse events remain hypophosphatemia (13/17, 76%; 8 grade 3 [gr3], 5 gr2), diarrhea (13/17, 76%; 1 gr3, 4 gr2, 8 gr1), nausea (11/17, 65%; 11 gr1), AST increase (11/17, 65%; 1 gr2, 10 gr1), and lymphopenia (11/17, 65%; 2 gr2, 9 gr1); no pts required a dose reduction after the second year of therapy. Bone fractures (fx) were reported in 4 pts (3 female/1 male) during the first 4 years of treatment (1 hip fx, 1 rib fx, 2 metatarsal stress fxs). Two of these 4 pts experienced a further fx approximately 1 year later (contralateral metatarsal; hip). Both pts with hip fx were > 10 years post-menopausal. Given median age at enrollment (34 years; range: 20-69 years) and reported fx events, bone health was evaluated with findings in keeping with expected range for age. No secondary malignancies have been identified to date. Conclusions: No patients receiving nirogacestat have progressed after a median of more than 4 years of treatment. The long duration of responses and lack of tumor progressions observed in this trial has informed the design of a phase III trial in pts with progressing desmoid tumors (NCT03785964) that is currently underway. Clinical trial information: NCT01981551.
Efficacy of liposomal doxorubicin in patients with intra- and extra-abdominal desmoid fibromatosis.
Authors: Dorand Rodney Dixon , Cohen Sean , Keedy Vicki Leigh , Borinstein Scott C. , Chugh Rashmi , Davis Elizabeth J. 
Published: June 2022

11581 Background: Desmoid tumors (DT) or aggressive fibromatosis are rare growths of fibroblastic connective tissue that can be locally aggressive but without metastatic potential. Most cases are sporadic, but 5-20% of cases are associated with Familial adenomatous polyposis (FAP). Despite numerous systemic options, optimal choice is unclear, and there is a paucity of studies comparing efficacy based on tumor site. Liposomal doxorubicin (LD) can be an appealing option for DT patients (pts) given its favorable schedule and toxicity profile. In this study, we compared outcomes in pts with intra-abdominal (IA) and extra-abdominal (EA) DT who received LD. Methods: We identified pts with DT who were treated with LD between 1/2010 - and 2/2022 at two sarcoma centers. Tumor and pt characteristics and outcomes were clinically (symptom improvement) and radiologically (RECIST 1.1) assessed. Results: 40 pts with DT treated with LD were identified; 58% female and 42% male. Pt characteristics and outcomes are summarized in Table 1. Primary tumor site was IA in 21 (53%) pts. FAP was present more commonly in pts with IA vs EA DT, 8/21 (43%) and 4/19 (21%), respectively. In the IA cohort, LD was given as first (15/21, 71%), second (10%) or third (19%) line therapy. LD was used more commonly as a later line in the EA cohort with 16%, 52%, 16%, and 16% receiving it in first, second, third, and fourth lines, respectively. 37 pts were evaluable for response. Response rate in the IA cohort treated in first-line was 50% (8 of 16) and 10 of 12 evaluable pts had symptomatic improvement. No first-line responses were seen in the EA cohort. As later lines of therapy, 7/12 pts had disease control in the second line, 6/8 pts in the third line, and 1/2 pts in the fourth line with LD in the IA cohort. 1 patient had fourth line response to LD in the EA cohort. Disease control rate with LD was 72.5% across all pts. Reasons for early discontinuation of LD included progression or lack of symptom improvement (20%), allergic reaction (12.5%), adverse effects (7.5%), or infection (2.5%). No acute or long-term cardiotoxicity was reported. 2 pts had no signs of recurrence or symptoms at follow-up, 33 pts were alive with symptomatic DT, 1 patient died from disease, and 3 were lost to follow-up. Conclusions: In our study, LD provided tumor response, disease control, and symptomatic improvement regardless of location or prior therapy, with responses most frequently seen in IA DT in first line setting. Further studies should include comparison of efficacy, adverse effects, and patient-reported outcomes while accounting for tumor location and line of therapy. [Table: see text]
Interim analysis of a single-center, single-arm, prospective phase 2 study to evaluate the efficacy and safety of benralizumab for alpelisib rash in metastatic PIK3CA-mutant, hormone receptor–positive breast cancer.
Authors: Lacouture Mario E. , Pan Alexander , Dranitsaris George , Harris Ucalene , Chandarlapaty Sarat , Dang Chau T. , Gajria Devika , Gordon Allison , Iyengar Neil M. , Robson Mark E. , Razavi Pedram , Rosen Ezra , Wong Serena Tsan-Lai , Jain Manu , Moy Andrea , Markova Alina 
Published: June 2022

12100 Background: Rash associated with increased peripheral eosinophils develops in approximately 50% of metastatic breast cancer patients receiving alpelisib. Antihistamines and corticosteroids have limited benefit. Refractory rash may lead to decreased dose intensity and affect clinical outcome. Benralizumab is an anti-IL-5Rα chimeric monoclonal antibody that depletes peripheral eosinophils and has demonstrated benefit in eosinophilic asthma and hypereosinophilic syndrome. We investigate the efficacy and safety of benralizumab for the treatment of alpelisib rash. Methods: We performed a single-center, single-arm, prospective phase 2 study to evaluate the efficacy and safety of benralizumab in cancer patients who developed CTCAE grade 2/3 skin events resulting from immunotherapy or targeted therapies with absolute blood eosinophil counts of ≥300/mcl. While remaining on culprit drugs, patients were treated with benralizumab 30mg once every 4 weeks for the first 3 doses followed by once every 8 weeks for 3 additional doses (approved dosing for eosinophilic asthma). Primary endpoint was clinical response measured as reduction in CTCAE grade 2/3 skin event to grade ≤1 by week 4. Secondary endpoints were patient quality of life (QoL) measured by skindex16, safety data, need for supportive oral corticosteroids, and changes in cytokines and eosinophil biomarkers. This interim analysis focuses on patients with PIK3CA-mutant metastatic breast cancer receiving alpelisib. Results: Between September 16th 2020 and January 1st 2022, we enrolled 10 metastatic breast cancer patients with grade 2/3 rash attributed to alpelisib (5 pts with G3). All patients had a reduction of rash to grade ≤1 (n = 10, p < 0.0001), and a decrease in peripheral absolute eosinophils (mean 500/mcl to 0, p < 0.0001). Of these, 6 patients had been on prophylactic oral antihistamines and 2 had oral steroid coadministration. QoL significantly improved (Skindex16 mean score 58 to 16, p = 0.0001) and eosinophils in skin histology decreased per HPF (mean 6.25 to 0.25, n = 8, p = 0.2) by week 4. An increase in IL-5 > 600% and reduction IL-6 and TNF-α > 50% were reported by week 4 and 8. Grade 1/2 mucositis in 4 patients were reported as adverse events. Conclusions: Our findings suggest that benralizumab is safe and effective for the treatment of grade 2/3 rash with eosinophilia related to alpelisib in patients with breast cancer. A reduction in rash severity was evidenced in all patients, along with improved QoL. Larger controlled studies are in development to evaluate the efficacy of benralizumab for the prevention of alpelisib rash. Clinical trial information: NCT04552288.
Evaluation of outcomes in patients (pts) with stage 4 non-small cell lung cancer (NSCLC 4) harboring actionable oncogenic drivers (AOD) when treated prior to report of mutation without tyrosine kinase inhibitors (TKI): An Integra Connect Database (ICD) retrospective observational study.
Authors: Smith Robert E. , Johnson Melissa Lynne , Gordan Lucio N. , Xue Mei , Varughese Prateesh , Dorrow Natalie A. , Wang Brandon , Vaidya Varun , Gart Mike , Gierman Hinco J. , Scott Jeffrey A. 
Published: June 2022

1530 Background: In a prior analysis, we identified 525 pts with newly diagnosed NSCLC 4 harboring AOD in the ICD. Of these, 141 were treated prior to the reporting of AOD with chemotherapy (C), immune checkpoint inhibitor (ICI), or both. This report details the clinical outcomes of these 141 compared to the 384 treated after AOD reported. Methods: Real world data (RWD) were obtained from a curated ICD for pts with NSCLC 4 diagnosed 1/1/2018-12/31/2020 with cutoff of data 3/31/2021. Pts with EGFR, ALK, ROS1, BRAF, MET, RET, HER2, and NTRK were included if their treatment record were captured. Also included were demographics, ECOG score, date of first report of AOD and dates of initiations of first and any second line of therapy and date of apparent death (AD). Outcome measures were time to next treatment or apparent death (TTNT) and apparent survival (AS) (ICD model does not allow date of death per HIPAA de-identified Expert Determination). Descriptive statistics were used with Kaplan-Meier (K-M) estimates and Hazard Ratios (HR) by Cox regression. 3 cohorts were defined: Group (Gr) A with 384 pts treated after AOD reported and used as the comparator; the 141 pts treated before AOD with C, ICI or both were divided into Gr B (n = 51) who subsequently switched to TKI within 35 days and Gr C (n = 90) who did not switch. Results: As shown in data table, AS was significantly worse in Gr B and Gr C, TTNT was significantly worse in Gr C and with worsening trend in Gr B. Two potential confounders were identified: higher ECOG scores might indicate more urgency to assign treatment, but pts with ECOG ≥ 2 were similar in all 3 groups; also, difference in proportion of EGFRm by Group (Gr A 62%, Gr B 57%, and Gr C 29%), but separating cohorts by EGFR mutation status did not alter results. Conclusions: While subject to the limitations of a retrospective observational RWD study, this study strongly suggests outcomes are significantly compromised in pts harboring AOD but who are treated initially with C, ICI or both, even in pts quickly switched to TKI. Since a prospective clinical trial is not ethically feasible, these findings may stimulate review of current guidelines, fuel optimization of universal testing in NSCLC 4, and encourage utilization of liquid or ultra-fast NGS with their rapid turnaround times in order to improve survival in this setting. [Table: see text]
Multiparametric analysis in GBM plasma extracellular vesicles (Evs) and surface marker expression profile.
Authors: Aibaidula Abudumijiti(Zack) , Fain Cori E. , Cumba Garcia Luz , Jung Miyeon , Johnson Aaron J. , Parney Ian F. 
Published: June 2022

2038 Background: Glioblastoma (GBM) is the most common malignant brain tumor with poor clinical prognosis. Management of GBM is hampered by the lack of an accurate test that can be used for differential diagnosis of tumor progression from inflammatory pseudoprogression. Plasma extracellular vesicles (EVs) has been shown to be a promising source for biomarker identification. In this project, we aimed to identify GBM plasma EV markers that could serve as the basis of a liquid biopsy. Methods: Sample preparation, assay controls and instrument calibration were performed following MIFlowCyt-EV guideline. Plasma samples were subjected to 2-step centrifugations to remove cell debris and platelets. 10ul of plasma sample was diluted with 90ul filtered PBS, then stained for EV surface markers including CD9, CD31, CD45, CD41a and CD11b, as well as actin phalloidin. Stained plasma samples were purified using IZON qEV1/70nm column, then EV fractions were analyzed using full spectrum Cytek Aurora flow cytometer. Clustering analysis was performed on EV events (CD9 +/ actin phalloidin -) using t-SNE and FlowSOM extensions from FlowJo plugins. Results: Compared to normal donors, GBM plasma EVs were bigger in size (higher SSC value) and expressed higher levels of CD9, CD31, CD45 and CD11b while ND plasma EVs had higher CD41a expression. t-SNE and FlowSOM analysis demonstrated that GBM plasma EVs had a unique surface marker expression profile compared to ND EVs. It also showed 10 EV sub-populations that differed in size as well as various surface marker expression levels. Four of these subpopulations were enriched in GBM EVs, while three of these were enriched in ND EVs. Conclusions: This multiparametric analysis revealed that GBM plasma EVs had a unique surface marker expression profile compared to ND plasma EVs. Further separation and molecular profiling analysis based on each sub population could reveal EV biomarkers that are unique to each sample population.
Prevalence of high tumor mutational burden (TMB-H) and microsatellite instability-high (MSI-H) status in neuroendocrine neoplasms.
Authors: Padda Sukhmani Kaur , Aggarwal Rahul Raj , Ashok Arya , Mauer Elizabeth , Shirazi Maryam , Bergsland Emily K. 
Published: June 2022

2625 Background: Neuroendocrine neoplasms (NENs) encompass a rare group of tumors arising in nearly any organ site. Patients with advanced-stage NENs have limited treatment options, and molecular profiling is not routinely performed in NENs. However, given tissue-agnostic FDA approvals for immunotherapy in biomarker-selected solid tumors, we sought to assess the frequency of TMB-H and MSI-H in NENs by organ site and in comparison to non-NEN counterparts. Methods: We retrospectively analyzed de-identified records from the Tempus database of NENs sequenced with the Tempus xT assay (DNA-seq of 595-648 genes at 500x coverage). Patients were included if their primary cancer arose in the lungs, GI tract (esophagus, stomach, small bowel, colon, rectum), pancreas, or prostate. Histologic diagnoses were grouped as NENs (including high grade or low/intermediate grade), and non-NENs (e.g. adenocarcinoma, squamous cell carcinoma) based on data abstracted from pathology reports. TMB-H was defined as ≥ 10 mutations/megabase. MSI-H was calculated as previously published (PMID: 31570899). Statistical comparisons were limited to groups of 10 or larger. Results: We characterized a total of 1,477 NENs from the following anatomic sites: lung (64%, N=951), pancreas (15%, N= 220), GI (15%, N= 224) and prostate (6%, N=82). TMB-H was most common in NENs arising in the lungs (17%, N=155), followed by the pancreas (5.4%, N=11), GI tract (4.8%, N=10), and prostate (3.8%, N=3) (p< 0.001). Overall, TMB-H was more common in high-grade NENs compared to low/int-grade NENs [17% (N=147) vs. 6.2% (N=31), P<0.001]. This was also observed in lung NENs [high-grade 19% (N=135) v low/int grade 10% (N=19), P=0.006], with other organ site analyses limited by sample size (although a similar trend was noted for GI NENs). The majority of patients with TMB-H lung NENs had a current or prior smoking history (94%, N=119). Overall, TMB-H was similar in NENs compared to non-NENs [13% (N=179) vs. 12% (N=3018), P=0.4]. However, in the pancreas, TMB-H was more common in NENs vs. non-NENs [(5.4% (N=11) v 1.6% (N=59), P<0.001] while the reverse was true in lung NENs [17% (N=155) v 22% (N=2006), P=0.001]. MSI-H was observed in only 0.9% (N=12) of NENs overall, including in 0.4% (N=4) of lung, 1.4% (N=3) of pancreas, 1.9% (N=4) of GI, and 1.2% (N=1) of prostate NENs. MSI-H status was less common in NENs compared to non-NENs [0.9% (N=12) vs. 2.5% (N=614), P<0.001]. Conclusions: In this real-world NEN cohort, the actionable molecular alterations of TMB-H (13%) and MSI-H (0.9%) were observed. Taken together, the data suggest that molecular profiling (regardless of grade) may help identify a small but meaningful subset of patients with NENs who may benefit from immunotherapeutic treatment approaches. Furthermore, the identification of MSI-H NENs has important implications related to germline testing.
Inpatient complications of immunotherapy-associated colitis in solid malignancies: Real-world data analysis.
Authors: Pichardo Rayli , Abu Omar Yazan , Wang Ding 
Published: June 2022

2657 Background: Immune checkpoint inhibitors (ICPis) and their containing regimens have been proven beneficial for the treatment of multiple malignancies, while immune-related adverse events (IrAEs) have become constant safety challenges in their clinical management through all ICPi therapies. Diarrhea resulted from immune-mediated colitis has been one of the most common IrAEs. The Aim of this study is to evaluate the real-world incidence and factors that contributed to colitis among patients hospitalized for anti-neoplastic immunotherapy using a large nation-wide database. Methods: We performed a retrospective analysis with the National Inpatient Sample (NIS) using ICD10-CM and PCS codes to identify patients with solid tumors hospitalized for immunotherapy between October 2015 and 2018. A comparison analysis was made between patients who developed diarrhea (or colitis) or not during their hospitalizations. Patient characteristics included past medical history, location, charges, length of stay (LOS) and inpatient complications variables, data were compared between the two groups. Results: The data from 5,795 admissions for immunotherapy were included, of which 615 (10.61%) inpatient events were complicated by diarrhea (colitis). Patients with diarrhea tended to be males (60%), slightly older at age 57 years, higher percentage of white patients (78%) though not statistically significant from those who did not have colitis. On the other hand, the length of inpatient stay was statistically longer (7 vs 5 days, p < 0.05), and associated with higher expenses ($214,612 vs $ 134,195, p < 0.05). In addition, inpatient admissions with colitis were more towards larger academic hospitals (80% vs 67%, p = 0.01). ICPi-treated patients with genitourinary (GU) cancers were observed more with colitis among these admissions (27% vs 15%, p < 0.05). Though no difference from mortalities observed, serious complications, such as acute kidney injury (AKI) (44% vs 20%, p < 0.05) and non-septic shock rates were higher (7% vs 2%, p = 0.01) among colitis admissions. Conclusions: This real-world data analysis of inpatient admissions from ICPi-treated cancer patients demonstrated colitis with diarrhea as a common safety concern over ICPi-therapies, a higher risk among patients of GU primaries, higher risk with serious medical complications: acute renal dysfunction and non-septic shock, led to increased length of stays (LOS) and financial burden. Special attention and further study may be placed among ICPi-treated GU cancer patients. [Table: see text]
Increased systemic toxicities from antibody-drug conjugates (ADCs) with cleavable versus non-cleavable linkers: A meta-analysis of commercially available ADCs.
Authors: Wynn Carrie , Patel Ritesh , Hillegass William B. , Tang Shou-Ching 
Published: June 2022

3032 Background: Though in theory ADCs should deliver high-dose chemotherapy directly to target cells with few systemic effects, in clinical practice numerous side effects have been observed. We hypothesized that ADCs with cleavable linkers would have more systemic toxicities than those with non-cleavable linkers due to the increased free payload released systemically. To compare their side effect profiles, we conducted a meta-analysis of adverse events (AEs) of commercially available ADCs. Methods: Systematic review yielded 12 phase II/III clinical trials that led to the FDA approval of commercially available ADCs. Polatuzumab vedotin was not included because it was only studied in combination with other agents. Any grade AEs and grade ≥3 AEs occurring in at least 5% of patients in each study were recorded. The estimated inverse variance weighted absolute average risk and 95% confidence interval (CI) were estimated for each AE. Absolute risk differences and 95% CIs were estimated by linker type. Results: Data from 2,417 patients treated with 9 ADCs were pooled. 7 ADCs had cleavable linkers (N = 1,082), and 2 had non-cleavable linkers (N = 1,335). At least half of studies reported thrombocytopenia, neutropenia, anemia, increased AST and ALT, nausea, vomiting, diarrhea, hypokalemia, headache, and fatigue, as well as rates of all grade and grade ≥3 AEs. AEs ≥ grade 3 occurred in 43% of patients overall, 47% in the cleavable linker arms and 34% in the non-cleavable arms. This was significantly different (weighted risk difference -12.9%; 95% CI -17.1% to -8.8%). There was also a significant difference favoring non-cleavable linkers for ≥ grade 3 neutropenia (-9.1%; 95% CI -12% to -6.2%) and ≥ grade 3 anemia (-1.7%; 95% CI -3.3% to -0.1%). Cleavable linkers were significantly associated with increased AST all grade (3.9%; 95% CI 0.3% to 7.5%) and increased ALT all grade (3.7%; 95% CI 0.2% to 7.3%), though notably the CI approached 0 on the low end of difference for each. There was no significant difference in rates of all grade AEs or in rates of discontinuation due to AEs. There was no significant difference in rates of all grade nausea, vomiting, diarrhea, hypokalemia, or headache. Finally, there was no significant difference in rates of grade ≥3 thrombocytopenia, increased AST/ALT, or fatigue. Conclusions: Cleavable linkers appear to have significantly higher rates of ≥ grade 3 AEs and neutropenia within the limitations of this non-randomized comparison and treatment of heterogeneous malignancies. The increased payload in the circulation likely accounts for this; however, it may also make them more efficacious, as suggested by the results of the DESTINY-Breast03 trial. In the final analysis, we will compare the efficacy of cleavable vs non-cleavable ADCs indirectly using the standard of care for each tumor and line of therapy, with the exception of breast cancer.