bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final analysis of the BIMES trial, a phase II single arm study assessing efficacy and safety of bintrafusp alfa in previously treated advanced malignant pleural mesothelioma (GECP 20/09).
Authors: Nadal Ernest , Martín-Martorell Paloma , Benítez Jose Carlos , Sala Maria Angeles , Cedres Perez Susana , Fernandez Carlos Álvarez , Domine Manuel , Sais Elia , Saigi Maria , Lopez Castro Rafael , Vilà Laia , Massuti Bartomeu , Campelo Rosario Garcia , Provencio Mariano , Campos Begona 
Published: June 2024

8084 Background: Transforming growth factor β (TGF-β) is involved in tumor immune evasion and epithelial–mesenchymal transition (EMT). As TGF-β upregulation and EMT are associated with resistance to anti-PD1 therapy, we evaluated the efficacy of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in malignant pleural mesothelioma (MPM). Methods: Patients with advanced MPM who were previously treated with platinum-based chemotherapy were enrolled and received bintrafusp alfa 1200mg/m2 every 2 weeks until progression or for a maximum of two years. The primary objective was to determine the progression-free survival (PFS) by modified RECIST v1.1. assessed by the investigators. The expected median PFS was 4.5 months. Secondary objectives were overall response rate, duration of response, overall survival (OS) and safety. Results: Between October 2021 to March 2023, 47 patients were enrolled. Mean age was 70 years (41-84) and 36 (78.3%) were males. Most patients had epithelioid histology (82.9%) and had received only 1 prior line of therapy (84.8%). With a median follow-up of 11.5 months, 43 patients had disease progression and 24 patients died. The median number of doses administered was 4 (1-21) and reasons for treatment discontinuation were disease progression (82.6%), toxicity (6.5%), investigator decision (4.4%) and death (6.5%) by tumor progression. The median PFS was 1.9 months (95% CI 1.7 – 5.4) and the 6 month-PFS rate was 15.9%. Disease control rate was 34.8% (95% CI 22.2-49.9) consisting of 2 patients with partial response and 13 patients with stable disease as best response. The median OS was 11.9 months (95% CI 4.4 – not reached) and 6, 12 and 18-month OS rate was 65.3%, 46.5% and 26.6%, respectively. No significant differences in OS and PFS were observed based on MPM histological subtype. Grade 3-4 treatment-related adverse events occurred in 16 (34%) patients, anemia being the most common (n = 5); skin toxicity (n = 3); colitis (n = 2); adrenal insufficiency, acute kidney injury, allergic reaction, lipase, and amylase increased (n = 1 each). Conclusions: Bintrafusp alfa did not reach the expected efficacy in patients with advanced malignant pleural mesothelioma previously treated with platinum-based chemotherapy. Clinical trial information: NCT05005429 .
IGF-1R, E-cadherin, N-cadherin, and occludin gene expression and resistance to EGFR tyrosine-kinase inhibitors in patients with lung adenocarcinoma in Serbia.
Authors: Jokic Vera , Cavic Milena , Spasic Jelena , Marinkovic Mladen , Savic Vujovic Katarina , Jankovic Radmila , Zaric Bojan 
Published: June 2024

8524 Background: Mutations in epidermal growth factor-receptor ( EGFR) are found in approximately 10% of patients with lung adenocarcinoma in Serbia. EGFR tyrosine-kinase inhibitors ( EGFR-TKIs) is a safe and effective targeted therapy. However, most patients develop resistance. Acquired resistance to EGFR-TKI is defined as disease progression after achieving response or stable disease and there is a possible molecular association with epithelial-mesenchymal transition (EMT), particularly N-cadherin, E-cadherin, occludin and insulin-like growth factor-1 receptor (IGF-1R). We assessed the gene expression levels of IGF-1R, E-cadherin, N-cadherin, and occludin as predictive factors of resistance to EGFR-TKIs and survival outcomes in patients with advanced EGFR mutation-positive lung adenocarcinoma in Serbia. Methods: 101 patients with stage IIIB/IV EGFR mutation positive lung adenocarcinoma treated with EGFR-TKIs were included in the study. Quantitative RT-PCR was performed to determine mutations in EGFR, and expression of N-cadherin, E-cadherin, occludin and IGF-1R. Kaplan-Meier method was employed to estimate overall-survival (OS) and progression-free survival (PFS), with significance set at p<0.05. Results: Median age of patients was 61.7 (39 - 81) years, 65.3% were females and 91% were diagnosed with metastatic lung adenocarcinoma. EGFR mutations were more frequently detected in females (p <0.001). Median overall survival (OS) was 21 months (15.2–26.7 CI 95%) and progression-free survival (PFS) was 10 months (7.4-12.5 CI 95%). Patients whose tumors had lower levels of IGF-1R, and N-cadherin expression had statistically significantly longer PFS (p <0.001). Patients with lower levels of IGF-1R and higher levels of E-cadherin gene expression were more likely to have a complete or partial response to therapy (p = 0.04). There was a statistically significant association between elevated IGF-1R expression and the occurrence of EGFR-TKI resistance in patients (p <0.001). There was a statistically significant association between increased N-cadherin expression and reduced E-cadherin expression with EGFR-TKI resistance in patients. Conclusions: The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin. In this group of patients, higher levels of IGF-1R and N-cadherin gene expression were associated with shorter PFS and resistance to EGFR TKI, compared to higher levels of expression of E-cadherin, which may indicate potential value of expression of these genes in predicting acquired resistance to EGFR-TKI. Therefore, more research is needed to prove the potential predictive value of E-cadherin, N-cadherin and IFG-1R in acquired resistance to EGFR-TKI and developing novel therapeutic options with anti-EMT properties that can overcome this problem.
Identifying digital pathology imaging based biomarkers of checkpoint inhibitor response in non-small cell lung cancer.
Authors: Patkar Sushant , Chen Alex , Rajendran Rahul , Basnet Alina , Turkbey Baris , Choyke Peter L , Harmon Stephanie A , Jamaspishvili Tamara 
Published: June 2024

8530 Background: Immune checkpoint inhibitors (ICIs) targeting Programmed Death 1 (PD1) or Programmed Death Ligand 1 (PDL1) have revolutionized non-small cell lung cancer (NSCLC) treatment, yet only 30% of patients respond effectively. Although approved for patient selection, using PDL1 expression as a biomarker of treatment response is controversial in predicting clinical outcomes, highlighting the need for more robust alternatives. Methods: We explore the potential of AI-based approaches using H&E-stained digitized images of resection and biopsy samples to enhance the prediction of ICI responses in NSCLC. A dataset of 692 NSCLC patients (n=1325 slides) treated with anti-PD1/PDL1 was collected from SUNY Upstate Medical University, focusing on a subset of 166 patients receiving first-line anti-PD1/PDL1 treatment for AI model training and evaluation. An attention-based deep neural network was trained to predict treatment responses of patients from whole slide H&E images while being challenged with additional auxiliary tasks such as interferon gamma gene expression prediction in order to enable a comprehensive analysis of the tumor microenvironment (TME) and mitigate overfitting. Overall, 60% of the SUNY cohort (N=104; 26 Partial/Complete response, 78 stable/Progressive disease) and the publicly available TCGA-NSCLC cohort (N=986) were-utilized for multi-task training. The remaining 40% of the SUNY cohort (N=62; 16 Partial/Complete response, 46 stable/Progressive disease) was used for testing. Training was done in 5-fold cross-validation. The final model was chosen as an ensemble of models trained over all 5 folds. Train and test splits were generated using a stratified random sampling approach, ensuring that the proportion of responders versus non-responders remained unchanged across splits. Performance was evaluated utilizing percentage accuracy (all true positive values), precision (positive predictive value), recall (sensitivity) and F1 scores (mean value of precision and recall). Attention maps generated by the AI model were used to highlight relevant spatial regions of the TME significantly associated with ICI responses. Results: Our multi-task attention-based approach achieves an overall predictive accuracy of 79%, precision of 0.53, recall of 0.24, and an F1 score of 0.33 on the held-out test set. In contrast, pathologist derived PDL1 IHC scores ≥50% exhibit an accuracy of 47%, precision of 0.09, recall of 0.125, and an F1 score of 0.11. Conclusions: Initial findings indicate that attention-based multitask learning of NSCLC H&E- images could uncover crucial tumor intrinsic and microenvironmental features that are predictive of ICI responses in patients. Inclusion of additional clinical and molecular data for training and validation holds potential to further improve ICI response prediction accuracy using AI-derived biomarkers and classifiers.
Young adults (YA) with non-small cell lung cancer (NSCLC): Snapshot of the oncogenic drivers and immune landscapes.
Authors: Pruitt Aaron , Hsu Robert , Gandhi Nishant , Olazapasti Coral , Rodriguez Estelamari , Owen Dwight Hall , Gheeya Jinesh , Zhang Jun , Furqan Muhammad , LoPiccolo Jaclyn , Elliott Andrew , VanderWalde Ari , Rock Stephanie , Ma Patrick C. , Halmos Balazs , Hao Zhonglin 
Published: June 2024

8538 Background: Approximately 5% of NSCLC occurs in patients 50 years or younger (median age:71) representing distinct clinicopathological features. Reports characterizing genomic alterations are scarce. Using a large real-world (RW) dataset, we characterize oncogenic drivers, and immune landscapes to better understand YA with NSCLC. Methods: 42,326 NSCLC specimens were analyzed using next-generation sequencing of DNA (DNA-592 panel or whole exome) or RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). YA (<=50 years) were categorized into three groups (years): 18-30 (A1, n=61), 31-40 (A2, n=277) & 41-50 (A3, n=1,549); vs >50 (A4, n=40,439). Composition of tumor microenvironment (TME) was estimated from bulk RNA sequencing using QuanTIseq method. RW survival on Osimertinib (Osi-OS) was obtained from insurance claims and calculated from initiation of Osi treatment to last contact and was compared between ages 18-50 and >50 years. Hazard ratio (HR) was calculated using the Cox proportional hazards model. Statistical significance was determined using Chi-square, Fisher’s Exact, Mann-Whitney U and log-rank tests and corrected for multiple comparisons where applicable (q<0.05). Results: Consistent with previous reports, NSCLC in YA was more prevalent in females, non-smokers and was associated with adenocarcinoma histology. Among driver alterations, ALK(IHC+), ROS1, RET and NTRK1 fusion were enriched and KRAS mutations were reduced in YA. Interestingly, while the prevalence of KRASG12D from transition (non-smoker related) and EGFRE746_A750 decreased with age, KRASG12C from transversion increased with age in YA. YA were also associated with improved Osi-OS (HR: 0.79, median Osi-OS=37.4 months vs 32 months in >50 years old, p=0.019). High tumor mutation burden (>=10 mut/Mb), the prevalence of mutations in TP53, KMT2D, NF1, RBM10, NFE2L2 and NOTCH1 increased while GNAS decreased with age. The expression of immune checkpoint genes such as PDCD1LG2(A1/A4: 0.63, A3/A4: 0.89), LAG3(A2/A4: 0.73, A3/A4: 0.89) and IFNG (A1/A4: 0.32, A3/A4: 0.75) were reduced, while M2 macrophage (A2/A4: 1.2) and neutrophil (A2/A4: 1.2) were increased in YA (all q<0.05). Conclusions: We report an increased prevalence of RET and NTRK1 fusions in YA and key differences in distributions of frequent KRAS and EGFR mutations in YA (vs A4) along with decreased expression of immune related genes in the tumor microenvironment. The implications are under active investigation. [Table: see text]
Impact of maintenance pemetrexed cessation on clinical outcomes of patients with metastatic non-squamous NSCLC.
Authors: Bhatia Shreya , Iams Wade Thomas , Lu Matthew , Lessans Spencer , Libre Michael 
Published: June 2024

8568 Background: Combination chemoimmunotherapy including pemetrexed and a PD(L)1 inhibitor is a common first line systemic approach for patients with metastatic non-squamous non-small cell lung cancer (NSCLC). Patients often discontinue maintenance pemetrexed due to adverse effects, and little is known about the impact of maintenance pemetrexed cessation on progression free survival (PFS) and overall survival (OS). Methods: 121 patients with stage IV or recurrent, metastatic non-squamous NSCLC treated at VUMC were included in this retrospective analysis. Patients diagnosed between 7/2017- 9/2023 were included if they received maintenance pemetrexed and pembrolizumab. Patients were divided into two groups: those who stopped pemetrexed due to toxicity and those who did not. PFS and OS were measured from time of stage IV or metastatic diagnosis to the date of radiographic progression or death, respectively, and compared with the Kaplan Meier method. Results: Among patients with stage IV or recurrent, metastatic NSCLC (n = 121), who remained on maintenance pemetrexed and pembrolizumab (n=68), the median PFS was 11.7 months (95% CI, 7.47-NA) compared to 24.3 months (95% CI, 19.4-NA) among patients who stopped maintenance pemetrexed (n=53; p=0.1). The median OS in the same patient groups was 25.8 months (95% CI, 13.8-NA) compared to 36.4 months (95% CI, 26.9-NA) (p=0.15), respectively. Among patients with stage IV disease at diagnosis (n = 97), the median PFS among patients who did not stop pemetrexed was 8.7 months (95% CI, 7.2–NA) compared to 24.3 months (95% CI, 17.3-NA) for patients who stopped pemetrexed (p=0.089). The median OS in these groups were 21 months (95% CI, 13.6-NA) and 38.6 months (95%, 28.0-NA) (p=0.054), respectively. Conclusions: In this study of patients with metastatic non-squamous NSCLC who received maintenance pemetrexed and pembrolizumab, patients who stopped pemetrexed due to toxicity experienced similar outcomes to those who continued with pemetrexed. The necessity of continuation of maintenance chemotherapy should be further evaluated in the immunotherapy era. [Table: see text]
Metabolic profile and therapeutic vulnerabilities of multi-omic characterization ofKRAS/STK11/KEAP1 co-mutant non–small cell lung cancer (NSCLC).
Authors: Sen Triparna , Sen Utsav , Coleman Charles , Elliott Andrew , Hasson Dan , Vanderwalde Ari M. , Ma Patrick C. , Gandhi Nishant , Halmos Balazs 
Published: June 2024

8576 Background: KRAS-mutant NSCLC with co-occurring loss-of-function mutations in STK11 and KEAP1(KSK) are remarkably aggressive and poorly responsive to chemo- and immunotherapy. Novel therapeutic strategies are urgently needed to improve outcomes for patients with KRAS/STK11/KEAP1co-mutant NSCLC (KSK). We interrogated the transcriptomic landscape using a large real-world dataset of NSCLC to identify therapeutic vulnerabilities that may help guide treatment selections in KSK. Methods: KRAS mutant NSCLC clinical samples (N=7210) were tested with NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). Specimens were stratified into KRASMUT/STK11MUT/KEAP1MUT (KSK; N=698), KRASMUT/STK11MUT/KEAP1WT (KS; N=786), KRASMUT/STK11WT/KEAP1MUT (KK; N=466), and KRASMUT/STK11WT/KEAP1WT (K; N=4536). Real-world overall survival (OS) data was obtained from insurance claims and investigated using Kaplan-Meier estimates. Additionally, an in vitro CRISPR screen, bulk RNA sequencing, and phospho-kinase arrays were performed in KRAS/STK11/KEAP1 co-mutant, single mutant, and wild-type cell lines to better characterize these models. Results: KEAP1mutations (median OS: KK=7.83 months, KSK=7.23 months) were strongly associated with poor OS compared to STK11 mutations (median OS: KS=17.6months). Pathways significantly upregulated in KSK clinical samples included fatty acid metabolism and redox pathways. When compared to single mutant or wild-type conditions, KSK clinical samples had significant up-regulation of genes involved in ferroptosis evasion and metabolism like SLC7A11(KSK/KK=1.28, KSK/KS=4.82, KSK/K=10.24; all q<0.01) and SCD1(KSK/KS=1.19, KSK/K=1.24; both q<0.01). To confirm our clinical findings, CRISPR/Cas9-based genetic screening identified SCD1, and SLC7A11 master regulators of fatty acid metabolism and ferroptosis, as a potential therapeutic target in the KSK cell lines. SCD1 inhibition augmented the effect of ferroptosis inducer, erastin. Targeting SCD1 led to global metabolomic changes in KSK cells, including key pathways involved in lipid and glucose metabolismas compared to single mutants or wild-type cells. Finally, pharmacological inhibition of SCD1 caused significant tumor regression and augmented the anti-tumor response of SLC7A11 inhibitor, imidazole ketone erastin (IKE), in KSK syngeneic mouse models. Conclusions: Our study is the first to highlight the importance of the ferroptosis regulators, SCD1-SLC7A11,in regulating unique metabolic and ferroptosis evasion pathways in KSK patient tumor and preclinical models. The study data furthers the understanding of ferroptosis in NSCLCand the potential to translate SCD1 inhibitors and ferroptosis inducers in KRAS NSCLC clinical trials.
Detection of comprehensive oncogenic driver alteration of non-small cell lung cancer from cytology specimens by multi-gene PCR panel.
Authors: Sakai Tetsuya , Izumi Hiroki , Matsumoto Shingo , Udagawa Hibiki , Tanaka Yu , Sugiyama Eri , Umemura Shigeki , Zenke Yoshitaka , Yoh Kiyotaka , Goto Koichi 
Published: June 2024

8579 Background: The analysis of the next-generation sequencing (NGS) panel test requires a sufficient amount of tissue specimens (TS), but the collection of tissue specimens can be sometimes challenging in clinical practice. Despite being easier and safer to collect than TS, cytology specimens (CS) are considered unsuitable for NGS due to the small number of tumor cells. The AmoyDx Pan Lung Cancer PCR Panel (AmoyDx), a multi-gene PCR panel that amplified mutation or fusion variants of 11 genes (EGFR, ALK, ROS1, RET, MET HER2, BRAF, KRAS, and NTRK1-3) by real-time PCR, can be performed with smaller amounts of nucleic acid than NGS, and CS may be suitable for multi-gene analysis using this panel. In this study, we evaluated the feasibility of multi-gene analysis using CS, and the concordance rate of gene alteration between CS and TS in non–small cell lung cancer (NSCLC). Methods: We enrolled consecutive NSCLC patients obtaining CS through bronchoscopy, including transbronchial brushing (TBB) and transbronchial needle aspiration (TBNA) from September 2020 to March 2023. These CS were preserved as frozen pellets. The difference in the amount of nucleic acid, the success rate and the concordance rate of gene alteration with AmoyDx were evaluated between CS and pared TS collected simultaneously with CS. Results: A total of 131 (Ad/Sq/NSCLC-NOS: 113/2/16) cases were enrolled in this study. Fifty-nine specimens were obtained through TBB and another 72 were obtained through TBNB. The median nucleic acid concentration (NanoDrop [ng/μL]) isolated from CS was comparable to that isolated from TS (DNA 114/99, p=0.96; RNA 36/27, p=0.63). However, the median DNA concentration in CS was significantly lower (80/102, p=0.01) in TBB samples, while in TBNA samples, it was higher (134/90, p=0.03). Almost all CS (99.2%,130/131) and TS (99.2%,130/131) were analyzed successfully with AmoyDx, with only one RNA analysis failure in each group. Among CS, 78 (60%) samples exhibit gene alteration, including EGFR/KRAS/BRAF/HER2/ALK/ROS1/MET/RET: 44/9/2/5/8/1/8/1, while 77 (59%); 44/9/2/6/6/1/8/1 in TS. The positive percent agreement, negative percent agreement, and overall percent agreement of CS using analysis compared with the results of TS using analysis were 99% (76/77), 96% (52/54), and 98% (128/131), respectively. Conclusions: CS exhibit an extremely high success rate for multi-gene analysis, with nucleic acid yield comparable to TS. Moreover, the concordance rate of gene alteration between CS and TS is also remarkably high. CS emerge as a viable alternative to TS for analyzing driver gene alteration in multi-gene PCR analysis.
Sacituzumab govitecan (SG) + pembrolizumab (pembro) in first-line (1L) metastatic non-small cell lung cancer (mNSCLC) with PD-L1 ≥ 50%: Cohort A of EVOKE-02.
Authors: Patel Jyoti D. , Cho Byoung Chul , Cobo Manuel , Reyes Cabanillas Roxana , Vicente David , Fuentes Pradera Jose , Garon Edward B. , Mok Tony S. K. , Cappuzzo Federico , Neal Joel W. , Mekan Sabeen Fatima , Safavi Farnoush , Fernando Nelumka , Chisamore Michael Jon , Reck Martin 
Published: June 2024

8592 Background: SG, a Trop-2–directed antibody-drug conjugate, has clinical activity and manageable safety in heavily pretreated patients with mNSCLC. EVOKE-02 (NCT05186974) is an ongoing, global, open-label, multicohort phase 2 study evaluating SG + pembro ± platinum agent as 1L treatment for mNSCLC. We report safety and efficacy results from Cohort A of EVOKE-02, with a median follow-up of 11.3 months. Methods: Patients aged ≥18 years with no prior systemic mNSCLC treatment, no actionable genomic alterations, and an ECOG performance status of 0 or 1 were enrolled into Cohort A [PD-(L)1 tumor proportion score ≥50%, 22C3 assay]. Patients received SG 10 mg/kg intravenously on days 1 and 8 + pembro 200 mg intravenously on day 1 of 21-day cycles. Primary endpoints include objective response rate (ORR; RECIST v1.1) per independent review committee (IRC); secondary endpoints include progression-free survival (PFS), duration of response (DOR), disease control rate (all per IRC), overall survival (OS), and safety. Results: As of December 1, 2023, 30 patients in Cohort A were enrolled and had received SG + pembro. Median age was 67 (range, 47-77) years; 60% had nonsquamous histology and 80% had an ECOG performance status of 1. Among all treated patients (n=30), ORR was 67% (95% CI, 47-83%) (squamous, 67% [95% CI, 35-90%]; nonsquamous, 67% [95% CI, 41-87%]). Median PFS was 13.1 (95% CI, 5.5-not reached [NR]) months (squamous, NR [95% CI, 1.2-NR] months; nonsquamous, 13.1 [95% CI, 5.5-NR] months). Median DOR was NR. In the safety population (n=30), the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) and of grade ≥3 TEAEs related to any study drug were 67% and 40%, respectively. Grade ≥3 TEAEs in ≥10% of patients were neutropenia (17%), diarrhea (10%), and respiratory failure (10%). TEAEs leading to SG discontinuation occurred in 17%. There was 1 (3%) treatment-related death due to neutropenic sepsis. Conclusions: SG + pembro demonstrated promising activity in patients with tumor proportion score ≥50% mNSCLC. AEs were manageable and consistent with the known safety profile of each individual agent. The EVOKE-03 study (NCT05609968) of pembro vs SG + pembro in mNSCLC is ongoing. Clinical trial information: NCT05186974 . [Table: see text]