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6028 Background: RET alterations are targetable oncogenic drivers in multiple solid tumors and TCs. Pralsetinib is an oral, potent, selective RET inhibitor granted accelerated approval by the FDA for adults and children aged ≥12 y with advanced/metastatic RET fusion-positive TC who require systemic therapy and are radioactive iodine-refractory, based on ARROW trial (NCT03037385) results. Accelerated approval for medullary TC (MTC) was withdrawn by the sponsor in 2023 due to recruitment challenges in the confirmatory trial. We report final efficacy and safety in ARROW patients with RET -altered TC and MTC. Methods: Phase 2 ARROW patients were enrolled from 84 sites in 13 countries. Primary end points were overall response rate (ORR; per RECIST v1.1) and safety. Progression-free survival (PFS), overall survival (OS), and safety were assessed in patients with advanced/metastatic TC and MTC who received ≥1 dose of pralsetinib (Efficacy Population [EP]). ORR and duration of response (DOR) were assessed in the Measurable Disease Population (MDP). Results: At the May 20, 2024, data lock, 28 patients with RET -altered TC and prior systemic treatment and 145 patients with RET -altered MTC received pralsetinib 400 mg/d (median treatment duration: 24.7 mo [TC]; and 35.4 mo [MTC]). In the TC and MTC groups, median age was 58 and 57 y; 39% and 64% were male; median (range) prior lines of treatment was 2 (1, 9) and 1 (1, 6). 53.8% of MTC patients had prior systemic treatment. In TC and MTC patients, ORRs (95% CI) were 91.7% (73.0, 99.0) and 68.2% (59.5, 76.0) (Table). Treatment-related adverse events (TRAEs) occurred in 27 (96%) TC and 142 (98%) MTC patients; 68% and 67% had grade ≥3. TRAEs in ≥35% of TC and MTC patients were increased AST (50% and 38%) and ALT (43% and 30%), decreased white blood cell count (39% and 30%), and anemia (39% each). Death due to a TRAE occurred in 1 TC patient (liver injury) and 1 MTC patient (pneumonia). Safety was consistent with prior reports. Conclusions: The final analysis of ARROW confirms that pralsetinib yields clinically meaningful and durable responses in patients with RET -altered TC and MTC with a manageable safety profile consistent with prior reports. Clinical trial information: NCT03037385 . Efficacy summary. All MTC MTCPrior Cabozantinib/Vandetanib MTC Treatment-Naïve TCPrior Systemic Treatment MDP, n 132 60 62 24 ORR, % (95% CI) 68.2(59.5, 76.0) 56.7(43.2, 69.4) 79.0(66.8, 88.3) 91.7(73.0, 99.0) Complete response, n (%) 12 (9.1) 2 (3.3) 7 (11.3) 4 (16.7) Partial response, n (%) 78 (59.1) 32 (53.3) 42 (67.7) 18 (75.0) DOR, median, mo (95% CI) 39.6(29.4, NE) 21.7(15.1, 34.8) NR(36.8, NE) NR(16.0, NE) DOR follow-up, median, mo (95% CI) 45.7(41.0, 48.4) 48.9(36.9, 58.7) 45.1(40.4, 47.8) 35.4(26.9, 40.0) EP, n 145 67 67 28 OS, median, mo (95% CI) NR(54.6, NE) 42.2(31.2, NE) NR(NE, NE) NR(25.4, NE) PFS, median, mo (95% CI) 37.2(27.5, 55.5) 24.9(19.9, 35.0) 55.3(36.8, NE) NR(14.7, NE) NE, not evaluable; NR, not reached.

1005 Background: In the phase 3 HER2CLIMB-05 study (NCT05132582), TUC + maintenance HP demonstrated a statistically significant improvement in progression-free survival (PFS) vs control treatment (Tx) (hazard ratio: 0.641, P < 0.0001) in patients (pts) with HER2+ locally advanced or metastatic breast cancer (MBC). Here we report additional efficacy and safety outcomes by stratified subgroups. Methods: Pts with centrally confirmed HER2+ MBC without evidence of progression following chemotherapy-based induction Tx (taxane + HP) were randomly assigned 1:1 to TUC (300 mg) or PBO BID + HP. Randomization was stratified by diagnosis ( de novo /recurrent), hormone receptor (HR) status (positive/negative), and presence or history of brain metastases (BM; yes/no). Endocrine therapy (ET) is permitted for pts with HR+ disease. The primary endpoint is investigator-assessed PFS. Confirmed objective response rate (cORR), duration of response (DOR), and safety were evaluated in stratified subgroups. Results: Among pts assigned to TUC + HP (n = 326) or PBO + HP (n = 328), ∼69% had de novo MBC, ∼53% had HR+ status with ∼45% having received concurrent ET, and ∼12% had baseline BM. At data cutoff (Sep 5, 2025), median PFS was longer with TUC than PBO + HP in all stratified subgroups; TUC + HP consistently improved cORR vs PBO + HP (Table). Safety outcomes in subgroups aligned with the overall population. Conclusions: TUC + HP demonstrated clinically meaningful efficacy vs PBO + HP in pts with de novo or recurrent disease, HR+ or HR− disease, and baseline BM or not, with no new safety signals identified. Results were consistent with the overall population and support TUC + HP as a potential new maintenance therapy across pts with HER2+ MBC. Clinical trial information: NCT05132582 . Efficacy outcomes. Overall De novo Recurrent HR+ (± ET) † HR− BM (yes) BM (no) TUC+HP(n=326) PBO+HP(n=328) TUC+HP(n=227) PBO+HP(n=226) TUC+HP(n=99) PBO+HP(n=102) TUC+HP(n=168) PBO+HP(n=176) TUC+HP(n=158) PBO+HP(n=152) TUC+HP(n=41) PBO+HP(n=40) TUC+HP(n=285) PBO+HP(n=288) Median PFS, mos (95% CI) 24.9(21.3−NE) 16.3(12.6−18.7) 28.9(22.7−NE) 16.8(12.9−19.2) 21.3(15.6−27.2) 12.7(8.3−18.1) 25.0(16.5−NE) 18.1(13.0−20.8) 24.9(19.4−NE) 12.6(9.4−16.8) 8.5(4.2−16.5) 4.2(2.2−8.1) 27.2(24.3−NE) 18.1(14.8−20.7) cORR*, % (95% CI) 22.6(18.0−27.8) 15.2(11.3−19.7) 26.1(20.2−32.7) 18.5(13.5−24.4) 15.1(8.5−24.0) 7.0(2.6−14.6) 20.1(14.0−27.5) 12.9(8.2−19.0) 25.2(18.4−33.0) 17.9(11.8−25.5) 15.0(5.7−29.8) 8.3(1.8−22.5) 23.8(18.7−29.5) 16.1(11.9−12.1) Median DOR*, mos (95% CI) 20.9(16.4−NE) 16.9(12.3−NE) NR(16.4−NE) 16.3(10.4−NE) 17.9(8.3−NE) NR(7.2−NE) 20.9(12.6−NE) 18.7(7.8−NE) NR(8.6−NE) 14.5(10.4−NE) 12.6(8.1−NE) 16.3(12.5−NE) 20.9(16.4−NE) 18.7(10.4−NE) *ORR and DOR were assessed in patients with target or non-target lesions at baseline. † Data on HR+ w/ ET will be presented.

1042 Background: The primary analysis of the phase 3 HER2CLIMB-05 study (NCT05132582) showed the addition of TUC to 1L maintenance HP yielded a statistically significant improvement in progression-free survival (per investigator) versus control treatment (hazard ratio: 0.641, P < 0.0001) in patients with HER2+ MBC. Here we report our findings from an in-depth safety analysis of HER2CLIMB-05. Methods: Patients with centrally confirmed HER2+ MBC without evidence of progression following chemotherapy-based induction treatment (taxane + HP) were randomly assigned 1:1 to TUC (300 mg) or placebo (PBO) BID, both in combination with HP. The safety analysis set included all randomly assigned patients who received ≥1 dose of any study treatment. Treatment-emergent adverse events (TEAEs), laboratory values, and TUC/PBO dose modifications and discontinuations were examined. Results: Among patients in the safety analysis set (TUC arm = 326; PBO arm = 324), median treatment durations of TUC and PBO were 17.1 months (range: 0.4–36.5) and 15.5 months (range: 0.5–41.3), respectively. Grade (G) ≥3 TEAEs occurred in 42.3% of patients in the TUC arm and 24.4% in the PBO arm; the most frequent G ≥3 TEAEs in the TUC arm were elevated alanine aminotransferase (ALT; 13.5%) and aspartate aminotransferase (AST; 7.1%). TUC was discontinued in 13.5% of patients due to a TEAE. Cardiac TEAEs were similar between TUC and PBO arms (4.3% vs 6.2%). TEAEs of hepatic events (43.6% vs 15.7%) and diarrhea (72.7% vs 51.2%) occurred at higher incidence in the TUC arm versus the PBO arm (Table). In the TUC arm, increased ALT (28.2%) and AST (25.8%) accounted for the majority of hepatic TEAEs. Most hepatic and diarrhea TEAEs were managed with TUC dose modifications and/or discontinuation; 7.7% of patients discontinued TUC due to hepatic TEAEs and 1.5% discontinued due to diarrhea (Table). Among the patients with a TEAE of diarrhea, 57.7% and 29.9%, respectively, in the TUC and PBO arms used antidiarrheals; the most used medication was loperamide. Further details of the in-depth safety analysis will be presented. Conclusions: TUC addition to 1L HP maintenance therapy may be an effective option for HER2+ MBC with a clinically manageable safety profile. Clinical trial information: NCT05132582 . TEAEs* Any Any hepatic Increased ALT/AST Diarrhea Arm TUC PBO TUC PBO TUC PBO TUC PBO Any G, % 99.1 96.6 43.6 15.7 28.2/25.8 7.1/9.0 72.7 51.2 G ≥3 42.3 24.4 18.1 1.2 13.5/7.1 0.6/0.6 6.1 4.0 Any G: Median time to onset (days) 34.5 85.0 11.0 32.0 Median time to resolution (days) 25.0 22.0 2.0 5.0 Any G: TUC/PBO dose hold, % 49.4 25.3 19.3 2.5 12.6/4.0 0.6/0.6 8.6 3.4 TUC/PBO dose reduction, % 29.1 11.1 16.3 0.9 11.7/2.8 0.3/0.6 6.4 3.1 TUC/PBO discontinuation, % 13.5 2.2 7.7 0 4.0/0.3 0/0 1.5 0.9 *As of data cutoff, Sep 5, 2025.

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.

Abstract Introduction Transthoracic echocardiography (TTE) identifies a hypercontractile phenotype (HP) in chronic coronary syndromes (CCS), characterized by elevated resting left ventricular (LV) elastance (force = systolic blood pressure/end-systolic volume). To evaluate the prognostic significance and functional correlates of HP. Methods In a prospective multicentre study, 10 677 patients with CCS underwent resting TTE to assess LV ejection fraction (EF), stroke volume, and force by quantitative volumetric echocardiography. All patients were followed for the endpoint of all-cause mortality. In a subset of 5834 patients, stress echocardiography (exercise or dobutamine) was performed for LV contractile reserve and heart rate reserve. Results Patients were stratified into Force quintiles (Q1–Q5). Patients with hypercontractile phenotype exhibited lower stroke volume at rest (Q5 = 34.8 ± 12.3 vs Q1–Q4 = 57.4 ± 19.1 mL; P &lt; .01) and higher EF at rest (Q5 = 64.8 ± 6.9% vs Q1–Q4 = 58.1 ± 8.7%, P &lt; .01). During a median follow-up of 24 months (interquartile range = 12–40 months), 509 deaths occurred. The exposure-adjusted death rate was lowest in Q3 (3.53–4.51 mmHg/mL; 1.03 per 100 person/years) and higher in Q1 (≤2.62 mmHg/mL, 2.88), Q2 (2.63–3.52 mmHg/mL, 1.86), Q4 (4.52–6.11 mmHg/mL, 1.56), and Q5 (HP, &gt;6.11 mmHg/mL; 1.88; P &lt; .0001 vs Q1 and Q3). Multivariable analysis identified HP (Q5; HR 1.531 vs Q3, 95% CI 1.116–2.099; P = .006) and EF (HR 0.963, 95% CI 0.953–0.972; P &lt; .0001) as independent predictors of death. During exercise or dobutamine stress, HP showed reduced LV contractile reserve (ΔEF: Q5 = 4.3 ± 9.4% vs Q1–Q4 = 7.0 ± 9.3%; P &lt; .001) and blunted heart rate reserve (Q5 = 1.77 ± 0.33 vs Q1–Q4 = 1.85 ± 0.39; P &lt; .01). All patients with force-based LV contractile reserve &gt;4.1 (present in 185, 3.2% of the population) survived. Conclusion Patients with CCS with HP assessed by resting TTE demonstrate higher mortality and multilayered functional impairment, including reduced LV contractile and chronotropic reserves. Hypercontractile phenotype improved the prediction of mortality by EF. A ‘stronger’ heart is, in fact, functionally and prognostically weaker.

Abstract Heart involvement in eosinophilia represents a rare entity with substantial cardiac morbidity and mortality. This disorder is often overlooked and diagnosed in its advanced stages. In a subgroup of patients with eosinophilic heart disease, peripheral blood eosinophilia may not be present, and the biopsy of the affected organ or tissue is essential to establish the correct diagnosis. In this clinical consensus statement, an expert consensus group reviews the epidemiology, aetiology, diagnosis, and management of eosinophilic heart disease. The aim of the document is to increase awareness about the cardiac involvement associated with eosinophilia in order to diagnose the disease in early phases and prevent deleterious heart damage and adverse outcomes of affected individuals. The spectrum of physiological and immunological derangements requires a multidisciplinary approach for optimal management of affected individuals.

Abstract Purpose Diagnostic bronchoscopy plays a critical role in management for immunocompromised patients hospitalized with new pulmonary infiltrations. Most existing data on bronchoscopy in immunocompromised patients are derived from ICU cohorts or mixed inpatient/outpatient populations. This study aimed to assess the relationship between specific immunosuppression types-classified per the 2025 IDSA guidelines-and bronchoscopy yield and its impact on hospital management among non-ICU patients with new pulmonary infiltrates compared to non-immunocompromised. Methods A retrospective review of 447 hospitalized (immunocompromised and non-immunocompromised) patients who underwent bronchoscopy for new pulmonary infiltrates was completed between January 2022 and December 2024 in a single center tertiary care center. Data collected included demographics, immunosuppression type, and bronchoscopy results (cell count, differential, cultures, biopsies). Post-bronchoscopy management changes were also recorded. Multivariate logistic regression was used to correlate immunosuppression subtypes to diagnostic yield and management impact. Results The overall positivity rate for significant findings was 46% (n = 205). 367 of 447 (82%) met criteria for immunosuppressed. The immunosuppressed positivity rate was 46% vs 45% for non-immunosuppressed (P=.43). Broken down by subtype, positivity rates were: Active immunotherapy 33%, active chemotherapy 45%, hematologic malignancy 45%, hematopoietic stem cell transplant 44%, solid organ transplant 43%, active HIV 66%, primary immunodeficiency 78%, autoimmune modulator therapy 45%, daily prednisone use &gt;20 mg 45%. Only primary immunodeficiency was associated with a statistical higher likelihood of a positive bronchoscopy (Odds ratio 4.69; P = 0.025).The overall rate of a significant change in management as a direct result of the bronchoscopy was 26%. Immunosuppressed was 26% compared to 22% for non-immunosuppressed (p = 0.5). Broken down by subtype management change rates were: Active immunotherapy 66%, active chemotherapy 18%, hematologic malignancy 19%, hematopoietic stem cell transplant 26%, solid organ transplant 32%, active HIV 100%, primary immunodeficiency 78%, autoimmune modulator therapy 70%, and daily prednisone use &gt;20 mg 23%. Active immunotherapy and active immunomodulator therapy were correlated with a significant change in management (OR 8.9; P = 0.02, OR 3.6; P = 0.02, respectively). Conclusions Bronchoscopy yield and management impact were similar between immunosuppressed and non-immunosuppressed hospitalized patients. However, bronchoscopy more frequently influenced management in patients receiving active immunotherapy or immunomodulators, supporting earlier diagnostic use in these populations. This abstract is funded by: None