NTRK gene fusions are oncogenic drivers across various pediatric and adult tumor types. The prevalence of NTRK gene fusions varies widely, from high (up to 90%) in rare tumors such as infantile fibrosarcoma and secretory carcinoma of the breast to low (<0.5%) in common cancers like non-small cell lung and colorectal carcinoma. Larotrectinib is the first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in patients with TRK fusion cancer based on a robust and durable objective response rate in both adult and pediatric patients with various tumor types. Here, we report updated data on larotrectinib-treated pediatric patients with TRK fusion non-primary CNS tumors. This analysis included patients from 2 clinical trials (NCT02637687 [SCOUT], NCT02576431 [NAVIGATE]). Responses were independent review committee-assessed (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). In SCOUT, patients could stop larotrectinib in the absence of on-treatment progression (“wait-and-see”). Responses in patients who were re-treated due to progression were assessed by investigators (RECIST v1.1). Ninety-nine patients with non-primary CNS tumors were eligible for analysis as of July 2024, including 49% with infantile fibrosarcoma, 41% with soft tissue sarcoma, and 9% with other solid tumors. Overall response rate was 86% (95% confidence interval [CI] 77–92). In total, 53 patients had complete responses (CR; including 17 pathological CR), 32 had partial responses (PR), 9 had stable disease (SD), and 3 had progressive disease (PD); responses were undefined in 2 patients. Median time to response was 1.8 months (range 0.9–7.3). Median duration of response was 51 months (95% CI 31-not estimable [NE]). Median progression-free survival and overall survival (OS) were 49 months (95% CI 32–NE) and not reached (NR), respectively. The 5-year OS rate was 87% (95% CI 80–95). Median time to investigator-assessed treatment failure (from larotrectinib initiation to earliest documented on-treatment disease progression, start of other anticancer treatment, or death) was NR. Of 54 patients who entered a first “wait-and-see” period (median duration 33 months [range 1–72]), 18 resumed treatment due to PD. Of these, 11 had a response (6 CR and 5 PR [including 2 pending confirmation]), 5 had SD, 1 was not evaluable, and 1 was undefined. Most treatment-related adverse events (TRAEs) were Grade 1/2. Three patients (3%) discontinued due to a TRAE. Larotrectinib demonstrated rapid and durable responses, extended survival, and favorable safety in pediatric patients with TRK fusion cancer. This supports the wider adoption of next-generation sequencing panels that include NTRK gene fusions to identify pediatric patients who may benefit from targeted treatment. Leo Mascarenhas, Theodore W. Laetsch, Birgit Geoerger, Steven G. DuBois, Miranda P. Dierselhuis, Catherine M. Albert, Claudia Blattmann, Helen Toledano, Noah Federman, Ramamoorthy Nagasubramanian, Alberto Pappo, Tanya Watt, Domnita-Ileana Burcoveanu, Esther De La Cuesta, Natascha Neu, Daniel H. Orbach, Yizhuo Zhang. Larotrectinib long-term efficacy and safety in pediatric patients with TRK fusion non-primary CNS tumors: Analysis update [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr A029.

Supplementary Table S7 shows stratified analysis by infection during pregnancy

Supplementary Table S5 shows negative control analysis

10035 Background: Identifying structural rearrangements and gene fusions is critical to providing high quality, precision-driven clinical care for many types of pediatric cancers. RNA next-generation sequencing (NGS) provides a functional readout of the genome that enables superior detection of chimeric transcripts and novel driver fusions, particularly when genomic breakpoints reside in complex intronic regions. This study demonstrates the benefit of concurrent DNA- and RNA-NGS for fusion detection in a real world pediatric cohort of 1,050 patients, one of the largest such studies to date. Methods: We used the Tempus de-identified multimodal database to select a cohort of pediatric solid tumor cancer patients (all stages) who received successful DNA (Tempus xT, 648 gene panel with enhanced detection of structural variants [SVs] in 22 genes) and RNA (Tempus xR, whole-transcriptome) NGS sequencing. All patients had a minimum tumor purity of 20% and were aged 0-21 at the time of sample collection (n=1,050). All assessed fusions appeared on clinical reports. Results: Overall, we detected a fusion in 35.1% of patients (n=369). The top 3 cancer types in our cohort were soft tissue sarcoma (n=321), brain/CNS cancer (n=280), and bone cancer (n=120), and fusion prevalence in these types was 53% (n=170), 30.4% (n=82) and 30% (n=36), respectively. The fusion types with the highest overall prevalence were: EWSR1 (9.0%, n=95), BRAF (6.1%, n=64), PAX3-FOXO1 (2.7%, n=28), ALK (2.2%, n=23), and RET (2.0%, n=21) fusions. In assessing the subset of genes that appear on both the DNA-NGS and RNA-NGS panel, 303 patients harbored one of these fusions and 38.6% (117/303) of those fusions were detected only via RNA-NGS. Among fusions with highest prevalence, the percentage detected only via RNA-NGS ranged from 3.1% (EWSR1 fusions) to 100% (PAX3-FOXO1); BRAF (53/64, 82.8%) and ALK (4/23, 17.4%) fusions both had comparatively high proportions detected only via RNA-NGS. RNA-NGS alone detected gene fusions in 65 additional patients where neither partner appears on the DNA-NGS panel. Considering only fusions associated with an indication-matched FDA-approved targeted therapy, we observed a prevalence of 9.0% (94/1050), and of these, 46.8% (44/94) were detected only by RNA-NGS. Overall, 49.3% (182/369) of fusion-positive patients would have been missed if RNA-NGS were not performed, representing 17.3% of the total cohort. Conclusions: Pediatric solid tumors are frequently driven by structural rearrangements and gene fusions that are difficult to characterize using DNA sequencing alone. This study demonstrates that performing combined DNA-NGS and RNA-NGS substantially improves the identification of patients with a clinically relevant fusion in a large real-world data set.

TPS10057 Background: Ewing sarcoma (EWS) is an aggressive tumor of the bone and soft tissue primarily affecting adolescents and young adults. For patients with recurrent disease, outcomes remain poor with 5-year survival rates of 10%–15%, highlighting the need for novel approaches. STEAP1 is highly expressed in EWS cell lines, xenograft models, and patient tumor samples 1 and is transcriptionally regulated by EWSR1::FLI1 , the main oncogenic driver in EWS. Xaluritamig, a humanized bispecific XmAb 2+1 T-cell engager targeting STEAP1 and CD3, has demonstrated potent, antigen-dependent T-cell–mediated lysis of STEAP1-expressing EWS cell lines 1 and induced robust in vivo antitumor activity in EWS xenograft models with concomitant CD8+ T-cell activation. In metastatic castration-resistant prostate cancer, another STEAP1-expressing solid malignancy, xaluritamig has shown meaningful antitumor activity and a manageable safety profile 2 supporting its clinical evaluation in R/R EWS. Methods: This ongoing, phase 1b, single-arm, open-label, two-part, multicenter study (NCT07297979) is evaluating xaluritamig in pediatric, adolescent, and adult patients with a histologic diagnosis of EWS and an EWSR1 :: ETS fusion gene locally confirmed by next-generation sequencing. Patients must have R/R EWS following ≥1 line of systemic therapy and Karnofsky or Lansky performance status ≥70. Part 1 (dose confirmation) consists of cohort 1 (age ≥12 years) and cohort 2 (age ≥2 to <12 years), and part 2 (dose expansion) includes patients aged ≥2 years with no upper age limit at enrollment. This study includes a 21-day screening period, a treatment period, a safety follow-up period, and a long-term follow-up period. Patients receive xaluritamig every 2 weeks once reaching the target dose until radiographic disease progression per RECIST v1.1, clinical disease progression, unacceptable toxicity, initiation of other anticancer therapy not permitted per protocol, withdrawal of consent, death, or end of study as determined by the sponsor, whichever is earlier. Primary endpoints are safety, tolerability, and determination of recommended dose(s) for expansion. Secondary endpoints are pharmacokinetics, preliminary antitumor activity, and immunogenicity. Biomarker evaluation as an exploratory endpoint includes assessment of serum cytokines, other pro-inflammatory markers, immune-cell subsets, circulating tumor DNA, STEAP1 protein expression, and tumor genomic profile and their association with safety and efficacy. CRS mitigation plan includes step-up dosing, steroid premedication, and administration of interleukin-6 inhibitors as needed. Site activation commenced in January 2026 and enrollment is ongoing. 1. Nolan-Stevaux O. Cancer Res. 2020;80(16_Suppl):DDT02–03. 2. Kelly WK, Danila DC, Lin CC, et al. Cancer Discov . 2024;14(1):76-89. Clinical trial information: NCT07297979 .

Supplementary Table S2 shows cancer types and corresponding ICD-9 and ICD-O coding

Supplementary Table S1 shows prevalence of acetaminophen and combination prescriptions

BACKGROUND:Hepatoblastoma (HBA) is a rare pediatric malignancy treatable with liver transplantation (LTx). Limited data exist on outcomes after LTx for HBA. This study evaluates the therapeutic efficacy of LTx in pediatric patients with HBA, delineates principal complications, and assesses long-term psychosocial outcomes. METHODS:This retrospective cohort study analyzed a prospectively maintained database of children undergoing LTx for HBA at a single US center from 1984 to 2025. Primary outcomes were patient and graft survival at 1, 5, and 10 years post-LTx and HBA recurrence. Secondary outcomes included post-LTx complications, recurrence predictors, and psychosocial parameters. RESULTS:Of 55 patients (60% female; 40% Hispanic; mean age at diagnosis, 36 months), most had PRETEXT stage III (44%) or IV (47%) disease; mean α-fetoprotein level at diagnosis was 569 355 ng/mL. All but 1 received chemotherapy; 15 (27%) had pre-LTx resection. Mean wait time to LTx was 10 months. Pre-LTx metastatic disease (pulmonary) was present in 5 patients (9%). Explant pathology showed macrovascular invasion (n = 16), positive lymph nodes (n = 3), and extra-hepatic tumor invasion/rupture (n = 2). Post-LTx complications included HBA recurrence (20%), hepatic artery thrombosis (11%), and biliary stricture (20%). Patient survival was 89% at 1 year, 74% at 5 and 10 years; graft survival was 89%, 73%, and 73%, respectively. Significant predictors of recurrence were older age at LTx (p = 0.01), longer waiting time to LTx (p = 0.02), prior resection (p = 0.01), larger tumor size (p = 0.03), vascular invasion (p = 0.02), and utilization of a segmental graft (p = 0.002). Mortality was mainly due to recurrence. Psychosocially, 14 patients needed special education, 10 had developmental delays, 5 of 12 adults completed high school, 2 earned college degrees, and 3 are employed. CONCLUSION:This large single-center study demonstrates favorable survival after LTx for high-risk HBA. Recurrence predictors support avoiding pre-LTx resection in high-risk cases. While living donor or split grafts can expedite transplantation, segmental grafts were independently linked to higher recurrence. Notably, metastases at diagnosis did not increase recurrence, supporting aggressive treatment. The rate of HAT and biliary stricture was significantly higher for children transplanted for HBA than for our overall pediatric experience. These findings help guide the management of this rare malignancy.

TPS11587 Background: Treatment for relapsed and refractory (R/R) osteosarcoma (OST) has not changed for decades. R/R OST has a poor prognosis with a 12% 4-month event-free survival (EFS). Leucine-Rich Repeat Containing 15 (LRRC15) is a type I transmembrane protein on OST cells and cancer associated fibroblasts. Approximately 90% of OST express LRRC15; high expression predicts aggressive disease and shorter survival. LNTH-2403 is a high-affinity LRRC15-targeting fully humanized antibody with a 177 lutetium payload. Preclinical data show anti-tumor activity in several OST models, demonstrating LNTH-2403’s potential to treat R/R OST. Methods: This first-in-human, multicenter, open-label phase 1/2 study will evaluate the safety, tolerability, pharmacokinetics (PK), biodistribution (BD), radiation dosimetry (RD), and preliminary anti-neoplastic activity in patients ≥12 years of age with LRRC15-expressing R/R OST. The primary endpoints are to identify the maximum tolerated dose (MTD; phase 1) and 4-month EFS (phase 2). LRRC15 expression by immunohistochemistry will be confirmed by a central lab; pre-screening is allowed. Initiated in Q1 2026, phase 1 will test LNTH-2403 at 30, 50, and 70 mCi/m 2 every 8 weeks in up to ~30 patients. A 3+3 design will be used to define the MTD and estimate the recommended phase 2 dose (RP2D). Phase 2 will evaluate LNTH-2403 at the RP2D in ~25 patients with R/R OST. Retreatment after Cycle 1 is permitted for patients who continue to meet initial eligibility requirements, have cumulative doses to target organs predicted to be below radiation tolerance limits, and whose bone marrow has recovered. Safety testing includes adverse events (AEs), serious AEs (SAEs), laboratory parameters (chemistry, hematology, coagulation, urinalysis), electrocardiograms, vital signs, and physical examinations. BD and RD are based on serial single photon emission computed tomography (SPECT)/computed tomography (CT) and planar imaging. PK data will be generated from serial blood sampling for radioactivity. Overall response rate (ORR) and EFS are defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 per investigator reads. As ORR by RECIST is challenging in OST due to tumor calcification, efficacy testing also includes physiologic response by fluorine-18 ( 18 F)-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT whole body scans and magnetic resonance imaging of the primary site, sites of known and presumed metastases, and the chest, abdomen, and pelvis. For this open-label study, all statistical methods will be descriptive in nature with no formal statistical hypotheses. NCT07357519; Research Sponsor: Lantheus. Clinical trial information: NCT07357519 .

Supplementary Table S3 shows parameters for probabilistic bias analysis

Supplementary Figure S1 shows cumulative childhood cancerincidence curves for the major cancer types

Ewing Sarcoma (ES) is a rare but aggressive malignancy of bone tissue in adolescents and young adults, where early detection of progression and real-time treatment monitoring remain unmet clinical needs. Tumor extracellular vesicles (EVs) carry surface markers and nucleic acid cargo that can serve as minimally invasive biomarkers, but single-marker EV assays often lack specificity, and colocalized-marker approaches may suffer from low sensitivity. Here, we report the ES EV Capture-Release-Capture (CaReCa) assay, a two-step enrichment strategy that combines desthiobiotin (DTB)-mediated capture/release of CD99+ EVs with click chemistry-mediated recapture of CD99+/B7-H3+ EVs, introducing molecular specificity to suppress background signals. To overcome limited yield from EVs with colocalized markers, we incorporated RT-digital PCR quantification of encapsulated ACTB mRNA, a stable housekeeping transcript, as a sensitive proxy for EV abundance. Using only 100 µL of plasma, the ES EV CaReCa assay distinguished ES patients (n = 20) from healthy donors (n = 20) with an AUROC of 0.98. Longitudinal analysis further demonstrated that dynamic changes in the assay readouts paralleled disease progression and treatment response, consistent with PET/CT findings. Together, these results establish CaReCa as a sensitive, specific, and scalable liquid biopsy platform with translational potential for noninvasive monitoring of ES patients.

BACKGROUND:The safety of using acetaminophen (paracetamol) during pregnancy has been questioned because of concerns about its potential negative impact on fetal development and the risk of adverse pediatric outcomes. We aimed to investigate whether maternal prescriptions of acetaminophen during pregnancy are associated with childhood cancer. METHODS:We conducted a population-based cohort study in Taiwan using data from the Maternal and Child Health Database linked to additional registries to identify children diagnosed with cancer between 2004 and 2017. Cox proportional hazard models were used to estimate effects. Probabilistic bias analysis was conducted to address potential biases and validate our findings. RESULTS:The cohort consisted of 2,269,384 mother-child pairs, among whom 2,754 childhood cancer cases were identified. The main analysis did not yield sufficient evidence to conclude that acetaminophen exposure during pregnancy increases the risk of all childhood cancers. However, a regular use of acetaminophen throughout all trimesters suggested an increase in the risk of medulloblastoma [adjusted hazard ratio (HR) = 2.43; 95% confidence interval (CI), 1.10-5.39], hepatoblastoma (adjusted HR = 1.73; 95% CI, 0.97-3.10), and bone tumors (adjusted HR = 1.85; 95% CI, 0.92-3.72). Probabilistic bias analysis supported positive effects. CONCLUSIONS:Although this study did not show a strong association between acetaminophen prescription during pregnancy and many childhood cancers, the results for regular use and three types of rare childhood cancer raise concern. IMPACT:Further research is needed to replicate these findings and to explore potential underlying mechanisms.

Supplementary Table S8 shows sensitivity analysis between acetaminophen and acetaminophen combinations prescription

Supplementary Table S4 shows sensitivity analysis additional accounting for maternal migraine, smoking, and alcohol consumption

Supplementary Table S6 shows stratified analysis by offspring sex for germ cell and bone tumors

134 Background: Nirogacestat (niro) is an oral, targeted gamma secretase inhibitor FDA-approved for adults with progressing desmoid tumors (DT) who require systemic treatment. In the phase 3 DeFi trial (NCT03785964), niro demonstrated significant improvement vs placebo (pbo) in progression-free survival (PFS; HR 0.29 [95% CI: 0.15–0.55], P <.001) and objective response rate (ORR; 41% vs 8%, P <.001). Most DT are sporadic tumors characterized by somatic mutations in the CTNNB1 gene. About 10%–20% of DT are associated with APC mutations, the majority being germline that may cause familial adenomatous polyposis (FAP), an inheritable trait linked to an increased risk of colorectal cancer and may also confer more aggressive DT behavior. Methods: In DeFi, adult patients (pts) were randomized to oral niro (150 mg) or pbo twice daily. In pts with evaluable blood and tumor samples, descriptive post hoc analyses assessed effects of niro in pts with germline and/or somatic APC mutations, including pts with co-occurring somatic mutations of APC and CTNNB1 . Results: Of the 142 pts in DeFi, 29 pts had APC mutations (niro=13, pbo=16; 22 somatic, 21 germline, and 14 somatic and germline), including 3 pts (niro=2, pbo=1) with co-occurring somatic mutations of APC and CTNNB1 . Of these 29 pts, 19 (66%) were female, 16 (55%) were aged ≤30 y, 22 (76%) had a family history of FAP, and 22 (76%) were refractory to prior therapy (median of 3 prior lines of therapy). PFS was improved with niro vs pbo (HR 0.21 [95% CI: 0.05–1.00], P =.016). Confirmed ORR was 38% (5/13) for niro vs 13% (2/16) for pbo; median time to response with niro was 8.31 months. All 3 pts with co-occurring somatic mutations of APC and CTNNB1 were female, aged 18–56 y, had DT in the upper extremity or abdominal wall, and had no family history of FAP. The 2 pts on niro had received prior systemic therapy and/or surgery and the 1 pt on pbo had no prior therapy. Of the 2 pts on niro, both achieved a partial response (median time to response: 9.9 months). The 1 pt randomized to pbo experienced disease progression in 2.6 months. In pts with APC mutations, diarrhea was the most frequently reported adverse event. In niro-treated pts, increased rates of skin events (maculopapular rash, 62%; dermatitis acneiform, 38%) and stomatitis (46%) were reported in pts with APC mutations compared with those in the overall DeFi population (32%, 22%, and 29%, respectively). Conclusions: Improvement in PFS and ORR was observed with niro vs pbo in pts with DT harboring APC mutations. Efficacy and safety of niro in pts with APC mutations were generally consistent with findings for the overall DeFi population. Although analyses were limited due to small sample size, these results suggest that niro can provide clinically meaningful benefit to pts with progressing DT and APC mutations, including those with co-occurring somatic mutations of APC and CTNNB1 . Clinical trial information: NCT03785964 .