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A phase I trial on the safety, tolerance, and preliminary efficacy of intracavitary injection of in situ vaccines (FOLactis) in patients with advanced solid tumors complicated with malignant pleural effusion.

2601 Background: Malignant pleural effusion (MPE) is caused by the metastasis of malignant tumors to the pleura. Traditional treatment have limited efficacy. In our preliminary research, a recombinant lactobacillus expressing the fusion protein Flt3L-OX40L (enhancing antigen-presenting function of dentritic cells and activation of antigen-specific T cells) named FOLactis was proved to have strong anti-tumor effect in early clinical trials. This clinical study was designed to explore the safety and efficacy of intracavitary injection of FOLactis for the treatment of malignant pleural effusion (NCT06512896). Methods: This is a single arm, single center study. In addition to systemic treatment, participants received intracavitary 2-4 injections of FOLactis. Primary endpoint was safety; secondary endpoints included Objective response rate of pleural effusion and the duration time of pleural effusion control. Results: From June 2023 to Oct 2025, a total of 38 patients were intracavitary injected with FOLactis, of which 29 patients completed more than 2 injections. Among these patients, the adverse reactions included Grade I-II fever (12/38, 31.6 %), chest wall pain (9/38, 23.68%), fatigue (2/38, 5.26%), and pneumothorax (1/38, 2.63%), while no adverse events above grade III were observed. Among the 38 patients with local treatment efficacy evaluation, 10 patients had complete disappearance of pleural effusion (10/38, 26.32%), 24 patients had reduction of pleural effusion (24/38, 63.16%), 4 patients had no significant change in pleural effusion (4/38, 10.53 %). Up to the current date, there are 21 patients whose pleural effusion has been controlled for more than one year. Among them, one patient with with advanced lung adenocarcinoma have had their pleural effusion controlled for over 30 months and is still under follow-up. It was found that patients with reduced pleural effusion had higher baseline secretion levels of IL-5 (P=0.0217), TNF-a (P=0.0178) and IFN-a (P=0.0278) in pleural effusion, while those with significantly increased levels of IL-6 (P=0.0076), IL-1B (P=0.0009) and IL-8 (P=0.0198) after treatment also had better control of pleural effusion. Further analysis of RNA sequencing in the pleural fluid of 15 patients revealed that patients with better therapeutic effects showed upregulation of CD4 + memory T cells, lymphoid precursor cells, CD8 + effector memory T cells and an upward trend in immune microenvironment scores after treatment. Conclusions: This ongoing phase I study with intracavitary injection of FOLactis in patients with malignant pleural effusion has preliminarily confirmed safety and clinical efficacy, which suggested to be a promising immunotherapeutic strategy for the effective control of malignant pleural effusion. Clinical trial information: NCT:06512896 .

NoLEEta: No chemotherapy in intermediate-risk HR+ HER2− early breast cancer treated with ribociclib in the adjuvant setting—A non-inferiority phase III trial.

TPS645 Background: Historically, the treatment paradigm for hormone receptor-positive, HER2-negative early breast cancer (HR+ HER2− eBC) has relied on endocrine therapy (ET) and adjuvant chemotherapy. However, the absolute benefit of adjuvant chemotherapy is closely tied to baseline risk, being notably modest in intermediate risk eBC, while associated with significant short- and long-term toxicities. The phase III NATALEE trial demonstrated the efficacy of an adjuvant three-year treatment with ribociclib and ET in prolonging invasive disease-free survival (iDFS) in patients with high-risk HR+ HER− eBC. Contrarily to similar studies of CDK4/6 inhibitors in this setting, NATALEE included a group of patients with intermediate clinical risk (pT1-2 pN1, pT3-4 pN0 or pT2 pN0 with histological grade 3 or grade 2 with Ki67≥ 20%). These patients are usually treated with adjuvant chemotherapy based on the tumor clinicopathological characteristics or the results of a genomic signature. Nevertheless, the absolute benefit of adjuvant chemotherapy in these patients is uncertain (and likely reduced) in the context of an adjuvant treatment strategy that includes a CDK4/6 inhibitor. The NoLEEta trial aims at demonstrating that patients with intermediate-risk HR+ HER2− eBC treated with ribociclib and ET could be spared chemotherapy side effects while ensuring similar survival outcomes. Methods: NoLEEta is an international, randomized, open-label, non-inferiority phase III trial. Main inclusion criteria are: HR+ HER2− eBC after curative surgery, at intermediate risk of relapse (pT0-2 pN1, pT3-4 pN0, pT2 pN0 G3 or pT2 pN0 G2 with Ki67≥20%), eligible for adjuvant chemotherapy (per investigator decision, based on clinicopathological parameters or using a genomic signature). Eligible patients are randomized (1:1) to either receive ribociclib and ET (investigational arm without chemotherapy) or chemotherapy followed by ribociclib and ET (control arm). Primary endpoint is invasive breast cancer-free survival (iBCFS), defined in accordance with the STEEP system as the interval between randomization and the earliest occurrence of ipsilateral invasive breast tumor recurrence, local–regional invasive recurrence, distant recurrence, invasive contralateral breast cancer, or death from any cause. Secondary endpoints include invasive disease-free survival, distant disease-free survival, overall survival, interval and type of iBCFS events, incidence and severity of adverse events, and health-related quality of life. Enrollment in NoLEEta started in December 2025, with a target objective of 3902 randomized patients across 8 countries. One interim analysis is planned. Clinical trial information: NCT07237256 .

Dual HER2-targeted therapy with pyrotinib plus inetetamab and adebrelimab in previously treated HER2-amplified metastatic colorectal cancer: A prospective, single-arm, phase II clinical trial.

e15532 Background: Various approaches to HER2 inhibition have been explored for HER2-positive metastatic colorectal cancer (mCRC). However, there is still a need for further improvement in efficacy, especially for those have undergone prior HER2-targeted therapy. Herein, we report the preliminary results of the efficacy and safety of adebrelimab, a novel anti-PD-L1 antibody, combined with dual HER2-targeted therapy-pyrotinib (a pan-HER2 receptor tyrosine kinase inhibitor) and inetetamab (an anti-HER2 monoclonal antibody)-in previously treated HER2-amplified mCRC. Methods: Patients (pts) with metastatic HER2-amplified CRC and having received systemic anti-tumor therapy were enrolled. Adebrelimab (20mg/kg) plus inetetamab (6mg/kg) were given intravenously once every 3 weeks, combined with pyrotinib (240mg for ≤50kg, or 320mg for＞50kg, orally) daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: As of December 30, 2025, 21 patients received treatment and were evaluable for safety and efficacy in the intention-to-treat population. The median age was 49 years (range, 27-75). This was a highly pretreated cohort: 38.1% (8/21) had received ≥3 prior lines of therapy, 4 patients had prior immunotherapy, and 4 had prior HER2-targeted therapies. Among 20 patients with post-baseline assessments, 17 (85.0%) experienced target lesion shrinkage. ORR was 60.0% (95% CI, 36.05-80.88) with 12 partial responses, including two patients pretreated with anti-HER2 ADCs who achieved maximum lesion reductions of 55.28% and 44.12%, respectively. DCR was 85.0% (95% CI, 62.11-96.79). Median time to response was 1.45 months (range 1.38–2.79). With a median PFS of 7.2 months (95% CI, 6.1-NR), 9 patients remain on treatment. Treatment-related adverse events occurred in 10 patients (48%), predominantly grade 1-2 diarrhea (24%). Grade 3 events were reported in 2 patients (10%), including one led to treatment discontinuation. Conclusions: The novel triple combination of adebrelimab, pyrotinib, and inetetamab represents a viable and active strategy for HER2-amplified mCRC after prior therapy. The observed efficacy in patients refractory to prior HER2-targeted therapies, including ADCs, warrants further investigation of this regimen in this population with limited options. Clinical trial information: ChiCTR2000038709.

Comparative effectiveness of antihypertensive drug classes in patients with gastrointestinal malignancy and incident hypertension.

e16359 Background: Over one-third of patients with cancer require antihypertensive therapy. Emerging evidence suggests renin-angiotensin system (RAS) inhibitors may improve survival in oncology populations, and the 2023 AHA Scientific Statement on Cancer Therapy-Related Hypertension highlights optimal antihypertensive selection as a key evidence gap. We compared outcomes between RAS and non-RAS antihypertensives, and between ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB), in patients with gastrointestinal malignancy and incident hypertension. Methods: Using the TriNetX Research Network (2017-2025), we conducted a retrospective cohort study with a new-user, active-comparator design and propensity score matching. Adults with incident gastrointestinal malignancy (ICD-10 C15-C25) who developed new-onset hypertension requiring antihypertensive initiation within 90 days of cancer diagnosis were included. ACEi/ARB initiators were compared with beta-blocker or calcium channel blocker (BB/CCB) initiators. Cox regression evaluated outcomes starting 91 days post-index. Sensitivity analyses compared ARB with ACEi, BB, and CCB. Results: After matching, 8,440 patient pairs were analyzed. ACEi/ARB initiation was associated with lower all-cause mortality (HR 0.83, 95% CI 0.77-0.90; p < 0.001) and reduced acute kidney injury (HR 0.81, 95% CI 0.70-0.92; p = 0.002). ARB use showed consistent mortality reductions versus ACEi (HR 0.85, 95% CI 0.76-0.96), BB (HR 0.74, 95% CI 0.66-0.84), and CCB (HR 0.76, 95% CI 0.67-0.85). Conclusions: In patients with gastrointestinal malignancy and incident hypertension, RAS inhibitor initiation, particularly ACEi/ARB, was associated with significantly lower mortality and reduced acute kidney injury. These data support preferential first-line use of ACEi/ARB for hypertension management in this population. Summary of primary and sensitivity analyses: Significant outcomes. Comparison N Mortality OR (95% CI) Mortality HR (95% CI) AKI OR (95% CI) AKI HR (95% CI) Thrombosis HR (95% CI) Primary: ACEi/ARB vs BB/CCB 8,440 0.87 (0.80, 0.94)* 0.83 (0.77, 0.90)* 0.86 (0.75, 0.99)* 0.81 (0.70, 0.92)* 0.86 (0.75, 0.98)* Sensitivity 1: ARB vs ACEi 3,622 0.90 (0.79, 1.03) 0.85 (0.76, 0.96)* 1.01 (0.82, 1.25) 0.92 (0.75, 1.13) 0.80 (0.65, 0.99)* Sensitivity 2: ARB vs BB 3,276 0.85 (0.74, 0.97)* 0.74 (0.66, 0.84)* 1.02 (0.81, 1.29) 0.83 (0.67, 1.04) 0.83 (0.66, 1.04) Sensitivity 3: ARB vs CCB 3,901 0.80 (0.70, 0.91)* 0.76 (0.67, 0.85)* 0.89 (0.72, 1.10) 0.81 (0.66, 0.99)* 0.90 (0.72, 1.12) *p < 0.05 (bold text with green shading indicates statistical significance). Abbreviations: OR = odds ratio; HR = hazard ratio; CI = confidence interval; AKI = acute kidney injury; Thrombosis = composite any thrombosis (arterial and venous events combined).

Risk-stratified cancer screening in idiopathic inflammatory myopathies.

e23127 Background: Idiopathic inflammatory myopathies (IIM) are high-risk cancer cohorts with 20–25% peri-onset malignancy, yet 83% diagnosed at stage III–IV. No consensus multidisciplinary screening pathway exists. We compared three screening strategies for early detection optimization. Methods: Systematic review and meta-analysis (PRISMA 2020) of 13 observational studies (n≈2,100; 69% good quality). Pooled proportion meta-analysis with random-effects modeling estimated peri-onset (≤3 years) cancer detection rates. Primary comparison: PET/CT vs. conventional screening (CI non-overlap); IMACS risk stratification (sensitivity, specificity, NPV). GRADE assessment applied. Results: PET/CT detected 24.6% (95% CI 19.1–30.9%) vs. conventional 11.5% (95% CI 9.2–14.3%); difference 13.1 pp (Z=2.18, p=0.029). IMACS risk stratification: 12.3% (95% CI 7.1–18.2%). Critically, standard-risk IMACS patients achieved 100% negative predictive value (0 of 12 cancers; p=0.028), enabling safe de-escalation. High-risk patients: 17.9% cancer incidence. Real-world survey (Dutton et al.): 77% of clinicians lack consensus; no standardized oncology-rheumatology pathway. Conclusions: Risk-stratified IMACS screening with selective PET/CT outperforms conventional screening. IMACS 100% NPV in standard-risk patients supports safe de-escalation, while high-risk patients (17.9% incidence) warrant PET/CT. Multidisciplinary implementation framework needed: (1) IMACS risk stratification at diagnosis; (2) PET/CT for high-risk; (3) age-appropriate screening for standard-risk; (4) rheumatology-oncology shared decision-making. Comparison of screening strategies. Modality Detection Rate (95% CI) Sensitivity Specificity Key Finding Evidence Conventional Screening 11.5% (9.2–14.3%) 45–62% 70–82% 37% miss rate; unreliable LOW PET/CT 24.6% (19.1–30.9%) 67–94% 80–98% 2.1× higher yield; more false positives LOW IMACS Risk-Based 12.3% (7.1–18.2%)* 82–91% 72–78% High-risk 17.9% vs. standard-risk 0% (100% NPV) LOW Whole-Body MRI 13.0% 71% 85% Radiation-free; limited evidence (n=1) VERY LOW

Tumor-specific supportive care utilization after first-line PD-1 inhibitor therapy: Real-world transfusion and mortality patterns in lung cancer and melanoma.

e20671 Background: Immune checkpoint inhibitors (ICIs) are standard first-line therapy for non–small cell lung cancer (NSCLC) and melanoma, but tumor-specific supportive-care needs remain poorly described. Clinicians often observe different clinical trajectories between these diseases. We conducted a descriptive, real-world comparison of transfusion and mortality after first-line PD-1 inhibitor monotherapy in NSCLC versus melanoma, using transfusion as a tumor-specific supportive-care endpoint. Methods: Using the TriNetX US Collaborative Network (69 healthcare organizations), we identified adults receiving first-line nivolumab or pembrolizumab monotherapy between January 2015 and May 2024. Cohort 1 included NSCLC (ICD-10 C34); Cohort 2 included melanoma (ICD-10 C43–C44). Patients with pre-treatment anemia (D64), neutropenia (D70), transfusion (CPT 36430), hospice/home health (HCPCS Q5001), or palliative care (Z51.5) before index were excluded. Outcomes (transfusion and all-cause mortality) were assessed from 1 day after PD-1 initiation through end of follow-up. Propensity score matching and time-to-event modeling were not used; all estimates are unadjusted cumulative risks and are interpreted descriptively, not causally. Results: The NSCLC and melanoma cohorts included 6,445 and 6,083 patients, respectively. Transfusion occurred in 141 NSCLC patients (2.2%) and 68 melanoma patients (1.1%), risk difference 1.1% (95% CI, 0.6–1.5; p < 0.001), risk ratio 1.96 (95% CI, 1.47–2.61). All-cause mortality was 38.5% in NSCLC (2,481/6,445) and 20.5% in melanoma (1,249/6,083), risk difference 18.0% (95% CI, 16.4–19.5; p < 0.001), risk ratio 1.88 (95% CI, 1.77–1.99). Mortality represents cumulative incidence over variable follow-up and not survival estimates from time-to-event analyses. In patients treated after 2020 (n = 4,847), transfusion patterns were similar, suggesting these descriptive findings are stable across more contemporary PD-1 practice. Conclusions: In this unmatched, federated EHR analysis, NSCLC patients had higher cumulative transfusion and mortality risks after first-line PD-1 therapy than melanoma patients, despite identical supportive-care exclusions. These differences are most plausibly explained by underlying tumor biology, comorbidities, and care patterns, and they should not be interpreted as causal treatment effects. Transfusion, although infrequent, may function as a marker of higher supportive-care intensity in select ICI-treated populations such as NSCLC, supporting future matched, time-to-event studies to design tumor-specific supportive-care strategies and earlier monitoring during immunotherapy.

Comparative effectiveness of CAR-T and bispecific antibodies in relapsed/refractory large B-cell lymphoma: A network meta-analysis of phase III trials.

7090 Background: Second-line and later-line cellular therapies and bispecific antibodies have transformed the management of relapsed/refractory large B-cell lymphoma (LBCL), yet comparative efficacy across platforms remains uncertain due to the absence of head-to-head trials. We conducted a network meta-analysis (NMA) to compare disease control and overall survival (OS) across contemporary randomized phase III studies, representing the first synthesis of contemporary CAR-T and bispecific antibody phase III data. Methods: A frequentist graph-theoretical NMA was performed using trial-level hazard ratios (HRs) extracted from five randomized phase III trials (ZUMA-7, TRANSFORM, BELINDA, STARGLO, SUNMO). Treatments included axicabtagene ciloleucel, lisocabtagene maraleucel, tisagenlecleucel, glofitamab-GemOx, mosunetuzumab-polatuzumab, and chemoimmunotherapy as the reference. Outcomes were disease control (EFS/PFS) and OS. Random-effects models were applied, and P-scores were used to rank treatment hierarchy. Results: Five trials encompassing approximately 2,000 patients were included. For disease control, lisocabtagene maraleucel (HR 0.35, 95% CI 0.23–0.53), axicabtagene ciloleucel (HR 0.40, 95% CI 0.31–0.51), glofitamab-GemOx (HR 0.40, 95% CI 0.28–0.57), and mosunetuzumab-polatuzumab (HR 0.41, 95% CI 0.29–0.58) each significantly improved outcomes, whereas tisagenlecleucel did not (HR 1.07, 95% CI 0.82–1.40). Ranking favored lisocabtagene maraleucel (P-score 0.82), followed by axicabtagene ciloleucel (0.67), glofitamab-GemOx (0.67), and mosunetuzumab-polatuzumab (0.64). For OS, lisocabtagene maraleucel (HR 0.59, 95% CI 0.40–0.87), glofitamab-GemOx (HR 0.62, 95% CI 0.43–0.89), and axicabtagene ciloleucel (HR 0.73, 95% CI 0.55–0.97) significantly improved survival, while mosunetuzumab-polatuzumab showed a non-significant favorable trend (HR 0.80, 95% CI 0.52–1.24). Tisagenlecleucel did not improve OS (HR 1.24, 95% CI 0.83–1.85). OS rankings again favored lisocabtagene maraleucel (P-score 0.84), followed by glofitamab-GemOx (0.80) and axicabtagene ciloleucel (0.61). Conclusions: Across randomized phase III evidence, lisocabtagene maraleucel demonstrated the highest probability of being the most effective therapy for both disease control and overall survival in relapsed/refractory LBCL, followed closely by glofitamab-GemOx and axicabtagene ciloleucel, while tisagenlecleucel consistently ranked lowest. Although limited by cross-trial heterogeneity inherent to indirect comparisons, these findings highlight meaningful differences across platforms and may inform treatment sequencing while prospective head-to-head studies mature.

A personalized digital approach to cancer risk assessment in a diverse gynecology clinic.

e22642 Background: Most individuals who qualify for cancer genetic testing and enhanced breast cancer screening are not identified. We aim to sustainably integrate digital cancer risk assessment into the daily workflow of a gynecology clinic. Methods: In an effectiveness-implementation quality improvement (QI) study in an urban academic gynecology practice serving patients with public insurance, a digital tool (DT) for cancer risk assessment was launched to identify those who meet NCCN (National Comprehensive Cancer Network) criteria for hereditary cancer screening and generate a Tyrer-Cuzick (TC) score. New gynecology patients > 18 years were invited to complete the DT via secure portal-based text messaging. Data were collected through chart review. Statistical analysis was performed using Stata version 19. Results: During 6 weeks pre-implementation, 131 new gyn visits were seen (median age 42). At least 14 (10.7%) patients were eligible for genetic testing by NCCN criteria, among which 1 was counseled and 3 had prior testing. Only 1 patient had a TC score calculated. In the initial 6 weeks post-implementation, 171 new patients were seen (median age 41), of which 153 were sent the DT with 82 (53.6%) completing it. Among this group, 18 (22.0%) met NCCN criteria for genetic testing and 12 (14.6%) had a TC score exceeding 20%. 21 of 24 (87.5%) patients meeting NCCN criteria and/or with an elevated TC score were counseled and/or referred to Genetics and Personalized Cancer Prevention Program (GPCP). In the first 6 weeks post-implementation, the QI team was onsite providing education and assistance. In the subsequent 5 weeks, there was no difference in DT completion rates (53.6% vs. 51.1% respectively, p = 0.70). In the absence of the QI team, there was a significant increase in “missed patients" (0% vs. 40% respectively, p < 0.001). For “missed patients” or patients with abnormal results on the DT that were not counseled, the QI team contacted the provider and encouraged follow-up with the patient. Conclusions: The QI initiative demonstrated a short-term sustainable effort to screen patients for increased cancer risk, with challenges in follow-up identified. This quality improvement project is working iteratively to implement universal personalized risk-based cancer prevention. Pre-Implementation(6 weeks, n = 131)n / n (%) Post-Implementation (6 weeks, n = 153)n / n (%) p-value Completed DT / Received DT - 82 / 153 (53.6) - Meet NCCN criteria for genetic testing 14 / 131 (10.7) 18 / 82 (22.0) - TC Score Calculated 1 / 131 (0.76) 77 / 153 (50.3) < 0.001 TC Score > 20% 0 / 1 (0) 12 / 82 (14.6) - Meet NCCN and/or TC Score > 20% 14 / 131 (10.7) 24 / 82 (29.3) - Referred to GPCP 0 / 14 (0) 14 / 24 (58.3) < 0.001 Documented discussion of risk/Genetic testing already done/Prior GPCP Referral/Declined GPCP Referral 4 / 14 (28.6) 7 / 24 (29.2) 0.97 Cancelled Appointment - 3 / 24 (12.5) - No documented discussion of risk or GPCP referral (missed) 10 / 14 (71.4) 0 / 24 (0) < 0.001

Comparative efficacy of antifungal prophylaxis in acute myeloid leukemia: A systematic review and meta-analysis.

e18515 Background: Acute myeloid leukemia (AML) is characterized by prolonged neutropenia and a high risk of infections, including invasive fungal infections (IFI), which are associated with substantial mortality rates of 40–70%. To mitigate this risk, antifungal prophylaxis (AFP) is often used. Current guidelines recommend posaconazole (PCZ) as the agent with the most robust data (Pagano et al. Leukemia 2025), but factors including cost, toxicities, and drug-drug interactions (DDIs) complicate use of common AFP agents, with a dearth of literature directly comparing them. Methods: We conducted a systematic review comparing IFI rate and AFP use in adult and pediatric patients with AML. In total, 2,994 records were identified, of which 367 underwent full-text review. Ultimately, 138 studies were analyzed. 81 studies reported rates of possible, probable, and proven (PsPbPv) IFI while 132 studies reported rates of probable and proven (PbPv) IFI. Patients received intensive therapy (n=78, 57%), less-intensive therapy (n=15, 11%), or both (n=25, 18%). Some (n=20, 14%) studies did not record therapy intensity. A mixed-effects model with PCZ IFI rate as reference/intercept was used. Results: When evaluating the rate of PsPbPv IFI (k=135), first-generation azoles (21.0%, p=0.027) and no AFP (29.2%, p<0.0001) were significantly higher than PCZ (15.3%). Limiting to PbPv IFI rate (k=226), first-generation azoles (9.6%, p<0.0001), amphotericin B (13.2%, p=0.0009), isavuconazole (8.8%, p=0.033), and no AFP (10.7%, p<0.0001) were significantly higher than PCZ (5.0%). IFI rate with voriconazole and echinocandin prophylaxis was not significantly different than PCZ. Subgroup meta-analysis of less-intensive patients was underpowered to detect any difference aside from a higher rate of PsPbPv IFI for first-generation azoles (20.8%, p=0.030) compared to PCZ (9.4%). Conclusions: Our study is the first comparative systematic review of all primary AFP strategies in patients with AML, with considerable dataset of 25,431 patients across 138 studies, the majority with data for patients on intensive therapy (74.6%). Results suggest that echinocandins and second-generation azoles offer comparable protection against PsPbPv IFI. Given the factors complicating the use of these agents including toxicities, DDIs, and no oral formulations, further prospective studies are imperative for further comparison. PsPbPv IFI [95% CI] p-value PbPv IFI [95% CI] p-value Posaconazole 15.3% [12.6-18.5%] --ref-- 5.0% [4.2-6.0%] --ref-- Voriconazole 14.3% [10.4-19.3%] 0.703 5.7% [4.2-7.5%] 0.489 Isavuconazole 15.1% [8.0-26.8%] 0.966 8.8% [5.4-13.9%] 0.033 First-gen azoles 21.0% [17.1-25.6%] 0.027 9.6% [8.0-11.5%] <0.0001 Echinocandins 14.0% [8.4-22.5%] 0.734 7.0% [4.6-10.5%] 0.161 Amphotericin B 28.9% [15.2-47.9%] 0.062 13.2% [7.7-21.5%] 0.0009 No AFP 29.2% [23.0-36.4%] <0.0001 10.7% [8.5%-13.4%] <0.0001

Analysis of sex-based differences in tumor microenvironments within hematopoietic and reticuloendothelial system malignancies.

7095 Background: While sex-specific disease incidence, genomic profiles, and survival outcomes are widely recognized in hematologic malignancies, the biological mechanisms and tumor microenvironment (TME) factors driving these sex-based disparities remain largely undefined, particularly at the level of the TME, which plays a key role in immune surveillance, therapeutic response, and disease progression. This meta-analysis investigates whether significant differences exist in the abundance of various cell types between males and females within lymphoid and myeloid leukemias, plasma cell tumors, mature B-cell lymphomas, and acute lymphoblastic leukemia. Characterizing these variations is essential for developing tailored therapeutic strategies that optimize clinical outcomes for both sexes. Methods: Computational meta-analysis was performed on the TCGA National Database, using xCell enrichment scores across transcriptomic samples from hematopoietic and reticuloendothelial system tumors, comparing males (n= 3,829) and females (n= 2,995). Mann-Whitney U testing with Bonferroni correction identified cell populations with differential enrichment (padj<0.05). Cohorts were balanced for age, race, and tumor type (primary, recurrence, metastatic) (all p>0.05). Results: Of the 64 cell types screened, 12 exhibited a significant difference in abundance between males and females. Nine of these were female-enriched populations (padj <0.01). These included erythrocytes (Mean Difference [Male-Female]: -0.5192), neutrophils (-0.4343), eosinophils (-0.4147), GMP (-0.1345), platelets (-0.1097), common myeloid progenitors (CMP) (-0.0917), mast cells (-0.0640), MPP (-0.0556), and megakaryocytes (-0.0131) indicating higher relative enrichment in females. Conversely, the male-enriched populations (padj <0.02) consisted of DC (0.2210), Th2 cells (0.0761), and Th1 cells (0.0634). Conclusions: This study demonstrates sex-based differences in TME cellular abundance in hematopoietic and reticuloendothelial tumors. Females exhibited a higher presence of early-stage progenitor populations, such as MPP and CMP, and innate immune cells, including neutrophils and eosinophils, potentially due to hormonal influences, differences in myelopoiesis, or sex-linked immune polarization. In contrast, males had a higher presence of DC and Th cells. Among all cell types analyzed, erythrocytes exhibited the greatest magnitude of difference in abundance between sexes, showing potential distinctions in metabolic and oxygenation profiles. These findings highlight biologically meaningful sex specific variations in the TME, underscoring the need for further mechanistic studies linking sex-specific TME compositions to therapeutic responses and incorporating biological sex as a critical variable in immunotherapy trial design.

Nociceptor circadian clock genes control excitability and pain perception in mice in a sex- and time-dependent manner

Multi-omics approaches to unveil the mixed molecular characteristics of hepatoid adenocarcinoma of the stomach with neuroendocrine differentiation.

e16109 Background: Hepatoid adenocarcinoma of stomach with neuroendocrine differentiation (HAS-NEC) is an extremely rare subtype of gastric cancer, and there is currently no systematic research focused on this uncommon subtype. This study aims to investigate the clinicopathological and molecular characteristics of this rare subtype, thereby providing a reference for precision therapy for such patients. Methods: We retrospectively collected tumor tissue and adjacent carcinoma tissue samples from 84 patients, along with corresponding clinicopathological information, for whole exome sequencing and transcriptome sequencing. Spearman correlation analysis and unsupervised clustering analysis were employed to explore the molecular characteristics of HAS-NEC and to assess the similarities and differences among the various sample groups. Results: From the perspective of clinical pathological features, HAS-NEC exhibited greater similarity to HAS patients, with no significant differences in all clinicopathological characteristics. HAS-NEC patients possessed distinct genomic features compared to both HAS and NEC patients, with TTN being the most frequently mutated gene, occurring in 90% of cases. Mutations in TET1 were exclusive to HAS-NEC patients and were not detected in the other two groups. At the transcriptional level, HAS-NEC patients showed greater similarity to HAS patients, demonstrating more comparable transcriptional expression patterns. Lastly, we identified a potential therapeutic target, ZFHX4, whose mutations influence the transcriptional expression and prognosis of gastric cancer patients, further impacting immune infiltration and response to immunotherapy. Conclusions: Patients with HAS-NEC exhibited unique molecular biological characteristics that could not be simply viewed as a combination of HAS and NEC.

Baseline characteristics of a phase III randomized controlled trial of acupuncture for chemotherapy-induced peripheral neuropathy (ACT trial).

e24173 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, painful, and disabling chemotherapy toxicity with limited effective treatments. The ACT trial is a two-arm, parallel, randomized controlled trial comparing electroacupuncture (EA) with sham acupuncture (SA) for CIPN pain management. Methods: Eligible participants were English-proficient adults (≥18 years) with no evidence of disease or stable disease who had completed neurotoxic chemotherapy ≥3 months prior and reported persistent moderate-to-severe CIPN pain (average pain score ≥4 on Brief Pain Inventory–Short Form [BPI-SF] and grade ≥1 sensory pain per CTCAE v5.0). Participants maintained stable pain medication regimens and avoided new medications during the initial 12 weeks.Those with pacemakers or electronically charged medical devices were excluded. Descriptive statistics summarized baseline characteristics. Results: A total of 255 participants enrolled across Memorial Sloan Kettering Cancer Center (70.6%) and Dana-Farber Cancer Institute (29.4%). Mean age was 60.6 years (SD 11.9); 77.3% were female. The participants were racially and ethnically diverse, including 64.7% White, 15.7% Black, 7.8% Asian, and 9.7% Hispanic participants. Mean BMI was 28.47 (SD 6.10). Prior cancer diagnoses included breast (43.1%), colorectal (16.9%), and ovarian (9.0%) cancers. Cancer stage at diagnosis was Stage I (25.7%), Stage II (28.7%), Stage III (31.6%), and Stage IV (13.5%). Baseline symptom burden was notable, with mean score of 5.18 (SD 1.84) for BPI average pain, 6.16 (SD 1.96) for BPI worst pain, 45.18 (SD 16.37) for the Neuropathy Pain Scale (NPS), and 23.61 (SD 8.25) for the Functional Assessment of Cancer Therapy–Gynecologic Oncology Group–Neurotoxicity (FACT-GOG-NTX). Conclusions: ACT trial participants represented a diverse patient population and reported clinically meaningful, moderate-to-severe neuropathic pain following neurotoxic chemotherapy. This highlights substantial unmet symptom management needs and supports evaluation of electroacupuncture as a non-pharmacologic CIPN intervention. Outcome analyses will be reported subsequently. Clinical trial information: NCT04917796 . Baseline characteristics of ACT trial participants. Study site MSK 180 (70.6%), DFCI 75 (29.4%) Age, mean (SD), years 60.6 (11.9) Female, n (%) 184 (77.3%) White, n (%) 165 (64.7%) Hispanic, n (%) 23 (9.7%) BMI, mean (SD) 28.47 (6.10) BPI worst pain, mean (SD) 6.16 (1.96) BPI average pain, mean (SD) 5.18 (1.84) NPS, mean (SD) 45.18 (16.37) FACT-GOG-NTX, mean (SD) 23.61 (8.25) Abbreviations: MSK, Memorial Sloan Kettering Cancer Center; DFCI, Dana-Farber Cancer Institute; SD, standard deviation; BMI, body mass index; BPI, Brief Pain Inventory; NPS, Neuropathy Pain Scale; FACT-GOG-NTX, Functional Assessment of Cancer Therapy–Gynecologic Oncology Group–Neurotoxicity subscale.

Trends in sepsis-related mortality among adults with cancer aged ≥ 25 years in United States, 1999-2020: A CDC WONDER study.

e22600 Background: Sepsis is one of the leading causes of death worldwide, while mortality in patients with cancer and sepsis is significantly higher than mortality in patients without cancer. Our study seeks to analyze trends in the age-adjusted mortality rate (AAMR) for sepsis-related deaths in adult patients (≥ 25 years old) with cancer in the United States from 1999 to 2020 using data from the recent CDC WONDER database. This analysis revealed significant temporal patterns, providing a framework for future studies and public health initiatives. Methods: The CDC WONDER database was used to track sepsis-related deaths in adult cancer patients in the United States from 1999 to 2020. This study analyzed the temporal mortality patterns in adults, categorized by age group, gender, race, census region, and urban/rural residency, using the joint point regression tool. We calculated the annual percent change (APC) and the average annual percent change (AAPC), and we applied 95% confidence intervals. Results: During 1999-2020, 599,604 deaths occurred in the United States involving cancer and sepsis. AAMR initially showed a decline in mortality; however, a significant surge in mortality was observed in 2013 [APC = 3.57 (95% CI 2.55 to 4.10)], with an overall AAPC of 0.28. Male patients consistently maintained a higher mortality rate; there was a notable increase in the trend in female patients, which was recorded [AAPC = 0.35 (95% CI 0.21-0.54)]. Analysis by race showed American Indian or Alaska Native patients had the greatest surge in AAMR, which significantly went high [AAPC = 2.38 (95% CI 1.65-3.43)], while Black or African American patients showed the highest mortality rate. The mortality burden increased with age, being highest at the 45-85+ age range. Regional analysis revealed that the West experienced the most significant rise in AAMR [AAPC = 0.77 (95% CI 0.54-1.16)]. A persistent disparity was observed between rural and urban populations, with rural individuals consistently demonstrating a higher AAMR compared to urban individuals [AAPC = 1.00 (95% CI, 0.82 to 1.24)]. Conclusions: Our analysis reveals substantial inequalities by gender, ethnicity, age, and region. These findings reveal important insights for future studies and policy efforts to lower mortality, especially for individuals at high risk.

Do we really know how many veterans have cancer in the Veterans Health Administration?

e13745 Background: Veterans living in isolated and rural geographies often face barriers to timely specialty oncology care services, like screening and treatment. Improved case identification of Veterans with cancer is essential to support health care delivery and resource planning in rural geographies where access is limited. Methods: Our team developed a SQL-based approach to create two distinct Veteran cohorts, an oncology cohort (OC) and analytic cohort (AC) using data from 2013-2023. The OC was created using VHA’s Corporate Data Warehouse (CDW) Oncology Raw Domain, which contains VA oncology patients with a confirmed cancer diagnosis and date of diagnosis as recorded in the Central Cancer Registry. The AC was created using a clinician validated list of ICD-9/10 diagnosis code groupings informed by the Surveillance, Epidemiology, and End Results (SEER) list of reportable neoplasms, to ensure alignment with standardized cancer classifications. ICD-9/10 codes were sorted into 12 classifications by prevalence. Diagnosis dates and ICD codes were derived from clinician-validated inpatient and outpatient encounter data. Results: The OC identified 488,273 Veterans with cancer. 908,060 Veteran encounters were included in the AC. A total of 406,242 Veterans were present in both the OC and AC. The AC identified substantially more Veterans not represented in the OC, suggesting a higher than expected upper-bound of cancer cases. Rural Veterans comprised a greater proportion of the AC compared to the OC (36.3% vs. 34.8%), indicating that case identification in rural areas is underestimated. Conclusions: Identifying Veteran’s with cancer using the registry alone may underestimate, especially in rural geographies. Given that coding clinical encounters in oncology has limitations, this study identified differences between traditional methods and our novel approach. By incorporating relevant diagnosis codes and encounter data, a more comprehensive estimate of oncology care demand can be used to determine the allocation of oncology resources. Veteran characteristics of defined cohorts (OC vs. AC). Oncology Cohort (N=488,273) Analytic Cohort (N=908,060) Characteristic n (%) Characteristic n (%) Sex Male 466,010 (95.4%) Male 877,454 (96.6%) Age 18-6465 & older 135,358 (27.7%)352,686 (72.2%) 18-6465 & older 164,708 (18.1%)742,290 (81.7%) Race WhiteBlack/African AmericanNHPIAsianOther 353,158 (72.3%)94,611 (19.4%)3,621 (0.7%)2,185 (0.4%)12,713 (2.6%) WhiteBlack/African AmericanNHPIAsianOther 679,842 (74.9%)129,261 (14.2%)7,190 (0.8%)5,300 (0.6%)49,620 (5.5%) Rurality Rural 169,903 (34.8%) Rural 329,888 (36.3%)

cfDNA WGS vs plasma proteomics for minimally invasive MRD assessment in multiple myeloma.

7546 Background: MRD assessment informs relapse risk in MM but is typically bone marrow-based and invasive. We therefore compared two minimally invasive MRD assays: BM-informed cfDNA whole-genome sequencing (cfWGS) and plasma proteomic MRD (EasyM). Methods: 71 longitudinal plasma samples (22 diagnosis, 49 follow-up) from 22 newly diagnosed MM patients across 8 Canadian sites (TFRIM4) had paired cfWGS and EasyM (Rapid Novor Inc). cfWGS MRD used patient-specific mutation lists from diagnostic BM WGS (Abelman et al., medRxiv 2025). EasyM used mass spectrometry to quantify residual M-protein from baseline. The primary endpoint was progression-free survival (PFS). Results: Among 22 MM patients (8 male, 14 female; median age at diagnosis 62 years), 8 progressed at a median follow-up of 52.6 months (range: 10-79 months). At 1-year maintenance (n = 18 available), cfWGS MRD+ (6/18) predicted inferior PFS (HR 20.12, 95% CI 2.23-181.60, p = 0.007). EasyM any-detect positivity was frequent (16/18, reflecting delayed clearance) and not prognostic (p = 0.99), with poor agreement vs cfWGS (44.4%, κ = 0.118). An exploratory EasyM clearance threshold of 0.93% (hypothesis-generating) classified 5/18 patients as MRD+ and stratified PFS (HR 8.78, 95% CI 1.55-49.82, p = 0.004), improving agreement with cfWGS (17/18, 94.4%, κ = 0.870). Progression clustered in cfWGS+/EasyM-high patients (EasyM >0.93%; 4/5; median 11.9 months post-collection [1.9–22.8]) and occurred once in cfWGS−/EasyM-low patients (1/12, 27.6 months). The only discordant case (cfWGS+/EasyM−) progressed 8.7 months after collection. Higher quantitative MRD burden was associated with inferior PFS (cfWGS: HR 2.92 per 1 SD, 95% CI 1.29-6.59, p = 0.01; EasyM: HR 5.48 per 1 SD, 95% CI 0.79-37.90, p = 0.085). At ~100 days post-autologous stem cell transplantation (ASCT; n = 16 available), EasyM was uniformly MRD+ (16/16) while cfWGS was MRD+ in 7/16 patients. Applying an EasyM clearance threshold (2.13%; 9 cleared vs 7 residual) improved agreement with cfWGS (14/16; 87.5%; κ = 0.746). Of two discordant cases, one cfWGS+/EasyM-cleared patient relapsed 38.6 months post-collection and one cfWGS−/EasyM-residual patient remained progression-free at last follow-up. At post-ASCT, both assays showed consistent but underpowered associations with PFS (cfWGS HR 6.32, 95% CI 0.70–56.76, p = 0.100; EasyM-clearance HR 2.36, 95% CI 0.39–14.18, p = 0.335). Across all post-treatment samples (n = 49), continuous cfWGS burden correlated with EasyM residual M-protein (rho = 0.535, p < 0.001). Conclusions: BM-informed cfWGS MRD strongly stratified PFS, whereas EasyM required a clearance definition due to near-universal early positivity. Concordant plasma burdens support complementary MRD information. Future work will validate these findings in larger cohorts and quantify the incremental value of combined cfWGS and proteomic MRD for early relapse prediction.

PRTH-101: An investigational treatment for thoracic solid tumors targeting discoidin domain receptor (DDR1) and the tumor microenvironment (TME).

e20510 Background: Many tumors are resistant to existing targeted therapies and chemotherapies, with high treatment failure rates in collagen-rich solid tumors. Collagen blocks T cell access to tumors, precluding effective anti-tumor responses. DDR1 binds collagen and is overexpressed in many solid tumors, including thymic epithelial cancers (TEC) and non-small cell lung cancer (NSCLC). Data show that high DDR1 expression in NSCLC is associated with poor prognoses and lack of response to immunotherapy, and low PD-L1 status is associated with T cell exclusion and worse responses. Immunotherapy for TEC leaves much room for improvement and treatment of PD-L1-negative NSCLC remains challenging. PRTH-101, a first-in-class, humanized monoclonal antibody, blocks the DDR1:collagen interaction and disrupts tumor collagen, facilitating T cell infiltration in tumors and tumor reduction in preclinical studies. Methods: PRTH-101 is being tested in an open-label Phase 1 clinical trial at doses of 8 to 1600 mg every 3 weeks, as a single agent and combined with pembrolizumab. In the dose escalation, multiple tumor types were enrolled. In the expansion phase, advanced TEC and NSCLC patients are being enrolled and treated with a provisional Phase 2 dose of 1200 mg PRTH-101, based on pharmacokinetics and target engagement, alone or with pembrolizumab. DDR1 density in tumors is evaluated by immunohistochemistry. Results: To date, 72 patients have been treated with PRTH-101, alone or with pembrolizumab; no dose-limiting toxicities have been seen. Most patients had progressed on multiple prior lines of therapy, including immunotherapy. Target engagement data correlate well with PK data. In TEC, 1 partial response (PR) by RECIST in a PD-L1-negative tumor (1200 mg combination therapy), and a PR (1600 mg monotherapy) by modified RECIST were seen; 72% of TEC patients had stable disease (SD), with median progression-free survival (mPFS) of 5.7 months for all patients and 8 months for those receiving more than one cycle. By MRI, tumors have also shown tumor cavitation and reduced vascularity. In NSCLC, a PR was seen in a PD-L1-negative tumor (1200 mg PRTH-101 alone after not tolerating first dose of pembrolizumab), and SD for 15 months was seen in a PD-L1-positive tumor (24 escalated to 80 mg, monotherapy). All tumors tested expressed DDR1, and patients with high-expressing tumors (≥25 th percentile) showed significantly longer PFS than patients with low-expressing tumors. Conclusions: PRTH-101 shows evidence of activity in this early phase clinical trial, with outcomes correlating with DDR1 expression. Analysis of the data by monotherapy and combination therapy in the context of PD-L1 expression, suggests that PRTH-101 contributes to or is responsible for PFS in these patients. Further clinical evaluation of PRTH-101 alone and with pembrolizumab in patients with TEC and NSCLC is planned. Clinical trial information: NCT05753722 .

Systemic cytokine dynamics during neoadjuvant chemotherapy versus endocrine therapy and CDK4/6 inhibition in high-risk luminal breast cancer: Results from the GEICAM/2019-01-CARABELA trial.

619 Background: Chemotherapy (CT) and CDK4/6 inhibitors modulate antitumor immunity primarily within the tumor microenvironment. Whether these effects are reflected systemically during neoadjuvant therapy, differ by treatment, or are associated with response remains unclear. Methods: CARABELA is a randomized neoadjuvant trial comparing letrozole (ET) + the CDK4/6 inhibitor abemaciclib vs standard CT in high-risk HR+/HER2− breast cancer. Plasma cytokines were measured at baseline (BL), 2 weeks (wks), 12 wks, and end of treatment (EOT) using multiplex proximity extension assay (Olink Target 96 Immuno-Oncology panel). Analyses included: (1) BL cytokine profiles by menopausal status, Oncotype DX Breast Recurrence Score test result (RS ≤25 vs >25), and Ki67 (<40% vs ≥40%); (2) longitudinal cytokine changes (BL to 2 and 12 wks, Δ) by residual cancer burden (RCB 0/I vs II/III), overall and by treatment; (3) EOT cytokine profiles by RCB. Group comparisons were adjusted by false discovery rate (FDR) threshold of 5% controlled by the q-value method. Multivariable logistic regression models were adjusted for menopausal status. Treatment–cytokine interactions were evaluated. Results: At BL, 40 cytokines were differentially expressed by menopausal status, with most showing higher levels in postmenopausal patients, including myeloid-associated inflammatory chemokines (CXCL9, CXCL10, MCP-1, MCP-4), angiogenic/matrix-remodeling factors (VEGFA, HGF, MMP7, MMP12), and TNF-related/immune regulatory molecules (TNFRSF12A, TNFRSF9, Galectin-9), indicating chronic systemic inflammation, without enrichment of cytotoxic immune effector programs. No BL cytokine differences met FDR threshold by RCB, RS or Ki67. Early cytokine changes (BL-2 wks) were not associated with RCB. In the ET + abemaciclib arm, no significant changes were observed between BL and 12 wks. In the CT arm, 25 cytokines had a significant increase (BL-12 wks) in patients with RCB II/III with respect to patients with RCB 0/I. These included inflammatory chemokines (IL8, CXCL1, CXCL5, CCL3, CCL4, MCP-3, MCP-4), angiogenic/growth factors (VEGFA, ANGPT1, EGF, PDGF-B), and stress-/TNF-related signaling molecules (CASP-8, TNFSF14, ADA). These cytokines were associated with RCB II/III in multivariable models adjusted for menopausal status. Cytokine–treatment interaction tests did not meet FDR threshold. Conclusions: Postmenopausal women display a distinct cytokine profile consistent with chronic systemic inflammation. Neoadjuvant CT induces pronounced systemic cytokine changes, while ET + CDK4/6 inhibition does not. Increased inflammatory and angiogenic cytokines during CT are associated with residual disease, supporting longitudinal systemic immune profiling as a marker of treatment resistance in high-risk luminal breast cancer. Clinical trial information: NCT04293393 .

Impact of the COVID-19 pandemic on early-stage breast cancer post-lumpectomy breast radiation therapy completion.

e12682 Background: Whole-breast radiation therapy (RT) following lumpectomy has become a standard of care for early-stage breast cancer (ESBC) treatment. Previous research has demonstrated superior compliance with hypofractionation (HFRT) versus standard fractionation (SFRT). However, the impact of the COVID-19 pandemic on RT completion rates in ESBC has not been well-characterized. Methods: Using the National Cancer Database, patients with ESBC who underwent post-lumpectomy RT from 2018 to 2022 were identified. SFRT was defined as 1.8-2.0 Gray (Gy) per fraction and HFRT as 2.66-2.70 Gy per fraction. RT completion was defined as receipt of ≥46 Gy for SFRT and ≥40 Gy for HFRT. Pre-COVID (2018-2019) and post-COVID (2021-2022) RT completion rates were compared using chi-square tests. Results: Among 25,658 patients, (pre-COVID n=13,381; post-COVID n=12,277), HFRT use increased from 82.9% to 93.6% (p< 0.0001), while SFRT declined (17.1% to 6.4%, p< 0.001). Overall RT completion improved from 94.8% to 96.4% (p< 0.0001). HFRT completion rates remained stable and were higher than SFRT (pre-COVID: 97.2% vs. 83.1%, post-COVID: 97.5% vs. 80.5%, p< 0.0001). HFRT adoption rose across all racial and income groups (p< 0.0001), with completion exceeding 96% across all subgroups. Racial differences in HFRT use decreased from 16.3 to 7.6 percentage points, while income-related differences decreased from 7.4 to 4.4 percentage points. Conclusions: Post-COVID, HFRT adoption after lumpectomy increased while SFRT use decreased by 62.6% of pre-COVID levels. These shifts were accompanied by completion rates exceeding 96% across all groups. A 53.3% and 40.5% relative reduction in racial- and income-related disparities in use were observed, suggesting more equitable treatment delivery. HFRT adoption pre- and post-COVID by race. SFRT HFRT Race Count % Count % p White 2018-2019 (Pre-COVID) 1865 16.32 9565 83.68 <.0001 2021-2022 (Post-COVID) 619 6.02 9669 93.98 African American 2018-2019 (Pre-COVID) 330 26.59 911 73.41 <.0001 2021-2022 (Post-COVID) 133 11.45 1029 88.55 Asian or Pacific Islander 2018-2019 (Pre-COVID) 45 10.34 390 89.66 <.0001 2021-2022 (Post-COVID) 19 3.81 480 96.19 Other or Unknown 2018-2019 (Pre-COVID) 52 18.91 223 81.09 <.0001 2021-2022 (Post-COVID) 18 5.49 310 94.51

Zongertinib combined with T-DXd in HER2-positive metastatic gastric, gastroesophageal junction, or esophageal carcinoma (mGEAC): First results from a phase Ib/II dose-escalation trial.

3106 Background: Zongertinib, an irreversible TKI, selectively inhibits HER2 while sparing wild-type EGFR, thereby minimizing associated toxicities. Beamion BCGC-1 (NCT06324357) is an ongoing Phase Ib/II multicohort trial investigating zongertinib, as monotherapy or combined with other agents, in HER2-positive metastatic breast cancer, metastatic colorectal cancer, and mGEAC. Here, we report the first data from Cohort C (Phase Ib), in which patients (pts) with HER2-positive mGEAC received zongertinib combined with T-DXd, as well as supporting preclinical data. Methods: Preclinical activity of zongertinib plus T-DXd was assessed in xenograft mouse models of HER2-positive gastric cancer. In Cohort C, pts with histologically/cytologically confirmed, unresectable, HER2-positive mGEAC were enrolled. Pts had documented HER2-positive disease (overexpression/amplification) and disease progression following HER2-directed treatment. Pts received escalating doses of zongertinib once-daily plus a fixed dose of T-DXd (6.4 mg/kg) every three weeks. Dose escalation was guided by a BLRM with overdose control. Pts remained on treatment until any protocol-defined stopping criterion occurred. The primary endpoint was the occurrence of DLTs during the MTD evaluation period. Secondary endpoints included further safety assessments and objective response (investigator-assessed; RECIST v1.1). Results: In mouse models, the addition of zongertinib to T-DXd led to increased antitumor activity. In Beamion BCGC-1, as of November 4, 2025, 19 pts had been enrolled to Cohort C and received zongertinib 60 mg (n=4), 120 mg (n=9), 240 mg (n=4), or 300 mg (n=2). Median age was 63 years, 74% male, 74%/26% ECOG PS 0/1. All pts had received prior trastuzumab-based therapy. Treatment-emergent adverse events (TEAEs; any grade [G]/G≥3) were reported in 17/9 (89%/47%) pts. AEs related to zongertinib (any G/G≥3) were reported in 13/2 (68%/11%) pts. There were no zongertinib-related G4/5 AEs. The most-common TEAEs (any G/G≥3) were nausea (53%/0%), decreased appetite (47%/5%), and diarrhea (47%/0%). One pt each had G1 pneumonitis and interstitial lung disease; both recovered. AEs leading to zongertinib dose reduction/discontinuation were reported in 1/2 pts. AEs leading to T-DXd dose reduction/discontinuation were reported in 8/1 pts. The first confirmed responses to zongertinib combined with T-DXd were observed across the different zongertinib dose levels (60 mg: 1 CR, 2 PR; 120 mg: 2 PR, 5 SD; 240 mg: 1 PR, 1 SD). Conclusions: No new safety signals were observed for zongertinib in combination with T-DXd; further dose escalation is ongoing. Encouraging clinical activity was observed in pretreated pts with HER2-positive mGEAC who had disease progression following prior trastuzumab-based therapy. Clinical trial information: NCT06324357 .