Citations

1056 Background: Resistance to HER2-directed therapies remains a major challenge in HER2-positiveMBC. In preclinical models, HER2+ tumors overexpress poly (ADP-ribose) polymerase (PARP), and PARP inhibition induces apoptosis through NF-κB suppression even in the absence of pathogenic mutations in BRCA 1/2 . We evaluated the safety, efficacy, and translational correlates of niraparib combined with trastuzumab in patients (pts) with refractory HER2+ MBC. Methods: This open-label Phase 1b/2 trial (NCT03368729) enrolled pts with HER2+ MBC (IHC 3+ and/or FISH amplified), measurable disease, LVEF ≥50%, and progression on ≥1 prior HER2-targeted therapy; stable CNS disease was allowed. Pts with germline BRCA1/2 mutations or prior PARP inhibitor exposure were excluded. Niraparib 300 mg orally was administered on Days 1–21 of a 21-day cycle with trastuzumab 6 mg/kg IV every 3 weeks (loading dose 8 mg/kg on cycle 1). The Phase 2 portion used a Gehan/Simon two-stage design with early stopping for futility (P0=24%); ≥1 response among the first 20 patients triggered expansion to 40 patients. ORR was assessed by RECIST v1.1, meeting the primary endpoint and allowing response rate estimation with <7% standard error and a two-sided 95% exact CI width of 0.28. Gene expression profiling of paired tumor tissue and peripheral blood mononuclear cells (PBMCs) was performed using the NanoString nCounter Tumor Signaling 360 panel at pretreatment compared to cycle 2. Results: Forty-six pts were enrolled (9/2019–2/2025); 41 were evaluable for response. Pts were heavily pretreated (median 3 prior regimens), including trastuzumab deruxtecan in 22 pts; 33% had brain metastases. Treatment-related adverse events were predominantly grade 1–2 and manageable. Clinical benefit rate (CBR) was 44% (18/41) including 1 complete response, 2 partial responses, and 15 stable disease. Eleven patients achieved disease control ≥ 6 months; 1 patient remained on treatment at data cutoff. Tumor profiling revealed enrichment of a B-cell–driven tertiary lymphoid structure signature with reduced hypoxia signaling in responders. Matched PBMC analyses demonstrated coordinated downregulation of interferon signaling, DNA damage response, metabolic activation, angiogenesis, and resistance pathways in clinical responders, whereas non-responders retained signatures of chronic stress and immune exhaustion. Conclusions: Niraparib plus trastuzumab demonstrated a favorable safety profile and durable clinical benefit in heavily pretreated HER2+ MBC. Integrated tumor and blood-based analyses identify immune-organized tumor microenvironments and systemic immune normalization as key correlates of prolonged response, supporting further investigation of PARP inhibition strategies. Clinical trial information: NCT03368729 .

1024 Background: Invasive lobular carcinoma (ILC) is a distinct breast cancer (BC) subtype with dissemination patterns differing from invasive breast carcinoma of no special type (IBC-NST). While genomic differences between ILC and IBC-NST have been described, the extent to which molecular and immune profiles vary by metastatic organ and histology is poorly characterized. Methods: We conducted a retrospective analysis to evaluate organ- and histology-specific molecular features of metastatic BC (mBC). Patients with metastatic IBC-NST or pure ILC underwent NGS (592, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences). Tumor mutational burden (high ≥10 mut/Mb), PD-L1 expression (22C3), and immune cell fractions (RNAseq deconvolution, quanTIseq) were assessed. Analyses were restricted to sites with ≥10 biopsies per histology. Comparisons used chi-square or Mann–Whitney U tests with multiple testing correction (q < 0.05). Results: A total of 2645 mBC biopsies (605 ILC; 2040 IBC-NST) were analyzed (Table). In ILC, ERBB2 mut frequency differed by metastatic site (q<0.01), with higher prevalence in liver (32.7%) and lower in gastrointestinal (GI) lesions (3.7%). In IBC-NST, ESR1 and GATA3 mut and FGFR1 amplification were enriched in liver metastases, whereas PD-L1 expression was highest in skin (20.7%) and lowest in liver (5.0%). No organ-specific differences were observed for PIK3CA, AKT, PTEN, BRCA1/2 or RB1 . Across metastatic sites, both ILC and IBC-NST showed differences in B cells, macrophages (M1/M2), neutrophils, NK cells, dendritic cells, CD8+ T cells, and Tregs (all q < 0.05); CD4+ T-cell differences were observed only in IBC-NST (q = 0.002). In organ-specific ILC vs IBC-NST comparisons, CDH1 mut were more frequent in ILC across sites, along with higher PIK3CA mut in skin (ILC 51.3% vs IBC-NST 34.4%) and higher ERBB2 mut in liver (32.7% vs 3.3%), whereas a higher TP53 mut frequency was observed in IBC-NST in skin (28.5% vs 52.3%) and lymph nodes (LND) (23.5% vs 55.5%) (all q < 0.01). Conclusions: mBC exhibits marked organ-specific molecular and immune heterogeneity that differs by histology. These findings support histology- and site-aware interpretation of metastatic biopsies and may inform biomarker assessment and treatment decisions in advanced disease. BC-NST ILC Skin LND Bone Breast Liver Perit. CNS q-value Skin LND Bone Breast GI Liver GYN Perit. CNS q-value N (specimens) 785 401 109 361 220 15 44 - 172 84 62 56 56 54 43 37 11 - ERBB2 mut (%) 3.2 3.1 3.2 2.3 3.3 7.1 2.5 1.0 7.1 7.4 16.4 15.4 3.7 32.7 2.4 5.7 11.1 <0.01 ESR1 mut (%) 9.4 5.2 8.3 16.0 28.2 7.1 2.4 0.0 7.8 7.2 8.9 9.8 16.7 26.0 4.9 20.0 0.0 0.9 FGFR1 amp (%) 10.1 6.6 5.6 12.8 16.5 0.0 9.7 0.02 4.4 3.4 6.7 6.1 2.4 5.6 7.7 18.5 0.0 1.0 IHC-PD-L1 (%) 20.7 - 5.3 16.0 5.0 11.1 10.3 0.02 8.9 - 5.0 5.7 6.1 0.0 0.0 0.0 14.3 1.0 TMB-High (%) 10.7 10.1 8.8 8.8 8.5 14.3 21.4 0.8 27.6 11.0 19.6 28.0 11.3 19.6 9.8 32.4 22.2 0.8 Perit: peritoneum; CNS: central nervous system; GYN: genital tract.

10030 Background: CABO is a multi-targeted kinase inhibitor of VEGFR2, c-MET, AXL and RET and has shown clinical evidence of activity in two prior studies of adult and pediatric patients with advanced OS. We report results of a feasibility cohort of CABO + MAP chemotherapy in patients with newly diagnosed high-risk OS. Methods: Patients <40 years, body surface area ≥ 0.8 m 2 and new diagnosis of high-grade OS with metastatic disease and resectable primary tumor were eligible. Patients were enrolled to two CABO dose levels (Dose Level 1 (DL1) 25 mg/m 2 /day, maximum 40 mg/day; Dose Level 2 (DL2) 35 mg/m 2 /day; maximum 60 mg/day) using a modified IQ 3+3 design. CABO was orally administered concomitantly with six 35-day cycles of MAP (cisplatin 60 mg/m 2 on days 1-2 (cycles 1-4), doxorubicin 37.5 mg/m 2 on days 1-2 (with dexrazoxane), methotrexate 12 g/m 2 on days 22, 29) and for 24 weeks as maintenance monotherapy. CABO was held after 7 weeks and resumed during 4 th MAP cycle to allow for primary tumor resection and metastatic surgeries. Dose-limiting toxicities (DLT) were assessed during weeks 1-6 of treatment; additional monitoring for post-surgical complications was conducted through completion of 4 th MAP cycle. The primary endpoint for this cohort was feasibility of combination therapy. Results: Ten patients (median age 11.5 years, 70% male) were enrolled and treated with CABO + MAP (DL1, n=4; DL2, n=6). Median cumulative doses of all MAP agents were maintained throughout treatment with no dose reductions. Concomitant dosing of CABO with MAP was tolerated with no protocol-specified DLTs occurring during the evaluation period. DL2 (35 mg/m 2 ) was established as the recommended dose for further study of combination therapy. Commonly reported adverse events included hematologic toxicities, febrile neutropenia, and alanine/aspartate aminotransferase (AST/ALT) elevation. Interruption of CABO was required in 6 patients for Grade 3+ AST/ALT elevation following methotrexate (n=3), wound complications (n=3), and Grade 3 pneumothorax (n=1). Wounds included two Grade 3 port site events and one Grade 1 primary tumor resection site; two patients later resumed CABO after healing without wound recurrence. Dose reduction of CABO was required in one patient for Grade 4 amylase elevation. Conclusions: The combination of CABO + MAP is feasible with no protocol-specified DLTs during the evaluation period. Generalizability is limited based on cohort size. Further evaluation of CABO + MAP is ongoing in a phase II/III randomized efficacy study in newly diagnosed standard and high-risk patients using CABO dose of 35 mg/m 2 /day (max 60 mg), with delayed initiation of CABO in patients with port placement and early safety monitoring for wound-related events, as well as full study monitoring of dose delivery, wound complications and systemic toxicity. Clinical trial information: NCT05691478 .

Abstract Background Whether outcomes of germline BRCA1/2 (gBRCA1/2)-associated breast cancer differ compared with sporadic tumors is controversial. We explored the impact of gBRCA1/2 pathogenic variant (PV) status beyond established prognostic features. Methods We conducted 2 retrospective, matched cohort studies comparing gBRCA1/2 PV carriers and noncarriers with HER2-negative, stage I-III breast cancer (Clinical Outcomes Quality Database [COQD] cohort: 185 carriers, 555 noncarriers; Young Women’s Breast Cancer Study [YWS] cohort: 113 carriers, 226 noncarriers). Matching factors were age, stage, hormone receptor status, and year of diagnosis. Clinicopathological features, treatments, and survival outcomes were compared between carriers and noncarriers. Results Most patients in COQD had stage I-II disease (87.2%), and more carriers than noncarriers had genetic testing before diagnosis (33% vs 5.6%, P &lt; .001). In YWS, 22.7% of patients had stage III tumors, and few were tested before diagnosis (14.8% of carriers vs 1.7% of noncarriers; P &lt; .001). Carriers in COQD received chemotherapy more often than noncarriers (81.1 vs 67.0%, P &lt; .001), including platinum (P = .010); the proportion was similar for carriers and noncarriers in YWS. After adjusting for chemotherapy, relapse-free survival was longer in carriers than noncarriers in COQD (adjusted hazard ratio = 0.48 [95% CI = 0.26 to 0.87], P = .016), and a favorable trend was observed for other survival outcomes in both cohorts. Triple-negative tumors appeared to drive the differences. Conclusions We observed a trend toward improved outcomes in gBRCA1/2 PV carriers compared with noncarriers. These findings suggest that carriers should not receive more aggressive treatment solely based on their germline mutation status. Prospective clinical trials in this population are warranted.

PURPOSE Integrating external control data into clinical trial designs and analyses has the potential to accelerate drug development processes. We reanalyzed the three experimental arms of the Individual Screening Trial of Innovative Glioblastoma Therapy (INSIGhT), a randomized phase II platform trial in newly diagnosed O 6 -methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780 ). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data. METHODS The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls. RESULTS After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data. CONCLUSION The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score–matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding.

Abstract The use of chimeric antigen receptor (CAR) T-cell therapy is increasing for adult B-cell acute lymphoblastic leukemia (B-ALL), with 3 CD19 CAR T-cell products commercially available. Several key clinical questions related to best practices for CAR T-cell administration in this population exist, and limited prospective randomized trials have been conducted to fill these knowledge gaps. Thus, to help guide clinical practice, we conducted a modified Delphi study to develop and validate consensus recommendations on the administration of commercially available CAR T-cell therapy for adults with B-ALL. Consensus panelists (n = 9) included principal investigators (PIs) from Real World Outcomes Collaborative of CAR T-Cell Therapy in Adult ALL (ROCCA) consortium sites and were selected based on expertise and CAR T-cell center volume. Final panel consensus recommendations were distributed for rating by the remaining PIs from ROCCA consortium sites, which served as the validation group (n = 27). Consensus topics included patient selection, bridging and pre–CAR T-cell leukemia staging, lymphodepletion, and CAR T-cell treatment setting, specific toxicity prevention and management, post–CAR T-cell response assessment and disease monitoring, and the role of consolidation and/or maintenance therapies after CAR T-cell therapy. Initially, 58 recommendation statements were evaluated for consensus. After 2 panel meetings, a total of 34 statements achieved consensus rating among the expert panel. After rating by the validation group, all but 1 recommendation statement continued to meet consensus, for a total of 33 consensus recommendation statements on the administration of CAR T-cell therapy in adult B-ALL.

IgG4-related disease (IgG4-RD) is a relatively recently described condition whose etiology and pathophysiology remain unclear. Histopathological features include dense lymphoplasmacytic tissue infiltration with numerous IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Most individuals with IgG4-RD are asymptomatic; however, the disease can affect nearly any organ, leading to a wide range of clinical presentations. The four most common patterns are hepatopancreatobiliary disease, systemic disease, head and neck disease, and retroperitoneal disease. Diagnosis is challenging due to diverse organ involvement and is most often confirmed by biopsy. Elevated serum IgG4 concentration can support the diagnosis, though high IgG4 levels are neither highly sensitive nor specific for IgG4-RD. Immunohistochemical IgG4 staining is crucial, especially in patients without elevated serum IgG4. Differential diagnosis is necessary, as IgG4+ plasma cell infiltration is also seen in inflammatory and malignant conditions. First-line treatment consists of glucocorticoids (prednisone), although favorable outcomes have also been achieved with rituximab. Prognosis varies: the disease may resolve spontaneously or follow a relapsing–remitting course. If left untreated or undertreated, IgG4-RD can cause irreversible organ damage and even death. Finally, correlations have been made between IgG4 and different allergic reactions.

Introduction Lynch syndrome (LS) is a hereditary cancer syndrome that increases risk for colorectal and other cancers. We hypothesize that vaccines against tumor-associated antigens CEA, MUC1, and brachyury, simultaneously delivered in an adenovirus serotype-5 vector (Tri-Ad5) combined with the immune-enhancing IL-15 receptor superagonist nogapendekin-alfa-inbakicept (NAI) will reduce the incidence of colorectal neoplasms in LS carriers. Methods In this ongoing phase IIB double-blind placebo-controlled trial, two open-label safety phases (SPs) assessed safety of Tri-Ad5 alone (SP1, n=10) and with added NAI (SP2, n=10). A randomized controlled trial (RCT) follows the SPs. After baseline colonoscopy, vaccine dosing occurs at weeks 0, 4 and 8; Tri-Ad5 alone in SP1 and Tri-Ad5 plus NAI in SP2, with identical boosters at Week 52. The RCT phase participants (n=138) were randomized to receive Tri-Ad5 plus NAI or placebo. All participants complete colonoscopy at Weeks 52 and 104 for assessment of the primary endpoint: cumulative colorectal neoplasm incidence. Secondary endpoints include safety, tolerability, and immunogenicity. Results All 20 SP participants (median age 57.5 (range 42–75), 70% female, 15% minority) received all prime and booster series. SP1 participants reported 139 adverse events (AEs) and SP2 participants reported 178. AEs were predominantly grade 1; no treatment-related serious adverse events (SAEs) occurred. The most common treatment-related AEs were reactogenic events including grade 3 rash (without skin necrosis or breakdown) at NAI injection site (100% of SP2 participants). The RCT phase (n=138) recently completed accrual. Discussion In LS carriers without active cancer, the combination of Tri-Ad5 + NAI was well-tolerated; the RCT phase is ongoing. Clinical Trial Registration https://clinicaltrials.gov/study/ , identifier NCT05419011.

Abstract Rationale Interstitial lung abnormalities (ILA) are abnormal findings on chest CT scans that may represent early-stages of interstitial lung disease. The presence of fibrosis (traction bronchiectasis and/or honeycombing) identifies those with ILA at an increased risk for mortality, however, determining who will progress remains a challenge, and the role of blood-based biomarkers in ILA risk-stratification is unknown. Methods Data from four prospective cohort studies were used to identify associations between plasma proteins measured with DNA aptamers (SomaScan) and ILA, fibrosis, and mortality. The Genetic Epidemiology of COPD Study (COPDGene) was used to identify protein associations, and findings were replicated by meta-analysis of the Age, Gene/Environment Susceptibility-Reykjavik study (AGES-Reykjavik), SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS), and Framingham Heart Study (FHS). Protein associations with ILA and with fibrotic ILA compared to non-fibrotic ILA were performed using multivariable logistic regression; among those with ILA, Cox proportional hazards models were used to identify protein associations with mortality. Models were adjusted for age, gender, race, BMI, smoking status, pack-year smoking history, and for mortality, COPD. Benjamini-Hochberg false discovery rate p-values &lt;0.05 were considered significant. Results 524 (10.7%) of 4,899 COPDGene participants had ILA, of whom 57 (10.9%) had fibrosis; of 8,146 AGES-Reykjavik, SPIROMICS and FHS participants included in the meta-analysis, 666 (8.2%) had ILA, of whom 198 (29.7%) had fibrosis. In COPDGene, 230 proteins were associated with ILA; the most significant of which were SFTPD (adjusted odds ratio per standard deviation [SD] of protein [OR]=2.21, p = 3.7E-41) and SFTPB (OR = 1.82, p = 7.9E-37). In the meta-analysis, 159 of the ILA-associated proteins were replicated. Of the 230 ILA-associated proteins in COPDGene, 9 were associated with fibrosis, and 5 of these 9 proteins were associated with mortality among those with ILA. The 5 proteins associated with all three outcomes were WFDC2 (ORILA=1.90, p = 2.6E-34; ORFibrosis=2.00, p = 0.0001; adjusted hazards of mortality per SD of protein [HR]=1.59, p = 3.4E-05), GDF15 (ORILA=1.67, p = 3.6E-23; ORFibrosis=1.78, p = 0.0006; HR = 1.63, p = 1.4E-06), SCGB3A1 (ORILA=1.52, p = 4.5e-14; ORFibrosis=1.80, p = 0.0002; HR = 1.25, p = 0.02), TREM1 (ORILA=1.44, p = 1.4e-14; ORFibrosis=1.62, p = 0.001; HR = 1.25, p = 0.02) ICAM5 (ORILA=1.42, p = 1.2e-11; ORFibrosis=1.79, p = 0.0001; HR = 1.31, p = 0.002). In the meta-analysis, 6 of the 9 fibrosis-associated proteins and all 5 ILA mortality-associated proteins replicated. Conclusion This represents the first plasma proteomic screen demonstrating reproducible biomarker associations not only with ILA presence, but also with measures of severity and adverse outcomes. These results provide compelling targets for further study, including their prospective evaluation as clinical biomarkers for early disease identification and prognostication. This abstract is funded by: Multiple Sources

Abstract Rationale To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting. Methods PRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic white participants (n = 6,647). Associations of PRSmulti with COPD status (GOLD 2-4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n = 2,466), ECLIPSE (n = 1,858), MassGeneral Brigham Biobank (n = 15,152), and All of Us (n = 118,566). Protein prediction models were applied to GWAS summary statistics from traits contributing to PRSmulti and were validated with proteomic data in COPDGene (n = 5,173) and UK Biobank (n = 5,012). Results PRSmix+ selected 7 traits for PRSmulti. In multivariable models, PRSmulti was associated with COPD status (meta-analysis random effects (RE) OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE beta 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRSmulti outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRS that were also validated with measured protein levels in COPDGene and UK biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include AGER (RAGE), IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations. Conclusions Multi-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management. Trial registration. COPDGene: NCT00608764; ECLIPSE: NCT00292552. This abstract is funded by: NIH and the COPD Foundation