bluuebunny/crossref_metadata_2025_split huggingface dataset:
SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx).
Authors: Rugo Hope S. , Im Seock-Ah , Wright Gail Lynn Shaw , Escriva-de-Romani Santiago , DeLaurentiis Michelino , Cortes Javier , Bahadur Shakeela Wazeen , Haley Barbara B. , Oyola Raul H. , Riseberg David A. , Musolino Antonino , Cardoso Fatima , Curigliano Giuseppe , Kaufman Peter A. , Pegram Mark D. , Edlich Sutton , Hong Sam , Rock Edwin P. , Gradishar William John 
Published: May 2019

1000 Background: Pretreated HER2+ MBC lacks a defined standard of care, although T is commonly used. M has similar HER2 binding and antiproliferative effects as T. By contrast, M’s Fc region is engineered to increase affinity for both alleles of the activating Fc receptor (FcR), CD16A, and decrease affinity for the inhibitory FcR, CD32B. The low affinity CD16A-158F allele (~85% of population) has been associated with diminished clinical response to T. In a Phase 1 trial, M demonstrated acceptable safety, anti-tumor activity, and evidence of HER2-specific antibody and T-cell responses. Methods: SOPHIA (NCT02492711), a randomized, open-label P3 trial, enrolled pts with HER2+ MBC after pertuzumab and 1–3 lines of prior Tx for MBC. Pts were randomized 1:1 to M (15 mg/kg IV q3w + C) or T (6 [8 for loading dose] mg/kg IV q3w + C), stratified by met sites (≤2, > 2), lines of Tx for met disease (≤2, > 2), and C choice (standard dose capecitabine, eribulin, gemcitabine, or vinorelbine). Primary endpoints are central blinded PFS and OS, assessed sequentially using the stratified log-rank test. Objective response rate (ORR) was a secondary endpoint. 257 PFS events were required to provide 90% power to show PFS superiority at 2-sided α = 0.05. Results: Intent-to-treat analysis (536 pts: M 266; T 270) occurred after 265 PFS events. M prolonged PFS over T (median 5.8 vs 4.9 mo, hazard ratio [HR], 0.76; 95% CI, 0.59–0.98; P= 0.033). Treatment effects were more pronounced in pts with CD16A genotypes containing a 158F allele (median PFS 6.9 vs 5.1 mo, HR, 0.68; 95% CI, 0.52–0.90; P= 0.005). In 524 pts with baseline measurable disease (M 262; T 262), ORR was higher with M (22%; 95% CI, 17.3-27.7%) vs T (16%; 95% CI 11.8-21.0%). Safety profiles were comparable in 529 pts who received study therapy. Grade ≥3 AEs and serious AEs occurred in 138 (52%) and 39 (15%) vs 128 (48%) and 46 (17%) pts on M vs T, respectively. PFS data cutoff: 10/10/18. Conclusions: In combination with chemotherapy in pretreated HER2+ MBC, M improves PFS over T with comparable safety. CD16A genotyping suggests a differential benefit in patients with a 158F allele. OS data are maturing. Clinical trial information: NCT02492711.
Efficacy and toxicity of pegaspargase and calaspargase pegol in childhood acute lymphoblastic leukemia/lymphoma: Results of DFCI 11-001.
Authors: Vrooman Lynda M. , Blonquist Traci M. , Supko Jeffrey G. , Hunt Sarah K. , O'Brien Jane E. , Kay-Green Samantha , Athale Uma H. , Clavell Luis Antonio , Cole Peter D. , Harris Marian H. , Kelly Kara M. , Laverdiere Caroline , Leclerc Jean-Marie , Michon Bruno , Welch Jennifer JG , Stevenson Kristen E. , Neuberg Donna S. , Sallan Stephen E. , Silverman Lewis B. 
Published: May 2019

10006 Background: DFCI ALL Consortium Protocol 11-001 assessed the efficacy and toxicity of Calaspargase pegol (SC-PEG), a novel pegylated asparaginase (ASP) formulation with longer half-life, compared with standard pegaspargase (SS-PEG). Methods: Patients (pts) aged 1-21 years with newly diagnosed acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) were eligible. At study entry, pts were randomly assigned to receive either intravenous SS-PEG or SC-PEG, 2500 IU/m2/dose. Pts received 1 dose during the first treatment month. Beginning week 7, SS-PEG was administered every 2 weeks for 15 doses, SC-PEG every 3 weeks for 10 doses (30 weeks). Serum asparaginase activity (SAA) (considered therapeutic at ≥ 0.1 IU/mL) was assessed 4, 11, 18, and 25 days after the induction dose and before each post-induction dose. End-induction minimal residual disease (MRD) was assessed in ALL pts by IGH/TCR PCR. Results: Between 2012-2015, 239 eligible pts enrolled (230 ALL, 9 LL); 120 assigned to SS-PEG, 119 to SC-PEG. After dose 1, SAA remained ≥ 0.1 IU/mL in ≥ 95% of pts on both arms through day 18. Median SAA was higher (0.319 IU/mL vs 0.056 IU/mL) and more pts had therapeutic SAA (88% vs 17%, p˂0.001) with SC-PEG vs SS-PEG 25 days after dose 1. Post-induction, median nadir SAA (NSAA) were similar ( > 1.0 IU/mL) for both arms. There was no difference in rates of ASP-allergy, pancreatitis, thrombosis, hyperbilirubinemia, osteonecrosis, or infection. Of 230 evaluable pts, 99% of SS-PEG and 95% of SC-PEG pts achieved complete remission (p = 0.12). For B ALL pts, there was no difference in frequency of high end-induction MRD (10.3% SS-PEG, 9.5% SC-PEG, p = 1.0). With 4-year median follow-up, 4-year event-free survival (EFS) (90% confidence interval) for SS-PEG was 90.2% (84.3, 93.9), 87.7% (81.5, 91.9) for SC-PEG (p = 0.78); overall survival (OS) was 95.6% (91.0, 97.9) for SS-PEG, 94.8% (90.0, 97.3) for SC-PEG (p = 0.74). Conclusions: Every 3-week SC-PEG had similar EFS, OS, safety profile, and NSAA compared with every 2-week SS-PEG. The high NSAA observed for both preparations suggest dosing strategies can be further optimized. These data informed FDA approval of SC-PEG for pediatric pts. Clinical trial information: NCT01574274.
Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors.
Authors: Robinson Giles W. , Gajjar Amar J. , Gauvain Karen Marie , Basu Ellen M. , Macy Margaret E , Maese Luke Devon , Sabnis Amit J. , Foster Jennifer Haunani , Shusterman Suzanne , Yoon Janet , Weiss Brian D. , Abdelbaki Mohamed , Farid-Kapadia Mufiza , Meneses-Lorente Georgina , Cardenas Alison , Hutchinson Katherine , Bergthold Guillaume , Chow Maneval Edna , Fox Elizabeth , Desai Ami Vijay 
Published: May 2019

10009 Background: Entrectinib is a CNS-penetrant oral inhibitor of TrkA/B/C, ROS1 and ALK tyrosine kinases. We report the efficacy of entrectinib in children with recurrent/refractory solid or CNS tumors. Methods: Patients ≤ 20y old with recurrent/refractory solid tumors were eligible. After determination of the recommended dose in all-comers, disease-specific expansion cohorts of CNS and solid tumors harboring target aberrations in NTRK1/2/3, ROS1 or ALK, and neuroblastoma (NBL), regardless of mutation spectrum, were enrolled. Response, assessed by Investigator, was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) using RANO for CNS tumors, RECIST for solid tumors, and Curie score for NBL. Results: Between May 2016 and October 2018, 29 patients aged 4.9m–20y (median 7y) were enrolled and 28 were evaluated for response. Entrectinib was well tolerated. Dose limiting toxicities were elevated creatinine, dysgeusia, fatigue and pulmonary edema. The recommended dose was 550 mg/m2 daily. All responses occurred at doses ≥ 400 mg/m2. In CNS tumors (n = 6), all high-grade with gene fusions: 1 achieved a CR ( ETV6-NTRK3); 3 achieved a PR ( TPR-NTRK1, EEF1G-ROS1, EML1-NTRK2); 1 achieved an unconfirmed PR ( GOPC-ROS1); and 1 has yet to be evaluated ( KANK1-NTRK2). In extracranial solid tumors (n = 8), 6 had a fusion of whom 1 achieved a CR ( DCTN1-ALK) and 5 achieved a PR ( TFG1-ROS1, EML4-NTRK3, ETV6-NTRK3, KIF5B-ALK, ETV6-NTRK3). In NBL (n = 15): 1 achieved a CR ( ALK F1174L). Median duration of therapy was 85d (6–592d) for all patients; 56d (6–338d) for non-responders; and 281d (56–592d) for responders. Median time to response was 57d (30–58d). Conclusions: Entrectinib produced striking, rapid and durable responses in all children with refractory CNS and solid tumors harboring NTRK1/2/3, ROS1 or ALK fusions (11 out of 11) as well as in an ALK-mutated NBL. No responses were seen in tumors lacking aberrations in target kinases. These results support the continued evaluation of entrectinib as a targeted therapeutic in solid tumors with NTRK1/2/3, ROS1 and ALK fusions, especially in high-grade CNS neoplasms. Clinical trial information: NCT02650401.
Larotrectinib efficacy and safety in pediatric TRK fusion cancer patients.
Authors: van Tilburg Cornelis Martinus , DuBois Steven G. , Albert Catherine Michelle , Federman Noah , Nagasubramanian Ramamoorthy , Geoerger Birgit , Orbach Daniel , Bielack Stefan S. , Shukla Neerav Narendra , Turpin Brian , Casanova Michela , Spunt Sheri L. , Qamoos Hope , Nanda Shivani , Childs Barrett H. , Cox Michael Craig , Pappo Alberto S. , Laetsch Theodore Willis , Mascarenhas Leo 
Published: May 2019

10010 Background: TRK fusions involving NTRK1, NTRK2, and NTRK3 genes have been identified in a broad range of pediatric and adult malignancies. Larotrectinib, a highly-selective oral TRK inhibitor, was well tolerated and showed encouraging antitumor activity in 17 pediatric patients (pts) with TRK fusion cancer (Laetsch et al, Lancet Oncol 2018). Here, we present data on the clinical efficacy and safety of larotrectinib in 38 pediatric pts with TRK fusion cancer from an expanded dataset. Methods: Pediatric pts enrolled in two larotrectinib clinical trials (NCT02637687, NCT02576431) with TRK fusion cancer detected by local testing were included; pts with primary CNS tumors were excluded from this report. Larotrectinib was administered until complete surgical resection, disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator-assessed using RECIST v1.1. Data cutoff: July 30, 2018. Results: As of July 30, 2018, 38 children and adolescents < 18 y with TRK fusion cancer were enrolled. Median age was 2.3 y (range 0.1–14.0); 14 (37%) were < 1 y. 18 (47%) had infantile fibrosarcoma, 15 (39%) other soft tissue sarcoma, 2 (5%) thyroid cancer and 1 (3%) each had gastrointestinal stromal tumor, melanoma, or mesoblastic nephroma. TRK fusions involved NTRK1, 2, and 3 in 18 (47%), 2 (5%), and 18 (47%) pts, respectively. Half of the pts had metastatic disease and half locally advanced disease at entry. 26 pts (68%) had received prior systemic therapy (median lines: 1 [range 0–4]) and 6 were treatment-naïve. In 34 evaluable pts, the overall response rate was 94%: 12 CRs, 18 confirmed PRs, and 2 PRs pending confirmation; 2 had stable disease. Median duration of response had not been reached (range 1.6+ to 26.7+ months); 84% > 1 y. At data cutoff, 28 pts (74%) remained on treatment; 4 pts discontinued due to complete surgical resection and 4 due to disease progression while on therapy, 2 of whom initially responded (PR). Adverse events were mostly grade 1–2. Conclusions: Larotrectinib treatment resulted in a high and durable response rate in pediatric pts with TRK fusion cancer together with a favorable safety profile. Routine testing for NTRK gene fusions in pediatric cancer pts is recommended in the appropriate clinical context. Clinical trial information: NCT02637687 and NCT02576431.
A revised Children's Oncology Group (COG) neuroblastoma risk classification system: Report from the COG biology study ANBL00B1.
Authors: Irwin Meredith , Naranjo Arlene , Cohn Susan Lerner , London Wendy B , Gastier-Foster Julie M , Maris John M. , Bagatell Rochelle , Park Julie R. , Hogarty Michael D. 
Published: May 2019

10012 Background: The COG risk classification system previously used the International Neuroblastoma Staging System (INSS). The pre-treatment INRG staging system (INRGSS) has been adopted internationally, requiring integration of INRGSS with known prognostic biological and clinical characteristics to evaluate outcomes and assess whether this incorporation will require revision to the established COG risk classifier. Methods: 4,037 newly diagnosed neuroblastoma patients were enrolled on COG ANBL00B1 between 2006-2014. Staging per the INSS and INRGSS was determined. Tumor biological and histologic features, including MYCN status [amplified (A) versus not amplified (NA)], ploidy, histology, and segmental chromosome aberrations (SCA) including 1p and 11q LOH, were assessed centrally. Survival analyses were performed to identify independent prognostic factors and to calculate event-free and overall survival (EFS, OS) for combinations of variables used to determine risk group assignments according to COG and INRG classification templates. Results: Using the original COG risk classifier 1,309 low (LR), 992 intermediate (IR) and 1,736 high-risk (HR) patients were identified with 5-year EFS of 91.4±2.1%, 84.3±2.9%, 45.2±3.1%, and OS of 98.1±1.0%, 94.0±1.9%, 54.1±3.0%, respectively. Outcomes based on combinations of clinical and biological prognostic factors were determined and compared for subsets of patients according to the COG (version1) and INRG risk classification systems to develop a revised COG risk classifier that incorporates the INRGSS (version 2, subset shown in table). Conclusions: Use of INRGSS requires a revision to the COG risk classifier. By combining INRGSS and presence of SCA together with age, MYCN status, ploidy, and histology to determine outcome of patients treated with modern era therapies, we developed a revised risk classification system to inform therapy and COG clinical trial eligibility. Clinical trial information: NCT00904241. [Table: see text]
Randomization of dose-reduced subcutaneous interleukin-2 (scIL2) in maintenance immunotherapy (IT) with anti-GD2 antibody dinutuximab beta (DB) long-term infusion (LTI) in front–line high-risk neuroblastoma patients: Early results from the HR-NBL1/SIOPEN trial.
Authors: Ladenstein Ruth Lydia , Poetschger Ulrike , Valteau-Couanet Dominique , Gray Juliet , Luksch Roberto , Balwierz Walentyna , Castel Victoria , Ash Shifra , Beck Popovic Maja , Laureys Genevieve , Chan Godfrey Chi Fung , Ruud Ellen , Vettenranta Kim , Owens Cormac , Schroeder Henrik , Loibner Hans , Ambros Peter F , Sarnacki Sabine , Boterberg Tom , Lode Holger N. 
Published: May 2019

10013 Background: We tested dose-reduced scIL2 in combination with DB-LTI and oral isotretinoin and evaluated toxicity and efficacy in high-risk neuroblastoma patients (EudraCT:2006-001489-17). Methods: High-risk patients (stage 4 ≥1y; stage 4 < 1y with MYCN amplification (MNA); stage 2, 3, 0-21y with MNA) received high intensity induction (rapid COJEC or N5-MSKC and TVD for insufficient response), surgery, high dose therapy with busulfan/melphalan and local radiotherapy. Patients ≤9 months between diagnosis and HDT/SCT who achieved at least a partial response prior to HDT/SCT and without progression thereafter were randomized to receive up to 5 cycles of 100mg/m2 DB-LTI (d8-17) ± 3x106 IU/m2 scIL2 (d1-5; d8, d10, d12, d14, d16) and 160mg/m2 oral isotretinoin (d19-32). Results: Between 04/2014 and 06/2018, 408 patients from 18 countries were randomized. Median follow-up is 1.8 years. Stage, age, MNA, induction treatments and remission status were well balanced between randomization arms. The 2yrs-EFS and -OS for DB-LTI (205 pts) vs. DB-LTI&scIL2 (203 pts) was 64%±4%vs63%±5% (p = 0.844) and 83%±3%vs74%±4% (p = 0.337). For patients in CR the 2yrs-EFS was 69%±5% for DB and 66%±6% for DB&scIL2. Patients with evaluable disease prior DB or DB&scIL2, the end of treatment response rate was 57% (26% CR, 31% PR) vs 52% (27% CR, 25% PR) with 2yrs-EFS rates of 58%±7% and 64% ±8%, respectively. Grade 3&4 toxicity was lower in the group with DB vs DB&scIL2 for fever (14%vs31%, p < 0.001) and pain (7%vs18%, p = 0.005), and no significant difference was seen for general condition (17%vs22%,ns), allergy (3%vs3%,ns), capillary leak (4%vs8%,ns), liver enzyme elevation (20%vs27%, ns) and neurological toxicities (2%vs2%,ns). Conclusions: We previously reported grade 3&4 toxicity to DB short-term infusion (STI) ± 10x6x106IU/m2 scIL2 for general condition (16%vs41%, p = 0.000), fever (14%vs40%, p = 0.000), allergic reaction (10%vs20%, p = p = 0.006), capillary leak (4%vs15%, p = 0.004), liver enzyme elevation (17%vs23%, ns), central neurotoxicity (3%vs8%, p = 0.034) and pain (16%vs26%, p = 0.048). Our results indicate that DB-LTI and dose-reduced scIL2 clearly reduced the toxicity profile, but showed absence of benefits of scIL2. DB-LTI achieved 2yrs-EFS in line with DB-STI (Ladenstein, Lancet Oncology 2018; Yu, NEJM, 2010) and a response rate > 50% supporting its use as standard of care IT. Clinical trial information: EudraCT:2006-001489-17.
Chronic health conditions (CHC) and late mortality in survivors of acute lymphoblastic leukemia (ALL) in the Childhood Cancer Survivor Study.
Authors: Dixon Stephanie , Chen Yan , Yasui Yutaka , Pui Ching-Hon , Hunger Stephen , Silverman Lewis B. , Green Daniel M. , Kadan-Lottick Nina S. , Ness Kirsten K. , Leisenring Wendy , Howell Rebecca M. , Oeffinger Kevin C. , Neglia Joseph Philip , Krull Kevin R. , Hudson Melissa M. , Robison Leslie L. , Mertens Ann C. , Armstrong Gregory T. , Nathan Paul C. 
Published: May 2019

10016 Background: The impact of evolving risk-stratified therapy on long-term morbidity and mortality in survivors of childhood ALL remains largely unknown. Methods: All-cause and health-related late mortality (HRM; captures death from late-effects occurring > 5 yrs from diagnosis), subsequent (malignant) neoplasm [S(M)N], CTCAE graded CHC and neurocognitive outcomes were assessed in 5-yr survivors of ALL diagnosed < 21 yrs of age from 1970-99. Therapy combinations defined 6 groups: 1970s-like ( 70s), standard and high risk 1980s- and 1990s-like ( 80sSR, 80sHR, 90sSR, 90sHR), relapse/transplant ( R/BMT). Cumulative incidence and standardized mortality ratios (SMR) were calculated. Piecewise exponential and log-binomial models estimated rate ratios (RR) with 95% confidence intervals (CI). Results: Among 6148 survivors (median age 31.5 yrs), 15-yr cumulative incidence of all-cause mortality was 5.8% (CI 5.3-6.2) and HRM was 1.5% (1.2-1.7). Compared to 70s, HRM was lower for 90sSR and 90sHR (RR 0.1, CI 0.0-0.3; 0.2, 0.1-0.7), similar to that in the US population (SMR; CI: 90sSR 1.1; 0.6-1.9, 90sHR 1.9; 0.8-3.7). 20-yr cumulative incidence of SN was 3.5% (CI 3.1-3.9). Compared to 70s, 90sSR had lower risk of benign meningioma (RR 0.1, CI 0.0-0.3) and SMN (0.3, 0.1-0.6) with no absolute excess risk compared to the US population. 90sSR was associated with a lower risk of CHCs (Table). Conclusions: More recent risk-stratified therapy has succeeded in reducing risk of late mortality and CHCs among long-term survivors of ALL. [Table: see text]
Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial.
Authors: Saura Cristina , Oliveira Mafalda , Feng Yin-Hsun , Dai Ming-Shen , Hurvitz Sara A. , Kim Sung-Bae , Moy Beverly , Delaloge Suzette , Gradishar William John , Masuda Norikazu , Palacova Marketa , Trudeau Maureen E. , Mattson Johanna , Yap Yoon Sim , Bryce Richard , Yao Bin , Bebchuk Judith D. , Keyvanjah Kiana , Brufsky Adam ,   NALA Investigators
Published: May 2019

1002 Background: NALA (ClinicalTrials.gov NCT01808573) is a multinational, randomized, open-label, phase III trial of neratinib (an irreversible pan-HER tyrosine kinase inhibitor [TKI]) + capecitabine (N+C) vs lapatinib (a reversible dual TKI) + capecitabine (L+C) in patients with stage IV HER2+ metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens for MBC. Methods: Patients were randomized 1:1 to N (240 mg qd po) + C (750 mg/m2 bid po) or L (1250 mg qd po) + C (1000 mg/m2 bid po). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints were investigator-assessed PFS; objective response rate (ORR); duration of response (DoR); clinical benefit rate (CBR); time to intervention for symptomatic metastatic central nervous system (CNS) disease; safety; and patient-reported health outcomes. Results: 621 patients were randomized (307 to N+C; 314 to L+C). The risk of disease progression or death was reduced by 24% with N+C vs L+C (HR = 0.76; 95% CI 0.63–0.93; p = 0.006); 6- and 12-month PFS rates were 47.2% vs 37.8% and 28.8% vs 14.8% for N+C vs L+C, respectively. OS rates at 6 and 12 months were 90.2% vs 87.5% and 72.5% vs 66.7% for N+C vs L+C, respectively (HR = 0.88; 95% CI 0.72–1.07; p = 0.2086). ORR in patients with measurable disease at screening was improved with N+C vs L+C (32.8% vs 26.7%; p = 0.1201), as was CBR (44.5% vs 35.6%; p = 0.0328) and DoR (HR = 0.50; 95% CI 0.33–0.74; p = 0.0004). Time to intervention for symptomatic CNS disease (overall cumulative incidence 22.8% vs 29.2%; p = 0.043) was delayed with N+C vs L+C. Treatment-emergent adverse events (TEAEs) were similar between arms, but there was a higher rate of grade 3 diarrhea with N+C vs L+C (24.4% vs 12.5%). TEAEs leading to neratinib/lapatinib discontinuation were lower with neratinib (10.9%) than with lapatinib (14.5%). Conclusions: N+C significantly improved PFS with a trend towards improved OS vs L+C. N+C also resulted in a delayed time to intervention for symptomatic CNS disease. Tolerability was similar between the two arms, with no new safety signals observed. Clinical trial information: NCT01808573.
Population-based cancer predisposition testing as a component of newborn screening: A cost-effectiveness analysis.
Authors: Yeh Jennifer , Stout Natasha K. , Chaudhry Aeysha , Gooch Michael , McMahon Pamela , Christensen Kurt D. , Diller Lisa , Wu Ann C. 
Published: May 2019

10021 Background: The role of population-based newborn genetic testing to identify infants at high risk of childhood-onset cancers has not been studied, despite the availability of cancer surveillance guidelines for early detection in high-risk infants and children. Methods: We developed the Precision Medicine Prevention and Treatment (PreEMPT) Model to estimate the value of targeted population-based newborn genomic sequencing (tNBS) for a select panel of genes associated with early onset pediatric malignancy. Cohorts of US newborns were simulated under tNBS screening vs. usual care, from birth to death. Six pediatric cancer predisposition syndromes were included in the model with mutations in RET, RB1, TP53, DICER1, SUFU or SMARCB1 assigned at birth, using mutation prevalence and disease risks drawn from the published literature, as well as SEER, ClinVar and gnoMAD databases. Newborns with mutations underwent cancer surveillance based on established guidelines for each gene-related pediatric malignancy. Survival benefit was modeled as a reduction in proportion of advanced disease, cancer deaths, and treatment-related late mortality risks. Costs were based on published literature and national databases. Results: In a typical US birth cohort of 4 million newborns, we estimated 1280 cancer cases in the malignancies associated with this gene panel would be detected before age 20 under usual care, resulting in 451 cancer deaths and 490 living with radiation exposure risks. tNBS would prevent 8 cancers (in RET mutation carriers), avert 34 deaths through surveillance, result in 3190 life-years (LY) gained and a 13% relative reduction in proportion of adult survivors at risk for radiation-associated late mortality. Given a sequencing cost of $30 (e.g., $5/gene), the incremental cost-effectiveness ratio (ICER) for tNBS was $230,500 per LY saved; if no additional cost was incurred beyond standard newborn screening, the ICER decreased to $101,100/LY. Conclusions: Population-based genetic testing of newborns can reduce mortality associated with pediatric cancers and could potentially be cost-effective as sequencing costs decline. Further work will include modeling a broader panel of predisposition genes.