bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial findings of the first-in-human phase I study of AGEN2373, a conditionally active CD137 agonist antibody, in patients (pts) with advanced solid tumors.
Authors: Tolcher Anthony W. , Carvajal Richard D. , El-Khoueiry Anthony B. , Ortuzar Feliu Waldo , Zang Hong , Ancukiewicz Marek , Shapiro Irina , Strauss James Fredric 
Published: June 2021

2634 Background: CD137 is a member of the tumor necrosis factor receptor superfamily that functions as a potent co-stimulator of both adaptive and innate immune cells, thus making it an attractive target for cancer immunotherapy. The development of first-generation anti-CD137 antibodies has been hampered by limited clinical activity or dose-limiting hepatotoxicity. AGEN2373 is a novel, conditionally active CD137 agonist antibody designed to selectively enhance tumor immunity while mitigating side effects associated with systemic activation of CD137. Here we report the initial findings from the first-in-human evaluation of AGEN2373 in pts with advanced solid cancers. Methods: Pts received AGEN2373 on day 1 of a 28-day cycle (Q4W dosing), with cycles repeated until progression, intolerable toxicity or investigator/patient decision. Dose-escalation followed a standard 3+3 scheme, with planned dosing of 0.03, 0.06, 0.3, 1.0, 2.0, and 3.0 mg/kg. The primary objective was to determine the safety, tolerability, and dose-limiting toxicity (DLT) of AGEN2373 as monotherapy. Secondary objectives included pharmacokinetics (PK) and preliminary clinical activity. Adverse events (AEs) were reported per CTCAE v5.0 and DLTs evaluated within a 28-day window. For PK analyses, serum AGEN2373 concentrations determined using a validated bioanalytical assay and simultaneously analyzed by an NLME model. Antitumor activity was assessed using RECIST v1.1. Results: As of January 21 2021, 19 pts (median age 54.4 years, range 33-74; 11 men, 8 women; 7 with prior immunotherapy) have been treated with AGEN2373 Q4W at escalating doses from 0.03 – 2.0 mg/kg across 5 cohorts. Eleven pts (57.9%) experienced treatment-related AEs; none were grade 3 or higher. The most common events were fatigue (4 pts, 21.1%) and nausea (2 pts, 10.6%). No DLTs have been observed. Importantly, no drug-related elevations in liver transaminases (ALT, AST) or bilirubin beyond 1 grade have been seen. AGEN2373 PK were consistent with linear elimination. Prolonged disease stabilization as best response occurred in 5 pts (26.3%; range, 6-41 weeks); three of which were seen in heavily pretreated pts with metastatic leiomyosarcoma, including one who had progressed on prior combination checkpoint immunotherapy. Enrollment into the 3.0 mg/kg cohort is continuing. Conclusions: AGEN2373 demonstrates good tolerability in pts with advanced solid tumors, with a safety profile characterized by a lack of hepatotoxicity frequently observed with CD137-targeting antibodies. These findings underscore the suitability of AGEN2373 as a potential partnering agent for other immunomodulatory agents, including planned expansion as combination therapy with balstilimab (anti-PD-1). Clinical trial information: NCT04121676.
Late immune-related adverse events with immune checkpoint inhibitors.
Authors: Ip Andrew , Wang Shuo , Cheruku Divya , Krishnamurthy Kanchi , Weber Melinda , Sinclaire Brittany , Gourna Paleoudis Elli , Alaoui Adil , lev-Ari Shaked , Serzan Michael T , Adams Shari , Kaufman Jordan , Parikh Sahil B. , Tonti Emily , Muller Eric , Williams Aquino , Ahn Jaeil , Pecora Andrew , Atkins Michael B. , Shah Neil J. 
Published: June 2021

2635 Background: Immune Checkpoint Inhibitors (ICIs) are associated with unique immune-related adverse events (irAEs). IrAEs can occur at any timepoint of ICI treatment. Late irAEs are not well reported in the literature. Herein, we attempt to characterize irAEs that occur 6-month, one year and two years after ICI treatment initiation. Methods: We identified patients treated with ICIs (anti-CTLA-4, anti-PD(L)-1 either alone or in combination or with chemotherapy) across Hackensack Meridian Health hospital and MedStar Georgetown University Health systems from 12011 to 4/2018. Patients' baseline demographics, treatment history, and irAEs were collected from EHR. CTCAE V4.03 was used to grade irAEs. Results: We identified 1332 patients treated with 1443 unique ICIs. The ICI therapies were nivolumab 38% (543), pembrolizumab 23% (332), ipilimumab plus nivolumab 12% (180), ipilimumab 11% (161), Atezolizumab 3% (47) and others 13% (180). Tumor types were lung cancer 34% (496), melanoma 27% (389), GI cancers 6% (92), kidney cancer 6% (87), and other cancers 26% (379). The median age was 66 (21-87), age >75 37% (541), Caucasian 67% (970). We identified a total of 911 any grade irAEs among 37% (552) therapies. Among, 911 irAEs, grade 1-2, grade ≥3 and unknown grade irAEs were 39% (572), 12% (182) and 11% (157), respectively. The most common any grade irAEs were skin rash 22% (202), colitis 13% (120), and hepatitis 12% (108). 84% of all irAEs and 85% of ≥ Grade 3 irAEs occurred within 6 months of treatment initiation. Of the 350, patients on active treatment at six months, 37 % (132) and 7% (26) developed any grade and grade ≥3 irAEs, respectively. irAEs that had > 10% of their occurrences after six months were skin rash and colitis 14% each. Other common irAEs were hypothyroidism, hepatitis, joint pain, pruritis and pneumonitis at 7% each. Among 170 patients on active treatment at one year, 37% (62) and 7% (12) developed any grade and grade ≥3 irAEs respectively. irAEs with >10% incidence after one year of treatment were rash 19% and hepatitis 13%. Conclusions: Our RWE findings suggest although 85% irAEs occurs within the first six months of treatment, late irAEs can occur with ICI treatment. The incidence and pattern of late irAEs appears similar to early irAEs, (e.g., skin rash, colitis, hypothyroidism and hepatitis) with pneumonitis being a notable exception. It is uncertain if these results will be influenced by changing patterns of ICI use (e.g. different diseases and/or regimens) over time.[Table: see text]
Infections in cancer patients treated with immune checkpoint inhibitors: Data from randomized trials.
Authors: Solinas Cinzia , Morelli Anna Maria , Luciani Andrea , Ghidini Antonio , Petrelli Fausto 
Published: June 2021

2637 Background: Febrile neutropenia and infections are well studied complications of chemotherapy (CT) and some targeted agents employed in oncology. Less is known about the risk of infection associated with the use of immune checkpoint inhibitors (ICIs) in cancer patients. The present systematic review and meta-analysis was performed to address this question in patients diagnosed with solid tumors enrolled in randomized trials employing ICIs as experimental treatment. Methods: The Cochrane Library, EMBASE, and Pubmed databases were searched from inception through December 1st, 2020. Randomized clinical trials comparing any ICI alone, with CT, or with other agents vs CT, placebo, or other agents in patients with solid tumors were included. Two independent reviewers used a standardized data extraction and quality assessment form. Discordant cases were discussed with a third independent investigator. The following information was extracted: baseline study characteristics, including the primary tumor, author, year of publication, type of trial, type of disease, and the type of therapy (experimental and control arms); and the incidence of any-grade (grades [G] 1–5), low-grade (G1–2), and high-grade (G3–4), fatal event (G5) infections, and type of event. Random or fixed-effect models were used according to the statistical heterogeneity. Results: 36 randomized clinical trials were deemed eligible. The total population reached 21451 patients. In the pooled analysis, the use of ICIs was associated with a similar risk of all-grade infections (relative risk, RR = 1.02; 95% CI 0.84–1.24; P = 0.85) compared to non-ICI treatments (G1-5 events: 9.6 vs. 8.3%). When the ICIs alone arms were compared to CT, the experimental arms were associated with a 42% less risk of all-grade infections (RR = 0.58, 95% CI 0.4–0.85; P = 0.01; N = 18 studies). Compared to CT, the combination of ICIs and CT increased the risk of all-grade infections (RR = 1.37, 95% CI 1.23–1.53; P < 0.01; N = 13 studies) and severe infections (RR = 1.52, 95% CI 1.17–1.96; P < 0.01; N = 12 studies). Fatal infections were similar in the experimental and control arms (0.5%). Conclusions: In patients with advanced solid tumors, when ICIs were administered with CT, the risk of all-grade and G3-5 infections was significantly increased. Compared to CT alone, ICIs were safer and their use should be recommended for frail patients. Further studies are required to identify high-risk patients and evaluate the need for CT dose reduction or prophylactic myeloid growth factors use.
Pseudoprogression and cancer immunotherapy: A seven year retrospective study of rate, temporal course, and predictive markers in an Irish tertiary referral center.
Authors: McKendry Kate , Desmond Fiona , Ward Cian , Duffy Austin G 
Published: June 2021

2651 Background: Immunotherapy is a relatively new treatment strategy which has achieved unprecedented clinical efficacy in many advanced malignancies. However, the pattern of tumour response to immunotherapy is distinct from other therapies and poses major challenges to clinicians. One such challenge is pseudoprogression. The aim of this study was to assess the current management of patients on immunotherapy with radiological evidence of disease progression at first restaging imaging in an Irish cancer centre, and to determine the rate, time course, and predictive markers of pseudoprogression in those patients treated beyond progression (TBP). Methods: Patients treated with immunotherapy for metastatic malignancy in MMUH between March 2013 and September 2020 were retrospectively drawn. Inclusion required follow-up restaging imaging every 4-12 weeks for the duration of treatment. Patterns of response during immunotherapy were established from radiology reports and categorized as stable (SD), response (R), mixed disease (MD), or progressive disease (PD). Pseudoprogression was defined as progression/ mixed disease at first restaging compared to baseline followed by subsequent response/stable disease. Results: The cohort of 228 patients was comprised of 80 NSCLC, 74 melanoma, 25 RCC, 19 gynaecological, 14 gastrointestinal, 6 breast, 1 ESSCLC, and 9 other cancer patients. Median age was 61.16 (IQR 49.47-69.44). Therapeutic agents were anti-PD1 alone (176) or in combination with targeted therapy (6) or CTLA4 (13), CTLA4 alone (15), and anti-PD-L1 alone (13) or in combination with chemotherapy (5). At first restaging, the number (%) classified as SD, R, MD, and PD, respectively, was 29 (12.8), 62 (27.2), 16 (7), and 76 (33.3). Treatment was stopped prior to restaging in 44 (19.3) cases. Of the 92 patients with mixed/ progressive disease, 41 were TBP and 51 were not treated beyond progression (NTBP). Evidence of radiological progression and worsening performance status (PS) were the most common reasons given by clinicians for NTBP. Of those TBP, 20 had subsequent response/stable disease, occurring at a median of 105.50 (range 58.0-420) days after the initial restaging scan and giving an overall pseudoprogression rate of 8.8%. At one year, 100% of the pseudoprogression group was alive. The neutrophil-lymphocyte ratio (NLR) was significantly lower in the pseudoprogression group compared to those with true progression (p = 0.006). There was no significant difference in performance status between the two groups. Conclusions: Pseudoprogression on cancer immunotherapy is real but uncommon, with an overall incidence of 8.8%. It can occur any time up to 420 days after initial progression and indicates a high likelihood of > 1 year survival. A low NLR may be a useful predictor of pseudoprogression but a technological solution is likely needed.
Genes copy number as a marker of low-invasive assessment of rectal tumors radiotherapy effectiveness.
Authors: Gusareva Marina A. , Kosheleva Natalia G , Fatkina Natalya B. , Solntseva Anna A. , Rozenko Lyudmila Ya. , Donskaya Aliya K. , Vasilieva Ekaterina O. , Karnauhova Elena A. , Krokhmal Julia N. , Gabrichidze Peter N. , Dontsov Vladimir A. , Gaziev Umar M. , Legostaev Vladislav M. , Shlyakhova Olga V. , Lyman Natalia A. , Balitsky Gennady V. , Nosov V. A. , Kravchenko A. B. , Kutilin Denis S. 
Published: June 2021

3025 Background: Radiotherapy (RT) is a key component of rectal cancer (RC) treatment, however, nonresponsiveness in patients to preoperative RT is very common, usually due to the tumor cells radioresistance, mediated by their molecular characteristics, such as gene expression. The features of mRNA rapid degradation in extracellular environment make this indicator unsuitable for low invasive diagnostics. The solution to this problem is possible by switching to a more stable marker - the copy number variation (CNV), which can be determined in the extracellular DNA (cfDNA) circulating in the blood plasma. Therefore, the aim of the study was to identify the relationship between the level of genes CNV in the cfDNA of blood plasma with the effectiveness of rectal tumors RT. Methods: We used cfDNA preparations from blood plasma obtained before RT from 200 patients with RC, as well as from blood plasma of 50 apparently healthy donors (AHD, without cancer). RT was carried out on a linear accelerator Novalis TX (SFD = 2.4 Gy, TFD = 54.0 Gy). Blood samples were separated into plasma and cell fraction by centrifugation. Isolation of cfDNA from blood plasma was performed using the phenol-chloroform method. Determination CNV of 5 genes (BRCA2, H2AX, CASP9, RBBP8 and BCL2) was performed using Real-Time qPCR method. Differences were assessed using Mann-Whitney test; the Bonferroni correction was used to correct multiple comparisons. Results: RT results for 200 patients allowed them to be divided into 2 groups. After RT, 120 patients showed complete tumor regression (group 1), 50 patients showed insignificant tumor regression and 30 patients did not regress (group 2). In cfDNA of group 1 patients was found CNV decrease (p < 0.05) of H2AX and RBBP8 genes by 2.5 and 2.0 times, respectively, relative to AHD group. In the cfDNA of group 2patients an increase (p < 0.05) of BRCA2, H2AX, RBBP8 and BCL2 genes CNV was found by 2.0, 2.2, 2.0 and 2.0 times, respectively, relative to AHD group. Only 2 genes CNV differed in group 1 from group 2: the CNV of H2AX and RBBP8 was 5.4 and 4.0 times less respectively (p < 0.005). Conclusions: Thus, it has been found that increased CNV of genes BRCA2, H2AX, BCL2, RBBP8 in blood plasma cfDNA is associated with low efficiency of RT. At the same time, the CNV of H2AX and RBBP8 genes in cfDNA of patients with RC has the greatest potential as a marker of the RT effectiveness.
Correlation between different levels of HER2 expression in circulating tumor cells (cHER2 ratio) and metastatic behavior in stageIVaggressive breast cancer.
Authors: D'Amico Paolo , Reduzzi Carolina , Gandini Sara , Gerratana Lorenzo , Qiang Wenan , Zhang Qiang , St-Pierre Frederique , Zhang Youbin , Shah Ami N. , Davis Andrew A. , Jacob Saya , Vagia Elena , Wehbe Firas Hazem , Behdad Amir , Curigliano Giuseppe , Cristofanilli Massimo 
Published: June 2021

3036 Background: The presence of HER2 expressing (HER2+) circulating tumor cells (CTCs) occurs often in metastatic breast cancer (MBC) patients (pts). We have previously showed that the ratio among CTCs expressing high level of HER2 and the total number of HER2+ CTCs (circulating HER2 ratio, cHer2 ratio) has a prognostic role in MBC patients. Here we further investigate the role of the cHER2 ratio in the process of metastatic spread. Methods: Under IRB-approved study we prospectively analyzed blood samples of patients with MBC enrolled before starting a new line of therapy. Samples were collected from pts treated at Northwestern University (Chicago, IL) between 2016 and 2020. CTCs were enumerated through CellSearch (Menarini Silicon Biosystems, Bologna, Italy) and characterized for HER2 expression using the CellSearch CXC Kit. HER2+ CTCs were divided in 3 different categories (1+,2+,3+) leaning on fluorescence intensity. Pts with <5 CTCs (stage IV indolent) were excluded from the analysis. The cHER2 ratio, defined as the sum of 2+ CTCs and 3+ CTCs divided by the total number of HER2+ CTCs, was used to split the remaining pts in 2 different cohorts: cHER2 ratio high (> 0.75) (cHER2high) and cHER2 ratio low (≤0.75) (cHER2low). The frequency of each metastatic site (i.e. liver, lung, central nervous system, bone, lymph nodes, skin/soft tissue, serosa) and the total number of different sites involved (1-7, ≤2 and >2 sites) were compared among the two sub-populations and analyzed through Fisher exact test. Results: Out of 98 pts enrolled, 77 were classified as cHER2low and 21 as cHER2high. We observed a higher frequency of oligometastatic pts (≤2 sites involved) in the cHER2high cohort (16, 76%), compared to only 29 (37%) in the cHER2low (p<0.005). Moreover, the cHER2 ratio was associated with a tropism toward specific sites of disease spread with higher incidence of liver, lung and lymph nodes metastases in the cHER2low cohort (p<0.05). No other statistical associations were observed in respect of specific organ tropism. The frequency of involvement for each metastatic site among the two cohorts are reported in the table. Conclusions: Measuring CTCs enumeration and HER2 expression we identified two cohorts, cHER2high and cHER2low, associated with distinct patterns of metastatic spread. The cHER2low pts were correlated to multiple sites of metastatic involvement, with particular tropism toward liver, lung and lymph nodes. These results confirm the prognostic role of the cHER2 ratio, suggesting a peculiar biological meaning of the HER2+ 1+ CTCs.[Table: see text]
Targeted ctDNA sequencing analysis reveals concurrent genomic alterations and its impact on TKI and immune checkpoint inhibitor therapy in advanced NSCLC from Asian population.
Authors: Wu Wei , Lim Jing Shan , Poh Jonathan , Bivona Trever G. 
Published: June 2021

3042 Background: For advanced non-small cell lung cancer (NSCLC), liquid biopsy followed by targeted DNA sequencing is used in the clinical setting for driver-gene identification in circulating tumor DNA (ctDNA), tumor evolution and treatment monitoring. To understand the complexity and diversity of genetic alterations in advanced NSCLC, we examined the genetic landscape of late-stage NSCLC from an Asian population and its association with tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI) treatment. Methods: Plasma cell-free DNA (cfDNA) from 142 Asian patients with advanced NSCLC underwent real-world testing in a CAP-accredited and CLIA-certified central laboratory. We analyzed genetic alterations in cfDNA using an amplicon-based next-generation sequencing assay that covers 61 NSCLC related genes. 88 patients (62%) had received one or more lines of treatment. A similar cohort from Caucasian NSCLC was used for comparison (Blakely et al. Nat Genet 2017). Systematic co-mutation analysis, functional annotation and pathway enrichment analysis were performed. Results: The top 10 mutated genes in the Asian cohort were EGFR (66.2%), TP53 (48.6%), KRAS (11.3%), BRCA2 (7%), CTNNB1 (6.3%), PIK3CA (6.3%), SMAD4 (5.6%), BRCA1 (4.9%), MET (3.5%) and RB1 (3.5%). EGFR mutations occurred at hotspots in exons 18 – 21, with exon19 deletion, L858R, T790M, C797S, and G719A being the top-ranking alleles, similar to the Caucasian NSCLC cohort. Concurrent KRAS and EGFR mutations were higher in Asian cohort (8.5%) than in Caucasian cohort (0.56%). A rare PD-L1 structural variant (1.1%), reported to be related to immune evasion in other cancers (Kataoka et al. Nature 2016), was detected in the EGFR-mutated subgroup. Within the first line TKI-treated group, responders (CR+PR) harbored more alterations than non-responders (p < 0.017). Among ICI-treated NSCLC patients (anti-PD-1/PD-L1 mono- or polytherapy), responders from 1st line or 2nd line ICI treatment harbored fewer mutations than non-responders, but the distribution of mutational allele frequency (MAF) in responders was shifted to the right (more clonal than subclonal mutations). Functional annotation suggests that concurrent mutated genes and copy number alterations in advanced EGFR-mutant NSCLC were enriched in cell cycle, DNA repair, PI3K-AKT signaling pathways. Conclusions: We characterized the ctDNA-derived genetic landscape of advanced NSCLC from an Asian population and dissected mutated genes with the outcome of TKI or ICI treatment. We also report a rare PD-L1 structural variant in the EGFR mutated subgroup, which could be associated with immune evasion. Our analyses support the occurrence of clonal and subclonal driver co-alterations in EGFR-driven NSCLC, underlining the clinical utility of ctDNA detection for NSCLC diagnosis and treatment selection.
Prediction of adenocarcinoma among other subtypes of lung cancer from CT using deep learning.
Authors: Waterfield Price Noah , Janes Sam , Gleeson Fergus , Massion Pierre P. , Lehman Jonathan 
Published: June 2021

3057 Background: Determination of histological subtype is a crucial step in the management of patients with lung cancer as it informs prognosis and management. The identification of adenocarcinoma (AC) is particularly important with new targeted treatments becoming available. Although the gold standard for diagnosing histological subtype is pathological analysis of tissue samples, interventions can present a risk of complication. Imaging-based, computational approaches to distinguishing malignant from benign lesions have shown promising results. A similar approach may also be applied to determining histological subtype, which could provide an early, non-invasive alternative or complimentary method to biopsy. Here, we investigate an imaging and machine learning method to predict the subtype of a malignant lung lesion. Methods: A dataset of 1493 primary lung cancer patients was collected, of which 943 were diagnosed with AC. The histological subtypes of the non-AC patients were, squamous-cell carcinoma (158), large-cell carcinoma (69), small-cell carcinoma (33), other subtypes (27), or unreported non-AC subtype (253). This consists of retrospectively collected CT images and demographic data from both screening and clinical settings, across 41 academic and community centres from the USA (35 centres), and Europe (6 centres). All patients included were aged ≥ 18 with no history of cancer in the last 5 years. Each CT was manually curated. Given a CT-image of a lung nodule, a Convolutional Neural Network (CNN) was trained to classify nodules as AC or non-AC, using 8-fold cross-validation. A logistic-regression model based on clinical parameters was also trained using the same data and cross-validation. Classification performance was evaluated using the Area-Under-the-ROC-Curve (AUC), sensitivity, and specificity. Confidence intervals and P values were calculated by nonparametric bootstrapping. Results: The median age of AC patients was 66 yr (non-AC 67 yr) and 62.3% of them were male (non-AC 57.8%). The median pack years for AC patients was 38.4 p.yr (non-AC 50.0 p.yr). For AC tumours, the median diameter was 14.0 mm (non-AC 14.0 mm) and the mean diameter was 15.0 mm (non-AC 16.4 mm). The AC-classification results are tabulated below. The CNN classification performance is significantly better than the logistic-regression baseline across all three measures of performance P <.001. AC classification results. All values are given in % with 95% confidence interval bounds in parentheses. Conclusions: We find that the CNN significantly outperforms a logistic model in identifying AC from other histological subtypes. With further development, this algorithm could prove a useful tool to aid management of lung cancer patients.[Table: see text]