tbuckley/cabot-search huggingface dataset:
Neoadjuvant chemoimmunotherapy in patients with limited-stage small cell lung cancer: A retrospective study.
Authors: Ting Wang, Kai LI Huang, Dan Pu, Ting Mei, Ming Yu Fan, Long Tian, Lu Li, Qing Hua Zhou
Journal: Journal of Clinical Oncology (2024)

e20002 Background: The addition of immune checkpoint inhibitors to chemotherapy significantly improves survival in extensive-stage small cell lung cancer (SCLC) and represents a promising advance in this field. However, the clinical benefit of the implementation of immunotherapy in the first-line setting for limited-stage SCLC (LS-SCLC) remains to be proven. Thus, we conducted a retrospective study to explore the efficacy of neoadjuvant chemoimmunotherapy as a first-line treatment for LS-SCLC. Methods: A retrospective study of patients with LS-SCLC who were treated with neoadjuvant PD-L1/PD-1 inhibitor combined with platinum-based chemotherapy followed by surgery between February 2020 and September 2023 was conducted. Clinical characteristics, R0 resection rate, pathologic complete response (pCR), major pathologic response (MPR), downstaging rate and disease-free survival (DFS) were evaluated. Results: As of September 30, 2023, all 21 patients (stage IIB, n = 4; stage IIIA, n = 9; stage IIIB, n = 8) received 2 to 6 cycles of neoadjuvant chemoimmunotherapy (Table 1). Nine (42.9%) patients achieved pCR and 10 (47.6%) presented an MPR (Table 2). Moreover, the R0 resection rate in total and stage III patients were 95.2% (20/21) and 94.1% (16/17), respectively. After a median follow-up of 11.2 months (range: 2.6-24.2), only two patients relapsed and the median DFS was not reached due to insufficient events. Conclusions: Neoadjuvant immune checkpoint inhibitors combined with chemotherapy demonstrated promising efficacy and feasibility, and are a potential strategy for the management of LS-SCLC. Further prospective clinical trials are necessary to clearly define the benefit of neoadjuvant chemoimmunotherapy and optimize LS-SCLC treatment. [Table: see text][Table: see text]
Single-cell landscape of the immune microenvironment of leptomeningeal metastases in non-small cell lung cancer treated with pemetrexed sheath injection.
Authors: Yiquan Xu
Journal: Journal of Clinical Oncology (2024)

e20026 Background: The incidence of leptomeningeal metastasis (LM) is increasing in non-small cell lung cancer (NSCLC) and pemetrexed injection is an important treatment for LM. Here, we used single-cell RNA sequencing (scRNA-seq) to define the immune landscape of LM in NSCLC treated with pemetrexed sheath injection. Methods: scRNA-seq was utilized on 27 cerebrospinal fluid (CSF) samples from 20 patients, including 7 pairs of pre- and post-treatment samples. Detailed immune landscapes were mapped, and key results were confirmed by flow cytometry and IHC. Biomarkers for the efficacy of pemetrexed sheath injection was analyzed. Results: The LM microenvironment was characterized by macrophages and cancer cells with decreased significantly after pemetrexed injection. The cancer cells in LM was highly expressed CEACAM6, SFTPB and NAPSA, and chemokines liked CXCL16 in macrophages decreased significantly after receiving pemetrexed sheath treatment than pre- treatment, which was validated by flow cytometry and IHC. In the signal pathway enrichment analysis, significant changes of metabolism and cell cycle genes occurred before and after pemetrexed injection. Moreover, the analysis of tumor cells and immune cells interaction showed that CSF1-CSF1R, AREG/HBEGF-EGFR, FD1-Intergrin_a2B1_complex, CCL5-CCR1, CD55_ADGRE play a key role in tumor cells recruiting monocytes and inhibiting macrophages. Gene set based on the efficacy of pemetrexed sheath injection was enriched, including C15orf48, CCL5, DUSP6, FLNA, TXNIP, TNNT1, was confirmed associating with increased overall survival. Conclusions: Our study characterizes the immune cell landscape of LM from NSCLC, and provided the biomarkers for the efficacy of pemetrexed injection.
Genomic characteristics of tumour necrosis in lung squamous cell carcinoma.
Authors: Longfeng Zhang, Gen Lin, Qiaofeng Zhong, Lin Wu, Jun Zhao, Jianguo Sun, Cheng Huang
Journal: Journal of Clinical Oncology (2024)

e20030 Background: Tumor necrosis and cavity on enhanced chest CT are common hallmarks of lung squamous cell carcinoma (LUSC). However, the genetic characteristics of necrosis on CT scan remain unclear. This study aims to elucidate the genetic landscape of LUSC with tumor necrosis. Methods: We implemented transcriptome and whole-exome sequencing to analyze early postoperative LUSC specimens. They were classified into necrosis and non-necrosis group based on preoperative enhanced chest CT. Subsequently, the genomic landscape between the two groups were compared. To substantiate our findings, we further employed immunohistochemistry and analysis of a clinical cohort as comprehensive methods of validation. Results: In study cohort (65 samples), the necrosis group (n = 37) showed a higher number and length of copy number variations (CNVs) and elevated Genomic Instability Index (GII) compared to the non-necrosis group (n = 28). Transcriptome sequencing revealed increased hypoxic hallmarks and activation of 11 fundamental metabolic pathways in the necrosis group. Endothelial cells were observably fewer, but matrix remodeling score was higher in the necrosis group. Here, the decreased activity of several immune-related pathways, such as antigen processing and presentation, natural killer cell-mediated cytotoxicity, etc, were notably suppressed in the necrosis group. Immunohistochemistry indicated that the expressions of hypoxy-related genes (HIF-1, NDRG1), proliferation-related genes (ki-67) and angiogenesis related genes (CD31) in necrosis group were significantly higher than those in non-necrosis group. In the clinical validation cohort, we enrolled 538 advanced LUSC patients from 25 medical centers receiving systemic treatment, categorized into chemotherapy (n = 270) and ICIs (n = 268) groups. A notable difference in progression-free survival (PFS) was observed in the ICIs group, with patients without tumor necrosis or cavity exhibiting significantly longer PFS (8.7 vs. 6.5 months; HR 0.67; 95% CI 0.42–0.63; p &lt; 0.001). Multivariate Cox analysis identified necrosis or cavity as an independent predictor of reduced PFS (HR 0.68; 95% CI, 0.51-0.9; p = 0.007). Conclusions: LUSC with necrosis is distinguished by increased genomic instability, hypoxia, enhanced tumor proliferation, matrix remodeling, and an immunosuppressive tumor microenvironment. Baseline chest CT findings of tumor necrosis or cavities may serve as negative predictors for the efficacy of ICIs treatment in LUSC.
Association of tissue microbiota with cancer stages in lung adenocarcinoma.
Authors: Yanfang Su, Shiyu Li, Die Sang, Yurong Zhang
Journal: Journal of Clinical Oncology (2024)

e20061 Background: There has been a lack of comprehensive investigation into changes in the tissue microbial environment at various stages of lung adenocarcinoma (LUAD). This study aims to identify and analyze microbial markers that show significant differences at different stages of LUAD and to assess their impact on the tumor microenvironment. Methods: Microbiome data, gene expression, and clinical information from LUAD patient tissues were retrieved by reanalyzing the sample sequencing data from the Cancer Genome Atlas (TCGA) database, as conducted by Rob Knight’s group. The samples, categorized into early (pathological stage I) and late (stages II-IV) following the initial diagnosis, were subjected to comparative analyses. Firstly, microbial alpha diversity metrics, such as the Shannon index, were computed for each sample. Subsequently, Principal Coordinate Analysis (PCoA) and the Wilcoxon rank sum test were employed to assess differences in microbial communities between the two groups. Furthermore, the study delved into the associations between microbes and host gene expressions using Spearman rank correlation to construct a heterogeneous network encompassing microbial interaction networks at the genus level, microbe-gene interaction network, and gene co-expression network. Various network features, including the clustering coefficient, were examined. Finally, diverse machine learning algorithms were employed to develop a diagnostic model for cancer stage based on microbial and gene expression data. Results: A total of 491 samples, including 267 in the early group and 224 in the late group, were matched with microbial data, mRNA expression, and clinical information. Our findings revealed distinct differences in the microbiome of patients with LUAD at various stages, particularly in the tissues of advanced patients, where in the co-abundance network exhibited a significantly higher level of complexity. Furthermore, we identified five bacterial biomarkers (Pseudoalteromonas, Luteibacter, Caldicellulosiruptor, Loktanella, and Serratia) that were associated with the LUAD stage. Notably, Pseudoalteromonas, Luteibacter, Caldicellulosiruptor, and Serratia were significantly overexpressed in advanced patients. Utilizing the random forest model, we determined that microbial markers possess predictive capabilities for the stage of lung adenocarcinoma and can compensate for deficiencies in other omics data for determining tumor stage. Integration of the mRNA and intratumor microbe biomarkers yielded a prediction area under the Receiver Operating Characteristic curve of 0.70. Conclusions: Our study unveiled the microbial profile of LUAD patients, elucidating the intrinsic pathogenic mechanisms linking the microbiome and the disease. Additionally, we developed a multi-omics model for determining the tumor stage of LUAD.
Evaluation of the toxicity and outcomes of the combination of midostaurin and CLAG-M in patients with FLT3-mutated acute myeloid leukemia (AML): A multi-center retrospective analysis.
Authors: Ashley Wen Chen, Grace Tonghwa Baek, Shannon Palmer, Jack Rasmussen, Joseph S. Bubalo, Swathi Namburi, Tenley Schwarz, Tenzin Tsomo, Jonathan Cohen, Kathryn Russell, Carole Shaw, Megan Othus, Anna B. Halpern
Journal: Journal of Clinical Oncology (2024)

6523 Background: FLT3-mutated AML is associated with poor outcomes. Addition of midostaurin (multi-targeted kinase inhibitor) to standard “7+3” with cytarabine and daunorubicin significantly prolongs overall and event-free survival for these patients (Stone 2017). At the University of Washington/Fred Hutchinson Cancer Center (UW/FHCC), the standard regimen for newly diagnosed (ND) and relapsed/refractory (r/r) AML is cladribine, high-dose cytarabine, GCSF, and mitoxantrone (CLAG-M); midostaurin is added if FLT3-mutated (Halpern 2018). There is currently no peer-reviewed literature to support this combination for these patients. The purpose of this study is to evaluate the safety and efficacy of the combination of midostaurin with CLAG-M in FLT3-mutated AML patients and compare the toxicity profile to midostaurin plus 7+3. Methods: This is a retrospective multi-center review conducted at three major cancer centers. Through pharmacy records and/or an institutional AML database, we identified adults with FLT3-mutated AML undergoing (re)induction chemotherapy who received either CLAG-M (UW/FHCC, Swedish) or 7+3 (OHSU, Swedish). The primary outcome was toxicity profile of the combination as measured by rate of adverse events ([AE], CTCAE Version 5.0). Secondary outcomes included disease response per ELN2017 AML working group criteria and 28-day mortality (TRM) (Döhner 2017). Patients treated on a clinical trial and in whom midostaurin was started &gt; 30 days after day 1 of chemotherapy were excluded. Rates of AEs were compared using Fisher’s exact test. Results: Eighty patients treated between 10/2022-12/2023 were included; 35 patients received CLAG-M, and 44 patients 7+3. Baseline characteristics were similar across all institutions, with most patients having adverse or intermediate risk disease. AE rates were similar between the two cohorts, (Table 1) except diarrhea and bleeding events were more common in the 7+3 vs. CLAG-M cohort (p = 0.004 and p = 0.037, respectively). The rate of complete remission (CR) plus CR with incomplete blood count recovery (CRi) did not significantly differ between the two cohorts: CLAG-M, 86% versus 7+3, 70% for 7+3 (p =0.11). No TRM occurred. Conclusions: The toxicity profile of CLAG-M combined with midostaurin is comparable to the combination of 7+3 with midostaurin, and induces high remissions rates in adults with FLT3-mutated AML. [Table: see text]
Comparison and performance of three plasma next-generation sequencing assays versus tissue testing for the detection of actionable driver mutations in advanced non-squamous non-small cell lung carcinoma.
Authors: Paul Hofman, Christophe Bontoux, Caroline Lacoux, Guylène Inaudi Rignol, Samantha Goffinet, Virginie Lespinet, Olivier Bordone, Virginie Tanga, Maryline Allegra, Georges Garnier, Jacques Boutros, Jonathan Benzaquen, Charles Hugo Marquette, Marius Ilie, Veronique Hofman
Journal: Journal of Clinical Oncology (2024)

e20018 Background: Liquid biopsy (LB) is a useful tool for the detection of actionable mutations in advanced non-squamous non-small cell lung cancer (NS-NSCLC) at progression. However, the clinical benefits of integrating both LB and tissue biopsy (TB)-based genomic profiling at diagnosis of NS-NSCLC remain uncertain. Methods: We tested three commercially available next-generation sequencing (NGS) gene panel assays in circulating cell-free DNA (cfDNA) using replicate sets of 85 LB samples from advanced NS-NSCLC patients at baseline and compared the results with matched TB for the detection of tier IA/B (AMP/ASCO/CAP classification) alterations. We used methylation testing of cfDNA to assess the tumor fraction (TF). We correlated molecular data with clinico-pathological features and follow-up data. Results: All TB-based NGS results were interpretable. 5 LB-based NGS results for one assay were not performed due to the material exhaustion. Tier IA/B gene alteration was detected by LB-based NGS and TB-based NGS in 18 to 23 (21 to 27%) patients and in 35 (41%) patients, respectively. The positive percent agreement of each LB-based NGS assay method compared with TB-based NGS assay ranged from 51% to 68%. The incremental add provided by first LB-based NGS ranged from 0 to 23% versus 25 to 45% for first TB-based NGS, depending on the LB-based NGS assay. It includes one EGFR uncommon mutation, 9 MET amplifications and 2 HER2 amplifications detected by LB-based NGS assays that were not detected by TB-based NGS. Overall agreement between the three LB-based NGS assays was 44%. Hybrid-capture based assay detects 14 MET/HER2 CNVs, two METex14 skipping mutation and two ALK fusions that were not detected by amplicon-based assay. Amplicon-based assay detects one uncommon EGFR mutation, one KRAS non-G12C and one ALK fusion that were not detected by hybrid-capture based assay. 64 LB samples were tested for cfDNA methylation. Positive predictive value and negative predictive value of the detection of TF by cfDNA methylation profiling was 90% and 92%, respectively. The only false-negative result of TF evaluation by cfDNA methylation profiling was observed for a variant with a cfDNA VAF &lt; 1%. Correlation analyses with clinicopathological data are ongoing. Conclusions: While concordance with tissue is relatively high, the incremental add provided by LB-based NGS at diagnosis of advanced NS-NSCLC compared to TB-based NGS is limited and greatly varies according to the sequencing method used. Thus, LB-based NGS at diagnosis of NSCLC can be used as a complement of TB-based NGS or as an alternative when tissue is not available.
Multiple sclerosis and lung cancer: A single cancer center experience in Philadelphia.
Authors: Julia Palecki, Andrew Bernstein, Garrett Melby, Matthew Tucker, Zoe Begun, Tingting Zhan, Ida Micaily
Journal: Journal of Clinical Oncology (2024)

e20027 Background: The association between multiple sclerosis (MS) and lung cancer remains poorly understood. This retrospective, single center study aims to characterize the clinical features and outcomes of lung cancer in patients with MS, shedding light on this unique patient cohort characterized by immune dysregulation and significant immunosuppressive therapy. Methods: This retrospective study analyzed 40 MS patients diagnosed with lung cancer at Sidney Kimmel Cancer Center in Philadelphia, PA between 1/1/2016 and 7/1/2023. Clinical data including patient demographics, MS treatments, cancer diagnosis details (date, stage, histology), molecular and fusion data, PD-L1 status, and patient mortality dates were recorded and analyzed. Results: In our cohort of 40 patients, 28 (70.0%) patients were female, with 28 (70.0%) identifying as White and 7 (17.5%) as Black. NSCLC was seen in 37 patients (26 adenocarcinoma, 5 squamous cell carcinoma), while 3 had SCLC. Among the 33 patients with available MS treatment data, 9 (26.5%) received steroids, and 15 (44.1%) received biologic therapy. The average age at lung cancer diagnosis was 62.8 (±10.9) years, with 18 out of 40 patients (45.0%) diagnosed with stage I disease. Advanced stages were found in 22 patients (55.0%) at diagnosis: 2 (5.0%) with stage II, 1 (2.5%) with stage III, and 19 (47.5%) with stage IV disease. Among 15 patients with molecular testing, BRAF mutation was found in 1 (6.7%), EGFR mutation in 4 (26.7%), and KRAS mutation in 2 (13.3%). One subject demonstrated an ALK fusion (7.1%). PD-L1 testing was recorded in 13 patients: 3 (23.1%) had 0%, 1 (7.7%) had 1%, 5 (38.5%) had 1-49%, and 4 (30.8%) had &gt; 50% PD-L1 expression. The average overall survival was 2.4 years (95% CI: 1.4-8.1 years). Conclusions: In this cohort, MS patients with lung cancer exhibited targetable mutations, such as EGFR mutations and high PD-L1 expression rates. While the use of immunotherapy in lung cancer with concurrent MS has been limited, our data suggests the importance of molecular profiling in all lung cancer patients. We consider that these patients received significant exposure to immunosuppressive therapies for MS, potentially impacting immune surveillance and lung cancer development. Despite this, nearly half of the cohort had Stage 1 lung cancer and showed favorable overall survival rates. Our cohort study suggests a need to investigate the relationship between MS and lung cancer further.
Recombinant <i>Erwinia</i> asparaginase (JZP458) in acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL): Post hoc analysis of adverse events of interest from AALL1931.
Authors: Etsuko Aoki, Luke Devon Maese, Mignon Loh, Shirali Agarwal, Vijayalakshmi Chandrasekaran, Yali Liang, Nalina Dronamraju, Robert Iannone, Lewis B. Silverman, Elizabeth A. Raetz, Rachel Rau
Journal: Journal of Clinical Oncology (2024)

6521 Background: The pivotal Children’s Oncology Group Study AALL1931 (NCT04145531) evaluated JZP458, a recombinant Erwinia asparaginase (ASP), in patients with ALL/LBL who developed hypersensitivity/silent inactivation to E. coli-derived ASPs, leading to approval of JZP458 by the FDA and EMA. Primary efficacy and safety data have been reported; here, we report on adverse events of interest (AEIs: allergic reaction, pancreatitis, thrombosis, hepatotoxicity) and nausea/vomiting, and summarize post hoc descriptive analyses of AEIs by timing and known risk factors (eg, age and ethnicity). Methods: Each pegylated E. coli ASP remaining on treatment was replaced by 6 doses of JZP458 administered Monday/Wednesday/Friday (MWF). Three intramuscular (IM) cohorts (1a [25 mg/m 2 MWF], n=33; 1b [37.5 mg/m 2 MWF], n=83; and 1c [25/25/50 mg/m 2 MWF], n=51) and 1 intravenous (IV) cohort (25/25/50 mg/m 2 MWF, n=61) were evaluated. Results: Rates of any-grade treatment-related allergic reactions, pancreatitis, thrombosis, increased ALT/AST, and increased bilirubin were 11%, 7%, 1%, 16%, and 7% in the total IM cohort and 26%, 5%, 2%, 18%, and 5% in the IV cohort, respectively. Rates of treatment-related grade ≥2 nausea/vomiting (N/V) were 32% and 64% in the total IM and IV cohorts. Table shows the median number of JZP458 doses on or before the first AEI. Notably, rates of grade ≥2 N/V events were similar after 25 and 50 mg/m 2 dosing. Subgroup analyses showed no consistent trends in the rates of any-grade AEIs by age except for pancreatitis where rates were numerically higher in patients aged 12 to &lt;18 (9/62 [15%]) and ≥18 years (4/31 [13%]) than in those aged 6 to &lt;12 (1/71 [1%]) or &lt;6 years (1/64 [2%]). Overall, incidences of any-grade treatment-related allergic reactions, pancreatitis, thrombosis, increased ALT/AST, and increased bilirubin among Hispanic patients (n=74) were 12%, 5% 1%, 19%, and 7% respectively, similar to non-Hispanic patients (n=140). Conclusions: The safety profile of JZP458 is consistent with other ASPs in patients with ALL/LBL and generally similar across age and ethnicity subgroups. Clinical trial information: NCT04145531 . [Table: see text]
Obecabtagene autoleucel (obe-cel, AUTO1) in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL): Overall survival (OS), event-free survival (EFS) and the potential impact of chimeric antigen receptor (CAR)-T cell persistency and consolidative stem cell transplantation (SCT) in the open-label, single-arm FELIX phase Ib/II study.
Authors: Elias Jabbour, Eleni Tholouli, Karamjeet S. Sandhu, Paul Shaughnessy, Pere Barba, Manuel Guerreiro, Deborah Yallop, Aaron Logan, Mehrdad Abedi, Pierre Lao-Sirieix, Yiyun Zhang, Wolfram Brugger, Martin A. Pule, Bijal D. Shah, Michael Russell Bishop, Jae H. Park, Daniel J. DeAngelo, Karl Peggs, Claire Roddie
Journal: Journal of Clinical Oncology (2024)

6504 Background: Obe-cel is an autologous CAR-T cell product with a fast off-rate CD19 binder designed to mitigate immunotoxicity and improve expansion/persistence. Pooled results from the pivotal FELIX phase Ib/II study (NCT04404660) of obe-cel in adults with R/R B-ALL were recently presented (Roddie C et al. Blood 2023;142[Suppl 1]:222). Here, OS and EFS in all patients (pts) treated with obe-cel are reported, alongside the impact of CAR-T cell persistency and consolidative SCT for pts in remission. Methods: Pts aged ≥18 yrs with R/R B-ALL were enrolled. CAR-T products were generated via an automated process (Roddie C et al. Blood 2023;142[Suppl 1]:222). Pts received bridging therapy as appropriate and underwent lymphodepletion (fludarabine, 4×30mg/m 2 ; cyclophosphamide, 2×500mg/m 2 ), followed by obe-cel split dose infusions on Days 1 and 10 based on pre-lymphodepletion leukemic burden at a target dose of 410×10 6 CAR-T cells. Results: A total of 127/153 (83%) enrolled pts were infused. At screening, pts’ median age was 47 yrs; 42%/31%/44% had received prior blinatumomab/inotuzumab ozogamicin/allogeneic SCT; median bone marrow blast burden was 36% (range: 0−100). At data cut-off (13 September 2023), median follow-up was 16.6 mos (range 3.7−36.6 mos). The overall complete remission or complete remission with incomplete count recovery rate among infused pts was 78%. Among responding pts, 17/99 (17%) proceeded to consolidative SCT while in remission; all 17 (100%) were in measurable residual disease (MRD)-negative remission (≤10 –4 leukemic blasts) and 10/17 (59%) showed CAR-T cell persistency prior to SCT. Loss of CAR-T cell persistency was associated with a hazard risk of relapse or death 2.9 times compared with pts who had ongoing CAR-T cell persistency. Pts who experienced B-cell recovery had a hazard risk of relapse or death 1.7 times compared with pts without B-cell recovery. At 12 mos, the EFS rate was 50% and 43% with or without censoring for consolidative SCT or new therapies, respectively; the OS rate was 61% and 59% with or without censoring for SCT, respectively. Conclusions: Ongoing CAR-T cell persistency and B-cell aplasia were associated with improved EFS without further consolidation post-obe-cel. At the current follow-up, consolidative SCT for pts in MRD-negative remission post-obe-cel did not improve EFS or OS. Clinical trial information: NCT04404660 .