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The effect of obecabtagene autoleucel (obe-cel) on adult patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and extramedullary disease (EMD).

6517 Background: Pts with R/R B-ALL and EMD have limited treatment options and are a population with an unmet need. Obe-cel is an autologous chimeric antigen receptor (CAR) T-cell therapy with a fast off-rate CAT19 binding domain and a 4-1BB-ζ co-stimulatory domain designed to improve persistence and reduce severe immunotoxicity. Here, we report a post-hoc analysis of the Phase Ib/II FELIX study (NCT04404660), evaluating efficacy and safety of obe-cel in pts with R/R B-ALL, by EMD status at lymphodepletion (LD). Methods: Following LD, adults with R/R B-ALL received obe-cel using a tumor burden-guided dosing strategy to minimize toxicity. Overall remission rate (ORR; complete remission [CR]/CR with incomplete hematologic recovery [CRi]), event-free survival (EFS), overall survival (OS), and safety are reported for pts with or without (w/o) EMD. Results: Of 127 obe-cel infused pts, 27 (21%) had EMD at LD and 100 (79%) did not. At screening, the median age (range) was 36.0 years (20–73) in pts with EMD, and 50.5 years (20–81) in pts w/o EMD. Of the pts with EMD, 13 (48%) were male and 11 (41%) were Hispanic or Latino; of those w/o EMD, 53 (53%) were male and 27 (27%) were Hispanic or Latino. The median number of prior lines of therapy (range) was 3.0 (1–6) and 2.0 (1–6) for pts with and w/o EMD at LD, respectively; prior SCT was received by 12 (44%) and 44 (44%) pts, respectively. At LD, the median bone marrow (BM) blast percentage (range) was 54% (0–100) in pts with EMD and 39% (0–100) in pts w/o EMD; Philadelphia chromosome-positive disease was observed in 6 (22%) and 30 (30%) pts, respectively. At 32.8 months’ (mos) median follow-up (range 20–53), the ORR (95% confidence interval [CI]) was 59% (39–78) in pts with EMD and 83% (74–90) in pts w/o EMD. Median DoR (95% CI) among responders was 42.5 mos (3.4–not evaluable [NE]) and NE, in those with (n=16) and w/o (n=83) EMD at LD, respectively. Overall, median EFS (95% CI) was 4.5 mos (0.0–NE) and 14.3 mos (9.0–NE) in pts with and w/o EMD at LD, respectively; however, median EFS appeared to be comparable in responders with (44.6 mos [6.0–NE]) and w/o EMD (NE). Overall, median OS (95% CI) was 15.3 mos (7.9–NE) and 21.0 mos (13.2–NE) in pts with and w/o EMD at LD, respectively. The incidence of Grade ≥3 cytokine release syndrome in pts with and those w/o EMD was 3.7% and 2.0%; the incidence of Grade ≥3 immune effector cell-associated neurotoxicity syndrome was 19% and 4.0%, respectively. Cerebrospinal fluid pharmacokinetic analyses are underway; data will be presented. Conclusions: Obe-cel treatment demonstrated favorable efficacy and safety outcomes in pts with and w/o EMD in the FELIX trial. Among responders, DoR in pts with EMD was comparable with that observed in pts w/o EMD. Overall, these findings support a positive benefit–risk profile for obe-cel, irrespective of EMD status at LD. Clinical trial information: NCT04404660 .

Doubling cascade testing uptake for hereditary cancer syndromes: Results from a cluster randomized controlled trial of a registry-aided outreach approach.

11007 Background: Cascade genetic testing for at-risk relatives (ARR) is the most critical strategy for cancer prevention in families with hereditary cancer syndromes. Affected ARR can benefit from increased awareness and frequent screening to ensure cancers are detected at an early, treatable stage. Locally, uptake is persistently low at 6-13%, reflecting a prominent clinical gap. The current standard of care, which relies on passive proband-dependent communication to disseminate genetic information to ARR, is highly inefficient. We hypothesized that a novel, structured, registry-aided outreach model would improve the uptake rate of cascade testing in Singapore, and thus conducted a trial to address the effectiveness of this approach. Methods: We conducted a cluster randomized controlled trial at the National Cancer Centre Singapore comparing two arms. (1) Control arm: Proband-dependent communication. (2) Experimental arm: Proband-dependent communication with systematic outreach to ARR, facilitated by a family registry and executed by trained genetics personnel. This solution shares the burden of disseminating genetic results, ensuring ARR receive accurate information from a healthcare professional. The primary endpoint was the proportion of at-risk first-degree relatives who completed cascade genetic testing. Results: A total of 150 probands from unique families and 386 ARR were recruited from February 2022 to March 2025 in National Cancer Centre Singapore. In the experimental arm, 78/196 relatives (39.8%) attended pre-test genetic counselling compared to 38/190 relatives (20.0%) in the control arm. In the experimental arm, 71/196 relatives (36.2%) proceeded with cascade testing after pre-test counselling, whilst 37/190 relatives (19.5%) in the control arm underwent cascade testing. In our study, with the addition of the novel registry-aided outreach approach, the percentage of relatives who attend the pre-test genetic counselling session doubled, whilst those who eventually had cascade testing increased by 86%, demonstrating its clear superiority over the passive proband-dependent approach. Conclusions: Our trial proves that a systematic, healthcare professional-driven, registry-aided outreach is an effective strategy to overcome the barriers in cascade testing. The registry-aided outreach approach is a feasible, successful and scalable solution to the low uptake of cascade testing in Singapore. Implementing this approach is essential for realizing the full potential of genetic medicine to prevent cancers in high-risk families with hereditary cancer syndromes.

Circulating tumor DNA monitoring in peptide receptor radionuclide therapy–treated patients with gastroenteropancreatic neuroendocrine tumors.

e16321 Background: Circulating biomarkers such as chromogranin A (CgA) are commonly used in the management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), but their clinical utility is limited by poor sensitivity, lack of specificity, and susceptibility to confounding factors including proton pump inhibitors, renal dysfunction, and systemic inflammation. As a tumor-agnostic marker, CgA cannot reliably track real-time disease dynamics. In contrast, circulating tumor DNA (ctDNA) offers a tumor-informed, minimally invasive strategy for monitoring treatment response and disease progression. This rertrospective series investigates ctDNA-guided disease monitoring in patients with advanced GEP-NETs treated with peptide receptor radionuclide therapy (PRRT). Methods: Four patients with metastatic, somatostatin-analogue–refractory GEP-NETs receiving PRRT were longitudinally monitored using serial ctDNA and CgA measurements alongside MRI or ⁶⁸Ga-DOTATATE PET/CT. ctDNA was assessed via a clinically validated personalized assay, Signatera, which tracks up to 16 tumor-specific variants identified by whole-exome sequencing. Results: ctDNA dynamics corresponded closely with therapeutic response and disease burden, and in some instances, changes in ctDNA levels preceded radiographic progression or stabilization. In contrast, CgA showed variable trends with limited concordance to clinical outcomes. Conclusions: Tumor-informed ctDNA can provide a sensitive, specific, and real-time molecular tool for response assessment in PRRT-treated GEP-NETs. These findings support its potential as a complementary biomarker to imaging and traditional serologic markers.

IDE892 as monotherapy and in combination with IDE397 in patients with 5-methylthioadenosine phosphorylase-deleted ( <i>MTAP</i> -Del) advanced solid tumors (IDE892001): Phase 1 trial.

TPS3182 Background: MTAP deletion in solid tumors causes intracellular accumulation of methylthioadenosine (MTA) which partially inhibits activity of the key methylating enzyme, protein arginine methyltransferase 5 (PRMT5) and creates synthetic lethal dependencies on PRMT5 and methionine adenosyltransferase 2A (MAT2A), the rate limiting step in the synthesis of PRMT5 substrate, S-adenosyl methionine. PRMT5 and MAT2A are essential to transcription modulation, gene splicing, and DNA damage response. IDE892 is an MTA-cooperative PRMT5 inhibitor designed to exploit this vulnerability in MTAPdel tumors. Preclinical studies report robust antitumor activity with IDE892 monotherapy in MTAPdel xenograft models and an enhanced response when combined with IDE397 (an allosteric MAT2A inhibitor). IDE892-001 is a Phase 1 study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of IDE892 alone and in combination with IDE397. Methods: IDE892-001 is an ongoing, open-label, multicenter four-part study: IDE892 monotherapy dose escalation (Part 1), monotherapy dose expansion in MTAPdel NSCLC (Part 2), IDE892 + IDE397 dose escalation (Part 3), and combination expansion in MTAPdel NSCLC (Part 4). Adults with advanced or metastatic MTAPdel solid tumors including lung, urothelial, gastrointestinal cancers (including pancreatic and biliary tract cancers) and mesothelioma are eligible following disease progression on standard therapies. Key exclusion criteria include symptomatic brain metastases, cardiac disease, active severe infection, and prior treatment with a PRMT5 or MAT2A inhibitor. Part 1 uses a Bayesian optimal interval design to determine maximum tolerated dose (MTD) and recommended doses for expansion (RDE). Part 3 uses a modified toxicity probability interval design to evaluate escalating combinations of IDE892 and IDE397. Oral treatment is given QD in 21-day cycles until progression or unacceptable toxicity. Serial blood samples are collected for PD analyses. Imaging will be performed every 6 weeks through week 24, then every 9–12 weeks. Efficacy endpoints will be assessed by RECIST v1.1. Primary objectives for dose-escalation cohorts (Parts 1 and 3) are safety and tolerability, including determination of MTD/RDE. In expansion cohorts (Parts 2 and 4), co-primary objectives include safety and preliminary antitumor activity (objective response rate and duration of response). Secondary endpoints for all parts include PK of IDE892 alone and in combination with IDE397. Exploratory assessments include progression free survival, changes in circulating and tumor-based markers of PRMT5 pathway modulation, molecular predictors of response, exposure–response relationships, and metabolite characterization. Clinical trial information: NCT07277413 .

Bifunctional therapeutic potential of hydroxyapatite nanoparticles surface functionalized with Rutin - L-Arginine bioactive complex for enhanced anticancer efficacy against osteosarcoma

Molecularly Engineered Spherical Hybrid Glass Scintillator Enables Portable Omnidirectional X‐Ray Detection With High Sensitivity

ABSTRACT Omnidirectional X‐ray detection is important for applications such as high‐energy astrophysics and environmental safety monitoring. However, conventional approaches to omnidirectional X‐ray detection, based on solid‐state flat‐panel detectors or gas/liquid‐state spherical detectors, are often hindered by fabrication complexity, insufficient omnidirectional response, or limited portability. Herein, we present a portable solid‐state omnidirectional X‐ray detector (ODXD) based on a spherical glass scintillator composed of (CPTP) 2 MnBr 4 (CPTP = cyclopropyltriphenylphosphine). From a crystallographic perspective, the cyclopropyl group in triphenylphosphine cation plays a critical role in modulating the phase transition of (CPTP) 2 MnBr 4 . This molecular design not only lowers melting temperature (170°C), enabling device fabrication via a low‐temperature melt‐quenching process, but also provides a sufficiently high glass transition temperature (61°C) to ensure operational stability. From a device perspective, the ODXD based on spherical (CPTP) 2 MnBr 4 glass offers excellent omnidirectionality and registers an X‐ray response limit of 0.49 µGy air s −1 , which is 11‐fold lower than the regular medical diagnostic dose rate (5.5 µGy air s −1 ), demonstrating exceptional capabilities for monitoring omnidirectional X‐ray sources with high sensitivity. Given the high processability of organic‐inorganic glasses and the simplicity of their fabrication, our findings provide a viable solution for constructing portable omnidirectional optical detectors toward advanced sensing and photonic applications.

Debio 0123 (zedoresertib), a selective WEE1 inhibitor, in combination with carboplatin in adult patients with platinum-resistant ovarian cancer: Expansion part of the Debio0123-101 phase 1 study.

e15154 Background: Debio 0123 is an oral, brain-penetrant, highly selective WEE1 inhibitor. WEE1 inhibition leads to S phase and G2/M cell cycle checkpoint abrogation, allowing mitosis without DNA repair, leading to mitotic catastrophe and subsequent cell death. Debio 0123 is in clinical development for solid tumors, as monotherapy and in combination with various therapeutic agents. Here, we report the safety, pharmacokinetics, pharmacodynamics, and antitumor efficacy of Debio 0123 in combination with carboplatin in adult patients (pts) with platinum-resistant, high-grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (PROC) during the expansion phase and for all pts with PROC treated at the recommended phase 2 dose (RP2D) of the Debio 0123-101 study. Methods: Pts with PROC were treated at the selected RP2D of Debio 0123 of 520 mg administered on Days 1–3 and 8–10, plus carboplatin on Day 1 of 21-day cycles. Pharmacokinetics was assessed in Cycle 1 and Cycle 2. Paired skin biopsies were performed at baseline (screening or pre-dose C1D1) and on treatment (C1D10 post-dose) to evaluate target engagement. The primary objective was to assess safety and tolerability, as well as to evaluate preliminary antitumor activity. Secondary objectives included additional parameters of efficacy and pharmacokinetics. Results: As of November 18, 2025, Debio 0123 was administered to 21 pts in the expansion phase (females with mean age of 63 years [range 48–79]). The most common Debio 0123 treatment-related adverse events (TRAEs) were nausea (66.7%), vomiting (52.4%), fatigue (52.4%),anemia (38.1%), ECG QT prolonged (38.1%), thrombocytopenia (33.3%), and neutropenia (23.8%). Additionally, 'ECG QT interval normal' was reported in 28.6% of patients (defined as QTc interval &lt; 450 msec and change from baseline of &gt; 30 msec and ≤60 msec). The most common Grade ≥3 Debio 0123 TRAEs were thrombocytopenia (23.8%), fatigue (19%), and anemia (14.3%). TRAEs led to Debio 0123 dose interruptions in 13 (61.9%) pts, dose reductions in 5 (23.8%), and treatment discontinuation in 5 (23.8%). Among 20 response-evaluable pts, 3 (15%) had partial response and 11 (55%) stable disease resulting in a disease control rate (DCR) of 70%. Median PFS was 3.8 months (95% CI, 2.1–5.5). Considering all pts with PROC treated at the RP2D (dose escalation + expansion), 4 (19%) out of 21 pts had PR, for a DCR of 71.4%. CA-125 decrease from baseline of more than 50% was observed in 10 (pts with SD/PR) out of 21 (47.6%) pts. A relationship between Debio 0123 plasma exposure and skin pCDC2 level decrease (pharmacodynamics marker) was observed. Conclusions: Debio 0123, combined with carboplatin, has a manageable safety profile at the tested dose of 520 mg; the combination showed signals of antitumor activity in pts with PROC. Clinical trial information: NCT03968653 .

Clinical impact of routine MRI screening for brain metastasis in patients with breast cancer: A meta-analysis.

e14031 Background: Brain metastases (BM) are a frequent and clinically significant complication of metastatic breast cancer (BC), often associated with substantial morbidity and poor prognosis. While brain MRI is routinely performed in symptomatic patients, the clinical value of routine MRI screening in asymptomatic patients remains uncertain and is not uniformly recommended by current guidelines. Clarifying the detection yield of routine MRI screening is essential to inform surveillance strategies and future recommendations. Methods: A systematic search of PubMed, Scopus, and Embase, supplemented by ASCO, SABCS, and SNO conference proceedings, was conducted through January 21, 2026. Studies evaluating routine brain MRI screening in patients with BC without known BM or clinically evident CNS disease at baseline were included. Observational studies and clinical trials with extractable detection yield data were eligible. The primary outcome was asymptomatic BM detection yield, defined as the proportion of screened patients with previously unknown, asymptomatic BM detected on MRI. The secondary outcome was total BM detection yield. Pooled estimates were calculated using random-effects meta-analysis of proportions with logit transformation. Heterogeneity was assessed using I², τ², and Cochran Q. Sensitivity analyses included leave-one-out analyses. Results: Of 744 records identified, 7 studies comprising 653 patients met the criteria for inclusion (5 observational [71.4%], 2 clinical trials [28.6%]). Median age was 51.5 years (IQR 42.5–53.7). Cohorts included patients with advanced (n=372) or any stage disease (n=281). All studies excluded patients with known BM or clinically evident CNS disease at baseline. Median follow-up was 16.0 months (IQR, 9.0–20.05). Routine MRI screening detected previously unknown asymptomatic BM in a pooled 14.9% of patients (95% CI, 8.4%–25.1%), with substantial heterogeneity (I²=84.9%, τ²=0.52; Q=33.1, df=5, p&lt;0.001). The pooled total BM detection yield was 13.6% (95% CI, 7.1%–24.5%), with high heterogeneity (I²=85.2%, τ²=0.67; Q=33.9, df=5, p&lt;0.001). Leave-one-out analyses demonstrated robust pooled estimates, with asymptomatic detection yields ranging from 12.1% to 18.6%, indicating no single study disproportionately influenced results. Conclusions: Routine brain MRI screening in patients with BC without known CNS disease identifies previously unrecognized asymptomatic BM, albeit with variable detection yields. These findings highlight the potential clinical relevance of routine MRI screening in selected populations and support the need for prospective, risk-adapted studies to define its optimal role. Meta-analytic results. Metric Asymptomatic BM detection yield Total BM detection yield Pooled detection yield 0.149 0.136 95% confidence interval 0.084–0.251 0.071–0.245 p value (Q) &lt;0.001 &lt;0.001 Heterogeneity (I², %) 84.9 85.2

Barriers and facilitators to multidisciplinary head &amp; neck cancer care coordination in Tanzania.

e13567 Background: Tumor boards (TBs) are considered a standard of care for multidisciplinary, patient-centered cancer management. In high-income countries, they have been shown to significantly influence treatment planning and clinical decision-making. However, there is scarce literature describing how to implement and sustain high-quality TBs in low- and middle-income countries (LMICs), where limited specialized infrastructure, workforce shortages, and fragmented diagnostic and referral systems may pose unique challenges. At Muhimbili National Hospital (MNH) and Ocean Road Cancer Institute (ORCI) in Dar es Salaam, Tanzania, a general adult tumor board currently functions as a referral mechanism between institutions, but stakeholders have identified the need for disease-specific TBs to improve coordination and efficiency. This study aims to characterize barriers and facilitators to implementing a disease-focused head and neck tumor board. Methods: We conducted thematic analysis of 15 semi-structured interviews with healthcare providers involved in head and neck cancer (HNC) care at MNH and ORCI, the two largest tertiary cancer centers in Tanzania. Interviews explored strengths and weaknesses of the current general TB, barriers and facilitators to effective multidisciplinary collaboration, and expectations for a disease-focused HNC tumor board. The interviews were coded and analyzed using Dedoose qualitative analysis software. Results: Providers described logistical and workflow challenges within the current general tumor board, including inconsistent meeting structure, unclear roles, and reduced engagement in the virtual format. Coordination challenges between institutions were frequently cited, particularly the absence of streamlined communication between providers and limited coordinated follow-up after tumor board discussions. Providers also highlighted barriers in cross-institution data sharing, noting that imaging and operative reports are not consistently available across sites. Despite these challenges, providers expressed a strong commitment to multidisciplinary cancer care. Facilitators included institutional prioritization of a disease-focused tumor board, buy-in across several specialties, and existing general tumor board and referral mechanisms that can be leveraged to support TB implementation. Conclusions: Barriers to a high-quality disease-focused tumor board at MNH and ORCI are largely structural. However, strong provider commitment and institutional momentum represent important facilitators that can support the implementation and sustainability of an HNC tumor board. These findings inform strategies for strengthening multidisciplinary cancer care and support the development of sustainable disease-focused tumor boards in resource-constrained settings.

Deep learning on routine histopathology to enable one-year survival prediction in pancreatic ductal adenocarcinoma.

e16016 Background: Pancreatic cancer ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis and limited tools for survival stratification. Our prior work demonstrated the feasibility of predicting Moffitt molecular subtypes from histopathology; however, these subtypes showed limited association with overall survival, motivating direct outcome-based modeling. We hypothesized that whole slide images (WSI) contain prognostically relevant morphologic signals that can be leveraged to predict short-term survival in PDAC. Methods: We analyzed PDAC cases from the Pancreatic Cancer Action Network (PANCAN) dataset (n = 846), including 272 patients with survival data. A WSI-based deep learning framework (PathRosetta) was trained to predict 1-year survival using five-fold cross-validation. In parallel, pretrained PathRosetta models predicting pan-cancer genetic alterations (APC, BRAF, KMT2D, KRAS, PIK3CA, TP53, and TTN) were used to extract mutation-relevant morphologic features for survival modeling, evaluated using leave-one-out cross-validation. The mutations were selected based on the availability of robust pretrained models with adequate case numbers in The Cancer Genome Atlas (TCGA), rather than PDAC-specific biological hypotheses. These represent mutations for which reliable pan-cancer prediction models currently exist. Results: At 1 year, 71 of 272 patients had died. Mutation-relevant morphologic-feature–based models demonstrated discrimination comparable to or superior to that of direct WSI modeling, with TP53 achieving the highest performance (Table). Conclusions: Deep learning applied to routine histopathology enables prediction of 1-year survival in PDAC. Leveraging mutation-relevant morphologic representations improves prognostic performance and supports a biologically grounded link between tumor genetics, tissue architecture, and clinical outcomes, highlighting the potential of WSI-based models for clinically meaningful risk stratification. It potentially aids in baseline risk stratification, with potential implications for clinical decision-making and trial enrichment. Performance for one-year survival Prediction in PDAC. AUC Accuracy Sensitivity Specificity PathRosetta (scratch) 0.768 ± 0.036 0.707 ± 0.018 0.634 ± 0.112 0.730 ± 0.054 APC 0.818 0.920 0.864 0.937 BRAF 0.791 0.905 0.841 0.926 KMT2D 0.786 0.904 0.851 0.922 KRAS 0.726 0.871 0.797 0.896 PIK3CA 0.729 0.890 0.771 0.933 TP53 0.877 0.935 0.938 0.934 TTN 0.745 0.862 0.846 0.868

Phase 2 multicenter trial of chemoimmunotherapy for patients with neuroendocrine or aggressive variant metastatic prostate cancer (CHAMP).

5016 Background: Platinum-doublet chemotherapy is effective in pts with neuroendocrine small cell neuroendocrine or aggressive-variant prostate cancer (NEPC/AVPC), but responses have limited durability. PD-1/PD-L1 inhibition in small cell lung cancer with chemotherapy is standard of care, but chemoimmunotherapy has not been tested in patients with NEPC/AVPC. Methods: We conducted a multicenter, phase II trial evaluating cabazitaxel, carboplatin, ipilimumab, and nivolumab (NCT04709276) in patients with metastatic NEPC/AVPC defined by histologic, clinical, or molecular features. Ipilimumab was dosed at 1 mg/kg q6w and nivolumab 360 mg q3w w/ongoing ADT. Cabazitaxel 20-25 mg/m2 + carboplatin AUC4 with GCSF was given q3w up to 10 cycles but could be stopped early for response or toxicity, followed by maintenance immunotherapy. Primary endpoint was immune modified iRECIST/PCWG3 radiographic progression-free survival (rPFS), hypothesizing a 55% 6-mo rPFS rate for cabazitaxel/carboplatin (1-sided α 0.1, 85% power) based on historic data. Secondary endpoints: overall survival (OS), rPFS, objective responses, safety. Results: We enrolled 40 patients across 3 centers in the Department of Defense Prostate Cancer Clinical Trials Consortium from 7/2021-8/2025, including 12 (32%) with NEPC and 28 (68%) with AVPC, with 38 evaluable for efficacy. Median age was 65 yrs, median PSA 2 ng/dl (range 0-807), and 75% with any visceral metastases including 58% with liver and 33% with lung metastases. The % with elevated serum CEA, LDH, or CgA was 88%; 85% had prior ARPI and 70% prior chemo. With a median f/u of 17 mo, CHAMP met its primary endpoint of improving 6-mo rPFS vs. cabazi/carbo with a 6-mo PFS rate of 78% (90% CI 69-100%); median rPFS was 12 mo. See Table for efficacy. We observed 20 G3 (50%) and 7 G4 (18%) toxicities related to treatment on a per patient basis. Two patients are free of disease and off therapy at 30+ mo. Most common overall G3-4 toxicities were anemia (n=15), neutropenia (n=5), sepsis (n=5), thrombocytopenia (n=5), colitis (n=5), febrile neutropenia (n=4), and UTI (n=4), with no treatment-related deaths. Conclusions: Dual PD-1/CTLA4 immune checkpoint blockade with platinum doublet chemotherapy is effective in patients with AVPC/NEPC, resulting in greater efficacy than expected with historic platinum chemotherapy alone, and with acceptable toxicity given disease risk. These results support randomized controlled clinical trials of chemoimmunotherapy in patients with NEPC/AVPC. Clinical trial information: NCT04709276 . Primary Endpoint (n=38) Outcome (95% CI) 6 mo PFS (%) by iRECIST/PCWG3 (1-sided 90% CI) 78% (69-100%) Secondary Endpoints 12 mo rPFS (%, 95% CI) 44% (29-69%) PFS, median by iRECIST/PCWG3, moPFS, median by RECIST/PCWG3, mo 12 (9.6-17)6.8 (4.3-9.2) OS, median, mo12-month OS (%) 12 (9.6-17)46% (30-69%) iRECIST Best Radiographic ResponseORR (CR+PR) %CRPRSDiUPD/iCPD 34%2.6%32%45%13/8%

Epidemiologic and clinicopathological characteristics of SMARCA4-deficient non–small cell lung cancer form a single center in Yunnan, China.

e20771 Background: SMARCA4-deficient non-small cell lung cancer (SMARCA4-d NSCLC) is an aggressive subtype with poorly defined geographic epidemiology. Yunnan Province is a lung cancer high-risk area with unique etiological factors. The characteristics of SMARCA4-d NSCLC in this region are unknown. Methods: We retrospectively identified SMARCA4-d NSCLC (confirmed by BRG1 IHC loss) from 3124 consecutive NSCLC cases at Yunnan Cancer Hospital (06/2025-11/2025). Clinicopathological data, IHC profiles, and imaging data were analyzed. This cohort forms the basis of an ongoing expanded multicenter study in Yunnan incorporating longitudinal follow-up, treatment response evaluation, and multi-omics profiling. Results: 40 SMARCA4-d NSCLC cases (approximately 1% prevalence) were identified. Patients were predominantly male (95.0%) with a male-to-female ratio of 19:1, 81.5% smokers (31/38) , with a median age of 63.5 years, and geographically clustered in high-incidence mining areas such as Kunming, Qujing City, and Honghe Prefecture . The right upper lobe was the most common primary site.SMARCA4-deficient NSCLC are characterized by bulky primary tumors, lymph node involvement, and distant spread. They show a particular predilection for retroperitoneal lymph node and adrenal metastases compared to typical NSCLC.Importantly, even upper-lobe tumors frequently involve station 7 and 10 lymph nodes. This pattern indicates unique biological behavior in the Yunnan population, which merits further exploration. IHC showed a heterogeneous/null phenotype: TTF-1+ (35.3%), Napsin A+ (16.1%), CK5/6+ (36.1%), P40+ (20.5%)(Table 1), with a high median Ki-67 index (60%). Conclusions: We report the unique clinicopathological profile of SMARCA4-d NSCLC in Yunnan, characterized by a specific high-risk demographic, heterogeneous immunophenotype, high proliferation, and a novel predilection for downward metastatic spread. These findings warrant enhanced abdominal staging awareness in this population. Our ongoing multicenter validation, coupled with planned deep molecular and microenvironmental characterization, aims to define the biological drivers of this aggressive variant and explore its therapeutic vulnerabilities. IHC profiles of SMARCA4-deficient non-small cell lung cancer in yunnan. Marker Positive Negative Unknown SMARCA4/BRG-1 0 (0%) 40 (100%) 0 (0%) TTF-1 12 (30%) 22 (55.0%) 6 (15.0%) NapsinA 5 (12.5%) 26 (65,0%) 9 (22.5%) CK5/6 13 (32.5%) 23 (57.5%) 4 (10.0%) P40 8 (20.0%) 31 (77.5%) 1 (2.5%) CD56/Syn/CgA 1 (2.5%) 29 (72.5%) 10 (25%)

NCDB analysis of follicular adenocarcinoma, well-differentiated: Demographic and clinical outcomes.

e18134 Background: Follicular adenocarcinoma, well differentiated (FAWD), is a slow-growing cancer that originates in the follicular cells of the thyroid gland and typically has a favorable prognosis, with over 92.3% of patients surviving 5 years after diagnosis. However, a subset of cases may exhibit aggressive behavior, including vascular or capsular invasion and distant metastases. Standard management involves surgical thyroidectomy, sometimes followed by radioactive iodine ablation. Because this malignancy is rare, population-level epidemiological data are limited, and a comprehensive analysis using data from a national cancer registry could help clarify how demographic and clinical factors relate to disease risk and treatment outcomes. Methods: This study employed a retrospective cohort design using the National Cancer Database (NCDB) from 2004 to 2020, encompassing 999 patients with histologically verified FAWD diagnoses (ICD-O-3 Code 8331). The analysis examined demographic characteristics (age, sex, race, Hispanic ethnicity, education, insurance coverage, treatment facility type, travel distance to facility, and Charlson-Deyo comorbidity scores) via descriptive statistics. Incidence patterns were evaluated using regression analysis. Results: A total of 999 patients were identified, demonstrating a stable incidence across the period (R^2 = 0.019). The mean age at diagnosis was 50.3 years, and the mean tumor size was 36.7 mm. The cohort was predominantly female (71.8%), White (78.7%), and non-Hispanic (87.5%). 42.3% patients resided in the highest socioeconomic strata (≥ $74,063), and the majority were insured by private carriers (61.5%). Surgical resection was the primary therapeutic modality (92.3%), with 88.0% of those cases achieving negative margins. Total thyroidectomy (65.4%) was the most common surgical procedure. Primary radiation treatment was utilized by 59.8% of the cohort, while chemotherapy and immunotherapy were rare (&lt;1%). The mean overall survival was 183.21 months, and the 2-year, 5-year, and 10-year survival rates were 96.9%, 92.3%, and 85.8%, respectively. Conclusions: To our knowledge, this is the first comprehensive NCDB analysis characterizing FAWD. Findings show that FAWD patients are predominantly White, non-Hispanic females with low comorbidity and early-stage disease, aligning with the known association between higher socioeconomic status and well-differentiated thyroid cancer. They were also more likely to belong to the highest socioeconomic strata and receive care in academic or comprehensive community centers. The high rate of R0 resections and favorable 10-year overall survival suggest an excellent prognosis. Further research is needed to clarify how demographic and socioeconomic factors influence outcomes.

Cocaine use disorder among hospitalized patients with non-Hodgkin’s lymphoma: A national study.

e19105 Background: Cocaine use disorder (CUD) continues to be a public health concern, with a documented global resurgence in recent years. Cocaine has demonstrated mutagenic and immunomodulatory properties through several mechanisms, such as oxidative stress, impaired DNA repair, dysregulation of apoptotic pathways, and altered lymphocyte signaling. Prior studies suggest a potential link between CUD and hematologic malignancies, most notably non-Hodgkin’s lymphoma (NHL). The impact of CUD on inpatient outcomes among patients with NHL is not well established, therefore we aim to characterize the association in a nationally representative cohort. Methods: We conducted a cross-sectional study using the 2016-2019 National Inpatient Sample database of adult (≥18 years) hospitalizations with NHL. CUD, NHL, and clinical outcomes were identified using ICD-10-CM diagnosis and procedure codes. The Charlson comorbidity index (CCI) was used to compare comorbidities. Significance of descriptive data was determined with chi-square tests. Multivariable logistic regression was used to evaluate the association of CUD with clinical outcomes, adjusting for demographics, CCI, human immunodeficiency virus infection, Epstein-Barr virus infection, autoimmune disease, history of organ transplant, chemotherapy or immunotherapy administration, other substance use, hospital region, type of hospital admission, and cancer stage. Survey weights were applied to generate nationally representative estimates. Results: Among 793,060 weighted hospitalizations of patients with NHL, 2,400 (0.3%) had CUD. Patients with CUD were more likely to be younger (51 vs 66 years), male (73% vs 57%), from a minority population (65% vs 25%), have Medicaid (48% vs 9%), and be in the lowest household income quartile (51% vs 23%) (all p&lt;0.0001). After adjustment, CUD was independently associated with higher odds of mortality (aOR 1.73, 95% CI: 1.34-2.17, p&lt;0.0001), sepsis (aOR 1.45, 95% CI: 1.28-1.65, p&lt;0.0001), nosocomial pneumonia (aOR 2.19, 95% CI: 1.17-4.09, p=0.014), neutropenic fever (aOR 1.61, 95% CI: 1.28-2.04, p&lt;0.0001), dialysis (aOR 2.20, 95% CI: 1.62-3.04, p&lt;0.0001), and mechanical ventilation (aOR 1.21, 95% CI: 1.01-1.47, p=0.044). No significant associations were observed with deep vein thrombosis, pulmonary embolism, acute kidney injury, or disseminated intravascular coagulation. Conclusions: Our results demonstrate that CUD is associated with significant sociodemographic disparities and worse clinical outcomes in hospitalized patients with NHL. These findings support previous studies associating cocaine use with immune dysregulation, which may increase susceptibility to infection and critical illness. Overall, these data identify CUD as a significant risk factor and highlight the need for improved multidisciplinary management in this vulnerable population.

Physics-informed neural network–driven early assessment of PEG feeding tube placement prediction for head and neck cancer.

e18113 Background: Percutaneous endoscopic gastronomy (PEG) feeding tubes are placed in patients with head and neck (HN) cancer to manage nutritional challenges during treatment. Developing a prediction model to assist clinicians in identifying patients requiring PEG feeding tubes is important for augmenting the clinical decision-making. This study focuses on developing Physics-informed Neural Network (PINN)-based prediction models utilizing the key features for PEG feeding tube placement. Methods: Data was collected from 65 patients who received radiation therapy (66-70 Gy in 33-35 fractions). Of which 32 patients underwent PEG placement in reactive condition and patients’ median age was 65 years (range: 42-93 yrs). To develop the PINN-based PEG feeding tube prediction model, clinically most impactful features were identified by the Radiation Oncologists, including Age, Performance status, Weight loss at first OTV, Weight loss at last OTV, Tumor (T-stage), Neck Involvement, Level 1 to Level 5 (index), Bi-neck (index), Pre-treatment Dysphagia, Mean dose to oropharynx, Mean dose to Hypopharynx, Mean dose to Oral Cavity, Mean dose to Cervical Esophagus, Mean dose to Pharyngeal Constrictor, and Mean dose to Parotid Gland combined. The designed predictive model comprises of three layers of dense neural network with the combination of binary cross entropy and physics-based mean square error residual loss function. The considered cost function minimizes the deviation between network output and an explicitly formulated analytical expression using input features to accurately predict PEG tube placement. Results: The developed PINN model with these 19 features as inputs, achieved performance as AUC of 0.78 (±0.09), sensitivity of 0.85 (±0.18), and specificity of 0.72 (±0.22) for five-fold cross validation. This study also highlights comparative analysis with conventional models (Random Forest (RF), K-nearest Neighbor (KNN), and Gradient boost (GB)), in which AUCs observed in the range of 0.65 to 0.70. Results also indicated that proposed PINN architecture achieved the best prediction performance with 11.4% improvement in AUC metric compared to other models. Conclusions: This study provided encouraging results while the influential features are employed for developing the machine learning (ML)-based prediction model with the objective of feeding tube placement for HN cancer patients. However, future study with multicentric large cohort of patients’ data is warranted. The performance analysis of PINN-based PEG feeding tube prediction models. ML-models AUC Sensitivity Specificity Weighted Avg F1-score RF 0.70 (±0.09) 0.90 (±0.07) 0.61 (±0.16) 0.75 (±0.06) KNN 0.67 (±0.18) 0.74 (±0.31) 0.69 (±0.21) 0.72 (±0.08) GB 0.65 (±0.09) 0.72 (±0.19) 0.70 (±0.16) 0.71 (±0.06) PINN (Proposed) 0.78 (±0.09) 0.85 (±0.18) 0.72 (±0.22) 0.76 (±0.09)

A multicenter single-arm phase II trial evaluating the safety and efficacy of panitumumab and irinotecan in patients with Neo <i>RAS</i> wild-type metastatic colorectal cancer (C-PROWESS trial).

3546 Background: Previous studies have demonstrated favorable efficacy of anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in metastatic colorectal (mCRC) patients with Neo RAS wild type (WT), ie, conversion of RAS status from mutant to WT following treatment. This multicenter, single-arm, phase II trial evaluated the efficacy and safety of panitumumab plus irinotecan for mCRC patients with Neo RAS WT. Methods: Patients with tissue-confirmed RAS mutant mCRC who developed intolerance to or disease progression after fluoropyrimidine, oxaliplatin, and irinotecan were screened for RAS mutation status in circulating tumor DNA (ctDNA) with the OncoBEAM RAS CRC assay. Those without RAS mutations detected within 28 days before enrollment received panitumumab (6 mg/kg) and irinotecan (150 mg/m 2 ) biweekly. The primary endpoint was a response rate (RR) per RECIST 1.1. Secondary endpoints included disease control rate (DCR; response or stable disease), progression-free survival (PFS), overall survival (OS), safety, and biomarker analysis using next-generation sequencing (NGS) of ctDNA (Guardant360). The null hypothesis was a RR of &lt; 4%, and the alternative hypothesis was ≥ 15%, with 80% power and a one-sided 10% significance level. The required sample size is 30. Results: Among 404 patients screened for RAS status in ctDNA, conversion to Neo RAS WT was observed in 54 (13.3%), and 30 patients were enrolled. Median age was 66.5 years old, and 20 (66.7%) were male. Lung was the most frequent site of metastasis (73.3%), and KRAS exon 2 accounted for 80% of prior tissue RAS MT. RR and DCR were 6.7% (80% CI, 1.8 to 16.8) and 76.7% (95% CI, 57.7 to 90.1), respectively. With median follow-up 22.4 months, median PFS was 4.1 months and median OS was 16.8 months. Grade 3 adverse events were observed in 14 patients (46.7%): skin toxicity (13.3%), hypomagnesemia (10.0%), diarrhea (10.0%), appetite loss (10.0%), and anemia (7.0%). No grade ≥4 adverse event was observed. ctDNA NGS results were available for 27 patients and included KRAS (44.4%), NRAS (3.7%), and PIK3CA (7.4%) mutations and ERBB2 amplification (3.7%). RR for patients with none of these mutations (negative hyper-selection cohort) was 16.7% (2/12) while no patient with any of these alterations achieved a response (0/15). Negative hyper-selection was associated with significantly longer PFS and OS (PFS: 6.1 vs 2.9 months, HR, 0.37, 95%CI, 0.16 to 0.87; OS: 25.5 vs 13.1 months, HR, 0.34, 95% CI, 0.12 to 0.99). In multivariate analysis, negative hyper-selection was an independent factor for PFS (HR, 0.12, 95%CI, 0.03 to 0.41) and OS (HR, 0.30, 95%CI, 0.10 to 0.96). Conclusions: Anti-EGFR mAb with chemotherapy may be effective for Neo RAS WT mCRC, especially for patients hyper-selected for absence of gene mutations related to anti-EGFR mAb resistance. Clinical trial information: s031210565.

Patient preferences regarding bispecific antibody (BsAb) treatment schedules and clinical profiles in second-line or later (2L+) diffuse large B-cell lymphoma (DLBCL).

e23129 Background: Recent trials have examined BsAb combinations in 2L+ relapsed/refractory (R/R) DLBCL: glofitamab plus gemcitabine-oxaliplatin (Glofit-GemOx) in STARGLO and mosunetuzumab plus polatuzumab vedotin (Mosun-Pola) in SUNMO are characterized by less frequent dosing vs epcoritamab plus gemcitabine-oxaliplatin (Epcor-GemOx) in EPCORE NHL-2 and by fixed-duration treatment (FDT). A survey was developed to understand patient preferences for clinical and treatment (Tx) attributes in the R/R DLBCL setting. Methods: An online rolling survey (Dec 2024–Oct 2025) was completed by US adults with DLBCL who had received ≥1 Tx. Preferences were assessed through direct elicitation (selecting between pairs of fixed Tx profiles) and object-case best-worst scaling (BWS; to identify the most and least burdensome process-related attributes). Tx attributes included administration mode, Tx duration, administration frequency in 1 year, risk of cytokine release syndrome (CRS), progression-free survival (PFS), and overall survival (OS). Results: Overall, 175 patients (pts) completed the survey (mean age: 65 years; male: 50%; White: 58%). Mean time from diagnosis to survey completion was 4.5 years; 40% were on active Tx; 65% had prior immunotherapy; 78% reported changing Tx ≥2 times due to disease progression. Of 115 pts who answered the direct elicitation question, 84% preferred a Glofit-GemOx-like (intravenous [IV], FDT, less frequent Tx, longer PFS/OS, lower CRS risk) vs an Epcor-GemOx-like profile (IV and subcutaneous, treat-to-progression [TTP], more frequent Tx, shorter PFS/OS, higher CRS risk). In addition, of 50 pts comparing between Mosun-Pola vs Epcor-GemOx, 86% preferred a Mosun-Pola-like (no chemotherapy, FDT, less frequent Tx, similar PFS/OS, lower CRS risk) vs an Epcor-GemOx-like profile (includes chemotherapy, TTP, more frequent Tx, similar PFS/OS, higher CRS risk). Among pts who chose the Glofit-GemOx-like (n=96) and Mosun-Pola-like (n=43) profiles, 77% and 72%, respectively, would choose that option if starting Tx today. When ranking features on a scale of 1 to 8 (1 = most important) between Mosun-Pola-like and Epcor-GemOx-like profiles, the three most important features were PFS (mean [standard deviation]: 2.4 [1.5]), OS (2.8 [1.7]), and Tx duration (3.9 [2.0]). BWS results revealed that longer travel times to receive Tx was most burdensome and having medical appointments for fewer days in a year was least burdensome. Conclusions: Among 2L+ multi-agent BsAb combinations for R/R DLBCL, pts showed a clear preference for a FDT option with less frequent administration and reduced CRS risk vs a TTP option with more frequent administration and higher CRS risk. These patient-centred data provide essential insights for clinicians and pts to make informed, preference-aligned, shared decisions in the R/R DLBCL setting.

Efficacy and safety of thoracic radiotherapy in metastatic non–small cell lung cancer during the immunotherapy era: A real-world study.

e20577 Background: The synergistic effect of immunotherapy combined with thoracic radiotherapy (TRT) in locally advanced non-small cell lung cancer (NSCLC) have been confirmed. However, the potential benefits of immunotherapy combined with TRT, especially conventional fractionated thoracic radiotherapy (ConvTRT) in patients with metastatic NSCLC remain unclear. Methods: This study retrospectively evaluated patients with metastatic NSCLC who received immunotherapy with or without TRT between January 2020 and December 2024. Propensity score matching (PSM) was used to balance baseline characteristics between the ConvTRT and non-TRT groups. The effectiveness and feasibility of the combination of immunotherapy and ConvTRT were evaluated in patients with metastatic NSCLC. Results: A total of 186 patients with metastatic NSCLC were included, with a median follow-up of 22.0 months. Survival advantage was observed in the group that received any form of TRT (n = 43). After PSM, ConvTRT cohort (n=34) showed a significant survival benefit with a median overall survival (OS) of 29.80 versus 20.3 months in patients without TRT (hazard ratio [HR] 0.44, 95% CI: 0.22–0.87; P=0.016), whereas progression-free survival (PFS) did not differ significantly between both two groups (HR 0.83, 95% CI: 0.49–1.38; P=0.462). The OS benefits were most pronounced among men, ever-smokers, patients with squamous histology, and those receiving first-line immunotherapy. Conclusions: The combination of immunotherapy and ConvTRT is associated with survival benefits and may represent an effective treatment strategy for patients with metastatic NSCLC.

Expansion of a highly activated (HLA-DR+/CD38+) CAR T cell population after mezigdomide exposure post–idecabtagene vicleucel infusion in relapsed multiple myeloma.

7540 Background: Herein, we report CAR T subsets from peripheral blood (PB) mononuclear cell (PBMC) samples from the NCT06048250 Phase 1 trial of mezigdomide (mezi) post idecabtagene vicleucel (ide-cel) in patients with RRMM. Prior studies used PCR for CAR T quantification but have not directly immunoprofiled CAR T. Additionally, we identified a highly activated CAR T cell subpopulation with HLA-DR and CD38 expression. These HLA-DR+/CD38+ T cells correlate with inflammation and disease activity in HLH and viral infections but have not been characterized in CAR T. Methods: Mezi was given orally on 21/28 day cycles after ide-cel infusion until disease progression, intolerance, or 12 cycles, whichever comes first. Immunoprofiling of PBMCs were performed at baseline (within two weeks prior to mezi start day of cycle 1 day 1 [C1D1]), C1D8 (early), and cycle 3 day 1 (C3D1; late) using Cytek Aurora spectral flow cytometry with 29-markers in 6 patients (3 in the DL-1 cohort receiving 0.3 mg and 3 in the DL-2 cohort receiving 0.6 mg). Changes in cell populations were measured as frequencies. The parent population was CD3+ BCMA CAR T+ cell for CAR T subsets, CD8+ T cells for CD8 subsets, CD3+ cells for the remainder of the T cell subsets, CD3- CD19+ cells for the B cell subsets, CD3-CD19-CD33+ for the monocyte subsets, and CD3- CD19-CD56+ for the NK cell subsets. Comparisons between groups were assessed using the Wilcoxon test. Mezi was started between D+60 to D+120 post ide-cel. Herein, we report the early translational data for this cohort. Results: As of 12/29/25, we enrolled 7 patients: 6 patients had evaluable PB immunoprofiling data. Median age was 81 years old (range: 38-85 years) and a median 5 prior lines of therapy (range 4-7). The median time from CAR T to mezi C1D1 was 108 days (range: 48-112). There was a trend towards increased BCMA CAR T cells at C1D8 (P=0.22) and increased BCMA CAR T % was associated with ³ CR (P=0.04). Early increases in HLA-DR+/CD38+ T cells (P=0.03) and HLA-DR+/CD38+ CAR T cells (P=0.02), CD8+ effector memory cells (P=0.03), BTLA+ T cells (P=0.03), CTLA-4+ T cells (P=0.02), monocytes (parent: PBMCs; P=0.04; higher in the DL-2 cohort, P=0.03), and activated B cells (P=0.04) compared to baseline were noted. Early decreases in CD8+ TEMRA (P=0.02), TIGIT+ T cells (P=0.04), monocyte-myeloid-derived suppressor cells (M-MDSCs; P=0.02), total B cells (P&lt;0.05), memory B cells (P&lt;0.05), and naïve B cells (P&lt;0.05) were noted. The DL-2 cohort had higher increases in helper T cells (P=0.007) and CD4:CD8 ratio (P=0.03) at C1D8. Conclusions: Preliminary results show that mezi induced a decrease in suppressive cells, a shift in T- cells from exhausted to activated phenotype, and expansion of highly activated HLA-DR+/CD38+ CAR T cells. Future studies should investigate whether it is correlated with efficacy. FP and MJ contributed equally to this work. Clinical trial information: NCT06048250 .

Efficacy of targeting replication stress in neuroblastoma.

3116 Background: Children with high-risk and relapsed neuroblastoma (NB) need improved therapies, and recurrent cytogenetic abnormalities, such as MYCN oncogene amplification, represent candidate therapeutic targets. MYCN amplification and increased MYCN expression drive deregulated hyper-transcription that leads to development and growth of NB tumors, and MYCN amplifications, which can be found both within the linear genome on homogenously staining regions (HSR) and on circular extrachromosomal DNA (ecDNA), are associated with significantly worse survival rates for children with NB. MYCN overexpression has been linked to an increase in replication stress (RS), and RS and subsequent genome instability are important drivers of tumor initiation and progression. Flap Endonuclease 1 (FEN1), a non-essential DNA replication enzyme, was identified as a synthetic lethal target in BRCA1 / 2 -deficient cancers via induction of RS. Recent success of targeting RS-elevated cancers with replication enzyme inhibitors opens a new avenue to target MYCN -amplified NB. Methods: Associations of gene expression with patient survival and prognostic features were performed on available neuroblastoma tumor databases using the R2 Genomics Analysis and Visualization Platform. The efficacy of FEN1 inhibition was assessed using live cell imaging and cell viability assays, comparing results in MYCN -amplified to -nonamplified NB cells and in NB cells with inducible MYCN expression and repression. Mechanisms of cell death and impacts on replication stress in cells treated with FEN1 inhibitors were evaluated by Western blots. Results: We have found that FEN1 expression levels are associated with NB patient outcomes and with features of high-risk disease, including tumor stage and MYCN amplification. FEN1 inhibition was effective against NB cells and was significantly more effective in HSR- MYCN -amplified NB cells, but not ecDNA-MYCN amplified NB cells, with reduced cell growth and viability. Increased MYCN expression also led to increased sensitivity to FEN1 inhibition, and reduced MYCN expression reduced sensitivity. FEN1 inhibition led to the induction of apoptosis but not necroptosis in NB cells and responses to FEN1 inhibition were associated with markers of replication stress, including activation of the ATR-CHK1 and ATM-CHK2 pathways. Conclusions: We have discovered that HSR-mediated MYCN -amplified NB cells are hypersensitive to FEN1 inhibition, suggesting that FEN1 inhibition may be a promising therapeutic strategy for children with high-risk and relapsed NB.