bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of single-click radiomic classifier with response and prognosis in non-small cell lung cancers (NSCLC) treated with immune checkpoint inhibitors.
Authors: Hiremath Amogh , Li Haojia , Clement Allison , Gupta Amit , Velcheti Vamsidhar , Mababhushi Anant , Braman Nathaniel 
Published: June 2023

8574 Background: Radiomics has shown promise to non-invasively phenotype disease and address the limitations of extant biomarkers (e.g. PD for immune checkpoint inhibitors (ICI) in cancers, such as NSCLC. However, considerable barriers to the clinical adoption of these tools remain, such as their dependence on precise annotation of tumor extent by experienced clinical users. Here, we demonstrate a radiomic solution that requires only a single user mouse click within one or more target lesions on a baseline CT scan, to contour tumors in 3D and generate a patient-level radiomic prediction of response and outcome in ICI treated NSCLC patients. Methods: 1778 CT scans from 1261 patients were used to develop and validate an interactive, semi-automated tool for predicting ICI outcomes in NSCLC patients prior to therapy. A user click based deep learning contouring model was trained and validated on 1146 patients, then used to create annotations for radiomic analysis. A least absolute shrinkage and selection operator (LASSO) Cox proportional hazards model was utilized to select features associated with post-ICI overall survival (OS) and derive a radiomic risk score within a training cohort (n=74) that can separate patients into high and low risk groups. The model was tested on held out pre-treatment CTs of 41 ICI recipients from 2 institutions for association with OS, progression-free survival (PFS), and objective response (OR). Results: A total of 77 lesions were identified and segmented within the testing set. Average volume per lesion was 54.10 mL and per patient was 101.60 mL. OR was observed in 48.70% of patients. A threshold of -0.31 defining high and low radiomic risk groups was chosen based on optimal separation within the training set (HR=2.59 [95% 1.48~4.50], p=0.0009). Radiomic risk groups significantly stratified patients by OS (C-index=0.64, HR=3.03 [95% 1.15~8.02], p=0.03) and PFS (C-index=0.59, HR=3.20 [95% 1.13~9.10], p=0.03). Radiomic IO risk group was independently prognostic of clinical variables (Table 1) and further predicted ICI response with AUC=0.74 [95% 0.71-0.78]. Conclusions: From a single click in target lesions, our model was able to predict response and prognosis of ICI recipients from a baseline radiology scan. Additional multi-site validation and prospective evaluation will assess the value of the radiomics classifier as a decision support tool in the clinic. [Table: see text]
A theranostic approach: Imaging and therapy of delta-like ligand 3–expressing small cell lung cancers.
Authors: Tendler Salomon , Hoang Tran T , Bauer David , Korsen Joshua , Michel Alexa , Degregorio Roberto , Carter Lukas , Pillarsetty Nagavarakishore , Poirier John T. , Lewis Jason Stuart , Rudin Charles M. 
Published: June 2023

8575 Background: Small cell lung cancer (SCLC) is a highly radiosensitive tumor, with selective cell surface expression of the inhibitory Notch ligand Delta-like ligand 3 (DLL3). This facilitates targeted radionuclide therapy accompanied by complementary imaging agents to evaluate and monitor disease progression. The project aims to identify the next generation of DLL3-targeting radioimmunoconjugates to improve the clinical outcome for SCLC patients. Methods: In collaboration with the Tri-Institutional Therapeutics Discovery Institute, we screened and assessed >100 humanized antibodies for their binding affinities, internalization rates, and other pharmacodynamic properties. Here, we present data on two leading candidates (mAb1 and mAb2) holding highest promise in both imaging and therapy studies conducted in DLL3-expressing SCLC tumors. For in vivo imaging, antibodies were radiolabeled with Zirconium-89 (89Zr), which allows for immuno-positron emission tomography (immunoPET). Therapeutic studies were performed with the same antibodies conjugated with Lutetium-177 (177Lu). Human SCLC NCI-H82 xenografts were implanted in nude athymic female mice. ImmunoPET scans were acquired during multiple time points post-injection of the imaging agent, and terminal biodistribution analysis was performed. Treatment studies included administration of 400 and 600 Ci 177Lu-conjugated antibodies in cohorts of mice, with appropriate positive and negative controls. Results: Both lead antibodies demonstrated efficient radioconjugation with either isotope. ImmunoPET imaging utilizing 89Zr showed specific high-level tumor uptake for both clones with low background in non-tumor organs. Ex vivo gamma counting biodistribution analysis, performed 120 hours post-injection, confirmed these findings. Dosimetry estimates suggested a similar therapeutic index between the two clones, with the bone marrow being the dose-limiting organ. Preliminary results from therapy studies demonstrate a statistically significant (p <0.05) prolonged overall survival for the experimental arms compared to controls, and include durable tumor responses. As expected for radionuclide therapy, transient hematologic suppression was observed within 7-10 days after the beginning of the treatment, with normalization of blood cell counts for all groups within three weeks. Conclusions: This study highlights the promise held by novel DLL3-direct radioimmunoconjugates as a diagnostic tracer, prognostic biomarker, and therapeutic agent. Both lead candidates appear promising for translation as both imaging and therapeutic agents for patients with SCLC.
Reconsidering the cutoff between sensitive and refractory relapses in extensive-stage small cell lung cancer in the era of immunotherapy.
Authors: Torasawa Masahiro , Horinouchi Hidehito , Nomura Shogo , Igawa Satoshi , Asai Maiko , Ishii Hidenobu , Wakui Hiroshi , Ushio Ryota , Asao Tetsuhiko , Namba Yukiko , Koyama Ryo , Katayama Isana , Matsuda Hironari , Sasaki Shinichi , Takahashi Kazuhisa , Hosomi Yukio , Naoki Katsuhiko , Ohe Yuichiro 
Published: June 2023

8576 Background: The use of platinum-based doublet chemotherapy combined with immune checkpoint inhibitors (ICIs) has demonstrated promising outcomes in the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Relapsed SCLC has been classified into "sensitive" or "refractory" relapse types according to cutoff values (60 or 90 days) of duration from the last chemotherapy administration to disease progression. However, it is unclear whether these cutoff values can be applied to ICI combination therapy. Methods: We retrospectively analyzed a multicenter database of ES-SCLC patients who received second-line therapy after the platinum-etoposide plus ICI (atezolizumab or durvalumab). An optimal cutoff value for the platinum-free interval (PFI) was selected, which minimized the two-sided p-value and maximized hazard ratio (HR) regarding relapse type (sensitive or refractory according to a cutoff value) calculated from a multivariable Cox regression model for overall survival (OS) including performance status (PS) and sex as covariates. The internal validity of the selected cutoff value was assessed via two-fold cross-validation (CV) manner. Results: A total of 101 patients (61 deaths) from 10 hospitals were included in the study. The median follow-up period was 21.1 months. The optimal cutoff value was 75 days (p=0.0002), and when applying this cutoff value, median OS was 15.9 and 5.0 months of sensitive- (n=51) and refractory- (n=50) relapsed patients, and the HR calculated from a two-fold CV was 3.13 (95% confidence interval [CI], 1.66 to 5.90). Additionally, traditional cutoff values of 60 and 90 days also predicted prognosis better, but cutoff values of 110 days or longer did not (Table). Conclusions: Even in the era of combined immunotherapy in ES-SCLC patients, the threshold days for classifying as sensitive- or refractory- relapse did not exhibit a significant change compared to the pre-immunotherapy era. Although further validation studies with a larger sample size would be needed, relapse type classification using the selected cutoff value of 75 days is worth considering as a new prognostic factor for relapsed ES-SCLC patients. [Table: see text]
Characteristics and outcomes of patients with small cell lung cancer (SCLC) detected with CT screening at a single health system.
Authors: Godbole Manasi Manoj , Li Pin , Wani Kashmira , Meranda Matthew , Simoff Michael J. , Gadgeel Shirish M. 
Published: June 2023

8581 Background: At diagnosis, the majority of SCLC patients have extensive-stage disease, and their median survival is only 13 months, even with the addition of checkpoint inhibitors. Previous CT screening trials did not reveal reduction in mortality for SCLC patients. The aim of our study was to analyze the baseline characteristics and clinical outcomes of SCLC patients diagnosed with low-dose CT scan as a part of lung cancer screening program. Methods: A retrospective chart review-based study of SCLC patients diagnosed clinically or by lung cancer screening between January 2018 and June 2022 at the Henry Ford Health System was conducted. Baseline characteristics, details of SCLC diagnosis and treatment, and outcome were recorded. Statistical analysis was performed using Chi-squared test, T-test and log-rank test. Results: Of the 258 patients who met eligibility criteria, 34 were diagnosed by lung cancer screening. Patients diagnosed with screening tended to be older (mean age- 70.5 years vs. 67.3 years, p=0.010). There were no differences in gender distribution, race and smoking status. Mean smoking history was 43 pack-years in both groups. Among screen-detected patients, 73.5% had limited-stage disease compared to 36.6% among clinically detected patients (p<0.001). No significant difference in the presence of brain metastases at diagnosis was observed. Among screen-detected patients, 97.1% received any therapy compared to 85.3% among the clinically detected patients (p=0.105). Overall survival (OS) was significantly better in screen-detected patients, with a 3-year survival rate of 45.5% vs. 17% (p=0.00027). By multivariable analysis, OS was better in screen-detected patients (HR=0.37, 95% CI 0.20-0.68; p=0.001) (Table). There was no significant difference in progression-free survival between the groups. Conclusions: Our results demonstrate that SCLC patients diagnosed through the lung cancer screening program have better overall survival rates than those diagnosed clinically. These results suggest that developing appropriate screening measures may impact SCLC-related mortality. [Table: see text]
Tarlatamab in small cell lung cancer (SCLC): Safety and efficacy analyzed by baseline brain metastasis.
Authors: Champiat Stephane , Boyer Michael J. , Govindan Ramaswamy , Paz-Ares Luis G. , Owonikoko Taofeek K. , Borghaei Hossein , Izumi Hiroki , Steeghs Neeltje , Blackhall Fiona Helen , Terbuch Angelika , Johnson Melissa Lynne , Yoshida Tatsuya , He Kai , Zhang Yuyang , Jones Simon , Chen Xi , Martinez Pablo , Hummel Horst-Dieter 
Published: June 2023

8582 Background: Tarlatamab, a BiTE molecule targeting DLL3 and CD3, is being studied in patients (pts) with extensive stage small cell lung cancer (ES-SCLC).1 Up to 25% of pts diagnosed with SCLC have brain metastases (BM) and 50% or more will develop BM during the course of the disease. Pts with ES-SCLC and BM have poor prognosis and quality of life. We analyzed the characteristics and outcomes of pts included in the tarlatamab phase 1 study (NCT03319940) who had baseline BM vs those who did not. Methods: Pts included in the phase 1 trial had SCLC that progressed after ≥1 platinum-based regimen and received tarlatamab (0.003–100 mg IV). Pts with treated BM were eligible if local therapy was delivered ≥ 2 weeks prior to first tarlatamab dose. Results: As of 03 January 2023, 192 pts had received tarlatamab as monotherapy. Median age was 62 (range, 32–80) y; 188 pts (98%) had ECOG PS 0–1 and median prior therapy lines was 2 (range, 1–6), with 107 pts (56%) receiving prior anti-PD1/PD-L1. 48 pts (25%) had BM at screening and 142 (74%) did not (No BM); data was missing for 2 pts (1%). Pts with BM were more likely to have received > 3 prior lines of therapy (BM, 29%; No BM, 9%) and have a record of prior brain radiation (BM, 85%; No BM, 40%); otherwise, characteristics of pts with BM were generally similar to those without. Tarlatamab delivered comparable activity in pts with BM vs. those without in terms of objective response rate (ORR; 20%, 25%) and disease control rate (DCR; 59%, 50%) (Table). Median duration of response (DoR) was 14.9 months (BM) vs. 13.0 months (no BM). Median overall survival (OS) was 13.2 months in the BM group vs 15.5 months in the no BM group. Safety outcomes were similar in terms of treatment-related AEs (TRAEs; BM, 90%; No BM, 94%) and grade (gr) ≥ 3 (BM, 38%; No BM, 39%). Groups were also comparable with respect to immune effector cell-associated neurotoxicity syndrome (ICANS) and associated neurologic events (any-grade, 6% vs 9%; gr ≥ 3, 4% vs 4%) and neutropenia (any-grade, 10% vs 15%; gr ≥ 3, 8% vs 8%). AEs numerically different in the BM vs No BM group included gr ≥ 4 TRAEs (17%, 7%) and any-grade CRS (67%, 54%). The only grade 5 TRAE (pneumonitis) occurred in the BM group. Conclusions: Tarlatamab continues to show promising efficacy and is generally safe in pts with ES SCLC irrespective of the presence of BM. Rates of ICANS and associated neurologic AEs were comparable between those with and without BM at baseline. Reference: 1. Paz-Ares L, et al. J Clin Oncol. DOI:10.1200/JCO.22.02823. Clinical trial information: NCT03319940 . [Table: see text]
Phase Ib/IIa study assessing the safety and efficacy of AL8326 monotherapy in patients with ≥3rd line small cell lung cancer (SCLC) treatment.
Authors: Zhang Xiaochun , Li Xingya , Bi Minghong , Su Chunxia , Fang Yong , WANG Zibing , Yuan Ying , Du Xiuping , Lv Tangfeng , Li Yingyin 
Published: June 2023

8585 Background: AL8326 is a novel, orally administered, small molecule tyrosine kinase inhibitor (TKI). The primary objective of this Phase Ib/IIa study is to evaluate the safety and efficacy of AL8326 monotherapy in patients with ≥3rd line small cell lung cancer (SCLC) treatment. Methods: Patients with a diagnosis of small cell lung cancer either limited or extended stage requiring third or further line treatment were eligible for enrollment. The regimen was a 28-day cycle with oral AL8326 administered at 60 mg once per day via RECISIT1.1 evaluation until disease progression (PD), or intolerable toxicity or any other reason discontinuations. Results: At the cut-off date Nov 30, 2022, total n = 30 patients were enrolled. The objective response rate (ORR) was 20% (6/30) (4 confirmed). The disease control rate (DCR) was 56.7% (17/30). Median progression-free survival (PFS) was 3.65 months (95% CI: 1.9 – 5.5) and median overall survival (OS) was 10.42 months (95% CI: 5.4, NE). The median duration of response (DOR) was 5.6months. All 30 subjects had reported AE at least once. Common treatment emergent adverse events (TEAE) were similar to other TKI drug and included (incidence ≥20%): thyroid stimulating hormone (TSH) increase (46.67%), proteinuria (43.33%), weight loss (40.00%), hypertension (36.67%), thrombocytopenia (33.33%), diarrhea (33.33%), positive fecal occult blood (30.00%), hypercholesterolemia (26.67%), hypertriglyceridemia (26.67%), hand- foot syndrome (HFS) (20.00%), loss of appetite (20.00%). Most of these AEs were grade 1-2 (CTCAE V5.0). Conclusions: AL8326 has demonstrated acceptable tolerability and positive efficacy on small cell lung cancer treatment. A US Phase 2 (NCT05363280) study is ongoing and a phase 3 study is in preparation. Clinical trial information: NCT04890795 .
Tumor microenvironment-mediated immune profiles and efficacy of platinum doublet chemotherapy plus ICIs stratified by DLL3 expression in small cell lung cancer.
Authors: Shirasawa Masayuki , Yoshida Tatsuya , Shiraishi Kouya , Yagishita Shigehiro , Matsumoto Yuji , Masuda Ken , Shinno Yuki , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Naoki Katsuhiko , Tsuchida Takaaki , Hamamoto Ryuji , Yamamoto Noboru , Motoi Noriko , Kohno Takashi , Watanabe Shun-ichi , Ohe Yuichiro 
Published: June 2023

8586 Background: Delta-like ligand 3 (DLL3) frequently expressed in small cell lung cancer (SCLC) and has been emerged as a therapeutic target. However, it remains unclear how DLL3 expression status affects tumor microenvironment (TME)-mediated immune profiles and clinical outcomes of platinum doublet chemotherapy plus ICIs in SCLC patients. Methods: We retrospectively reviewed post-surgical limited-stage (LS)-SCLC, and extensive-stage (ES)-SCLC patients treated with platinum and etoposide (PE) plus anti-PD-L1 antibody. In LS-SCLC cohort, the transcriptome and whole-exome sequencing (WES) analysis were performed to assess the immune profiles, mutation status and neoantigen status. In ES-SCLC cohort, the association between the efficacy of immunochemotherapy and DLL3 expression by transcriptome analysis were evaluated. Results: Fifty-nine and 17 patients were included in the LS- and ES-SCLC cohort, respectively. In LS-SCLC cohort (n = 59), WES analysis revealed that SCLC with DLL3High had a significantly higher number of neoantigens (77 [95% confidence interval [CI] 65-113 ] vs. 48 [95% CI 17-58], p = 0.004), and a significantly higher rate of signature SBS4 associated with smoking (43% [95% CI 28-53] vs. 28% [95% CI 15-36], p = 0.02), although TMB did not differ according to DLL expression (6.6 mut/Mb [95% CI 5.3-9.6] vs. 6.5 mut/Mb [95% CI 5.2-9.9], p = 0.26). The transcriptome analysis in LS-SCLC cohort revealed that SCLC with DLL3High tumors had significantly suppressed immune-related pathways (IFN-γ response, inflammatory response, and TNFα signaling via nfkb), and dendritic cells (DC) function (DC Differentiation, DC Antigen Processing and Presentation, DC Migration). Profiling tumor infiltrating immune cells with CIBERSORT showed that SCLC with DLL3High had significantly lower proportions of T-cells, macrophages, and DCs compared with those with DLL3low. These results suggested that DLL3High tumors suppressed tumor immunity by inhibiting antigen-presenting function. In ES-SCLC cohort (n = 17), the PFS of PE plus anti-PD-L1 antibody in patients with DLL3High was significantly worse than those in patients with DLL3Low (4.1 months [95% CI, 2.0-6.3] vs. 7.4 months [95% CI, 2.5-12.3]; HR 3.78 [95% CI, 1.1-12.5], p = 0.03). Conclusions: SCLC with high DLL3 expression was characterized by resistance to immunochemotherapy due to suppressed tumor immunity, although those tumors had higher neoantigen loads.
Dissecting small cell lung cancer subtypes with cell-free DNA fragmentomes.
Authors: Rinaldi Lorenzo , Skidmore Zachary L. , Alipanahi Bahar , Graham Garrett , Chesnick Bryan , Takahashi Nobuyuki , Kumar Rajesh , Goyal Shubhank , Abel Melissa Lauren , Malin Justin , Desai Parth Anil , Dracopoli Nicholas C. , Velculescu Victor E. , Thomas Anish , Leal Alessandro 
Published: June 2023

8592 Background: Although small cell lung cancer (SCLC) is managed as a single cancer type, new evidence supports that subtypes (high vs low neuroendocrine) of SCLC acquire diverse transcriptional and epigenetic states. Furthermore, distinct SCLC subtypes acquire unique therapeutic vulnerabilities, such as the low-neuroendocrine highly inflamed SCLC subtype that has been linked to immunotherapy sensitivity. We have previously shown that DELFI (DNA evaluation of fragments for early interception) can be used to non-invasively distinguish SCLC from non-small cell lung cancer (NSCLC). Here, we report a preliminary analysis of using the DELFI approach for distinguishing among SCLC subtypes. Methods: Circulating cell-free DNA (cfDNA) was isolated from plasma samples of patients diagnosed with relapsed SCLC and treated with durvalumab plus olaparib in a phase II trial (NCT02484404). Over 200 cfDNA libraries were prepared for whole genome sequencing in batches with internal controls. To infer tumor gene expression profiles in cfDNA, we investigated genome-wide signals of tissue-specific transcription factors differentially regulated in SCLC, and applied a novel DELFI-based approach to inform SCLC molecular subtypes. Clinical information, patient-matched tissue transcriptome (RNA-seq), and chromatin accessibility data (ATAC-seq) were examined in orthogonal analyses. Results: The DELFI classifier detected SCLC cases (N = 47) with a median DELFI score of 1.0 (95% CI 0.99-1), significantly higher than previously reported scores for other lung cancer subtypes. Comparison of DELFI fragmentome signals to publicly available tumor transcriptomes shows subtype-level concordance ( r = 0.78, p < 0.001, Pearson), particularly in pre-treatment SCLC cases separating high- vs low- neuroendocrine subtypes. High-neuroendocrine SCLCs exhibited a decrease in aggregate cfDNA fragment coverage at ASCL1 transcription factor binding sites relative to low-neuroendocrine SCLCs (r = 0.90, p < 0.001, Pearson). Additionally, low-neuroendocrine SCLCs revealed a significant decrease in aggregate cfDNA fragment coverage at genomic binding sites regulated by hematopoietic transcription factors, reflecting the inflamed phenotype of this SCLC subtype. Integration of these approaches provided a cfDNA fragmentation-based machine learning model that distinguished SCLC subtypes with high performance. Conclusions: Genome-wide cfDNA fragmentome analyses can differentiate high- and low-neuroendocrine SCLC subtypes. Given the challenges for performing SCLC biopsies in a clinical setting, we believe this approach could be a viable method of subtyping SCLC in a non-invasive manner.
Brain metastasis burden and management in small cell lung cancer: An analysis of 8705 patients.
Authors: Gaebe Karolina , Erickson Anders W. , Leighl Natasha B. , Chan Kelvin K. , Lok Benjamin H. , Das Sunit 
Published: June 2023

8596 Background: Patients with small cell lung cancer (SCLC) have historically been characterised by poor overall survival (OS) and high risk for intracranial metastatic disease (IMD), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking. These patients traditionally receive whole brain radiation therapy (WBRT) for IMD, however, a recent systematic review has indicated that OS following stereotactic radiosurgery (SRS) may be non-inferior compared with WBRT. We aim to describe the clinical characteristics and outcomes of patients with SCLC and IMD in Ontario, Canada. Methods: We included all patients diagnosed with SCLC between April 2007 and March 2018 identified through a provincial health administrative database. Information on patient and treatment characteristics, incidence and time to IMD, and OS from time of SCLC diagnosis were collected and analyzed using R. Results: A total of 8705 patients were included. Median age was 68 years (range 18-103). Most patients presented with extensive disease (n = 5625) and were diagnosed after 2011 (n = 5768). Patients who received chemotherapy (n = 5563) had significantly longer OS than those who did not (median 10.64 vs 1.58 months (mo), hazard ratio (HR) 0.36, 95% confidence interval (CI) 0.34-0.37). 6662 patients received brain imaging at the time of primary diagnosis (CT: 5126, MRI: 1536), and 88% of patients surviving longer than 6 mo received more than one follow-up brain scan. 31% developed IMD (synchronous: 1175, asynchronous: 1511) with median intracranial progression-free survival of 5.65 mo. Median OS of patients with IMD was 9.76 mo, 29 and 1300 received SRS and WBRT as first treatment for their IMD, respectively. OS was in favour of SRS over WBRT (median 20.47 vs 8.74 mo, HR 0.57, 95% CI 0.39-0.84), which remained significant in multivariate analysis (p < 0.001). Conclusions: OS for patients with SCLC remains poor, and many patients present with IMD. With careful selection, patients with SCLC may benefit from SRS treatment.