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561 Background: Obesity and other lifestyle factors are associated with breast cancer (BC) risk and outcomes. These relationships appear to vary in pre- vs postmenopausal women. Here we explore associations between pathological features, diet quality and physical activity (PA) in patients (pts) with BC enrolled in the BWEL (Alliance for Clinical Trials in Oncology A011401) trial, stratifying for menopausal status. Methods: BWEL is a phase III trial evaluating the impact of a weight loss intervention on disease outcomes in 3180 pts with stage II-III HER2– BC and body mass index ≥27 kg/m 2 . The first 542 BWEL pts underwent assessment of PA (7-Day PA Recall) and diet (24-hour Diet Recall) at enrollment. Healthy Eating Index 2020 (HEI) score (0-100, higher value = healthier diet) and minutes/week (min/wk) of moderate/vigorous PA (MVPA) were calculated. Estrogen receptor (ER) and progesterone receptor (PR) expression level (%) were abstracted from pathology reports. Analyses of links between HEI score, MVPA min/wk, % ER/PR, stratified by menopausal status, were conducted using t-tests; differential associations by menopausal status used linear regression models with interaction term. Results: In 523 pts with available pathology data, 76.5% had ER/PR+ BC, 56.2% were postmenopausal. Median HEI score was 50.1 (range 18.1-96.4), median MVPA min/wk was 0 (range 0-630), median time from diagnosis to enrollment was 10.0 months (range 2.4-13.1). In postmenopausal pts, higher diet quality was linked to increased % ER and PR (HEI above vs below median, mean % ER 78.0 vs 66.1, p=0.012; mean % PR 57.7 vs 43.1, p=0.004). The relationship between HEI score and % ER/PR differed significantly by menopausal status (interaction term of menopausal status and % ER: p=0.006; and % PR: p=0.012); there were no significant associations between HEI scores and % ER/PR in premenopausal pts. There were no significant associations between PA and % ER/PR. Conclusions: Healthier diet was associated with higher % ER and PR in postmenopausal pts with BC, but no relationship was seen in premenopausal pts. These data suggest that lifestyle factors may influence BC pathologic features related to outcomes in older women. Support: U10CA180821, U10CA180882, UG1CA189823, U24CA196171, https://acknowledgments.alliancefound.org . Clinical trial information: NCT02750826 . % ER mean (SD) p value % PR mean (SD) p value Post-Menopausal HEI* score≤50.1 [n=134]>50.1 [n=156] 66.1 (43.3)78.0 (36.8) 0.012 43.1 (41.8)57.7 (41.0) 0.004 MVPA † min/wk0 [n=147]≥1 [n=147] 74.5 (39.3)70.3 (41.2) 0.37 50.0 (41.8)53.0 (42.0) 0.41 Pre-Menopausal HEI* score≤50.1 [n=124]>50.1 [n=103] 70.5 (38.5)65.5 (43.0) 0.15 53.5 (41.1)49.1 (43.0) 0.43 MVPA † min/wk0 [n=112]≥1 [n=113] 66.3 (41.0)66.3 (41.2) 0.99 49.5 (41.4)52.6 (42.7) 0.59 *Healthy Eating Index. † Moderate/Vigorous Physical Activity.

6506 Background: NPM1 -m drives leukemogenesis in ~30% of AML. Despite current risk stratification, nearly half will have R/R disease within a year, after which outcomes are poor with <10% complete response following chemotherapy. Ziftomenib – a potent, highly selective, oral, investigational menin inhibitor – has shown clinical activity as monotherapy and in combination for adults with R/R NPM1 -m and KMT2A -r AML, with 600 mg once-daily (QD) as the recommended phase 2 monotherapy dose for NPM1 -m. Here we present the primary analysis for NPM1 -m patients (pts) treated with ziftomenib 600 mg QD in the pivotal KOMET-001 study. Methods: KOMET-001 (NCT04067336) is a multicenter, open-label phase 1/2 study of ziftomenib in adults with R/R AML. In phase 2, pts with NPM1 -m R/R AML received ziftomenib 600 mg QD. Phase 2 primary endpoint: complete remission with full/partial hematologic recovery (CR/CRh); key secondary endpoints: composite complete remission (CRc), durations of CR/CRh and CRc, and safety. The analyses below include NPM1 -m pts pooled from phase 1b/2. Results: The phase 2 primary endpoint was met ( p =0.0058). As of 20 Dec 2024, 112 pts were enrolled (51% US/Canada, 49% Europe/UK) in phase 1b/2 and treated with ziftomenib 600 mg QD, with a median follow-up of 4.2 months. Median age was 69 yrs (range 22–86), 56% female, 83% ECOG PS 0–1, median of 2 prior therapies (range 1–7), including 60% prior venetoclax (VEN) and 23% prior transplant. CR/CRh rate in all phase 1b/2 pts was 25% (28/112; 95% CI 17–34) and overall response rate was 35% (39/112; 95% CI 26–44). In phase 2 pts, 23% (21/92; 95% CI 15–33) achieved CR/CRh (Table), with 67% (10/15) MRD negativity among CR/CRh responders tested (local). Comparable CR/CRh rates were observed in both VEN-naïve and exposed pts (21% vs. 24%). Ziftomenib was well tolerated with 3% (3/112) discontinuing due to treatment-related adverse events (TRAEs). 40% (45/112) of pts had Grade (Gr) ≥3 TRAEs, including 13% differentiation syndrome (all Gr3), ≤5% each anemia, febrile neutropenia and thrombocytopenia, and 2% QTc prolongation (Gr3). Updated clinical activity and safety data will be presented. Conclusions: In the pivotal KOMET-001, the phase 2 primary endpoint was met: Ziftomenib achieved deep and durable responses in R/R NPM1 -m AML, regardless of prior VEN. Ziftomenib was well tolerated with limited myelosuppression and only 3% ziftomenib-related discontinuations. Taken together, these data support the potential use of ziftomenib monotherapy as a new treatment option for R/R NPM1 -m AML. Clinical trial information: NCT04067336 . Response, n (%) Phase 2600 mg QDN=92 Phase 1b/2600 mg QDN=112 CR 13 (14) 20 (18) CR/CRh 21 (23) 28 (25) CRc 24 (26) 32 (29) Median duration, months (95% CI) CR/CRh 3.7 (1.9–NE) 3.7 (1.9–7.7) CRc 4.6 (2.8–11.4) 5.1 (2.8–8.1) Restricted mean duration, months (95% CI) CR/CRh 4.3 (3.1–5.6) 5.2 (3.6–6.7) CRc 5.9 (4.0–7.7) 6.4 (4.6–8.1)

604 Background: The addition of OFS to standard endocrine therapy (ET) improves iDFS for preM women with early-stage hormone receptor positive (HR+) breast cancer (BC). Incomplete OFS occurs in a subset of women, the long-term clinical significance of which is unclear. This study evaluates local sE2 levels in preM women receiving OFS with an oral SERD in the neoadjuvant (NA) setting. Methods: The EOP is a I-SPY2 sub-study investigating NA endocrine-based strategies in pts with HR+ HER2- Stage 2/3 BC predicted to have lower benefit from chemotherapy. Pts were randomized to oral amcenestrant 200 mg/d, alone or in combination with either letrozole 2.5 mg/d or abemaciclib 150 mg bid. Additional pts were randomized to a standard of care (SOC) arm consisting of an aromatase inhibitor. All PreM pts received OFS with monthly GnRHa up to 2 wks prior to C1D1 of study therapy. Pts were treated for 6 months prior to surgery. sE2 levels were collected locally prior to each GnRHa injection. Tumor Ki67 was assessed at 3 weeks and surgery, and associated with sE2 level. Statistical significance was determined using a two-sided Student’s t-test and a significance level 0.05. Results: Between 5/2021-8/2022, 74 pts were enrolled to an amcenestrant containing arm, 40 of whom were preM. 38/40 pts had at least one local sE2 level measured in follow up. Of these 38 pts (median age 45 years), 37 suppressed sE2 into the postmenopausal (postM) range at one or more follow-up timepoints. Of the 37 pts that completely suppressed into the postM range, 6 pts had sE2 levels rebound into the preM range (mean 319 pg/mL, range 20-848 pg/mL) with peak sE2 levels occurring at a median of 12 weeks from C1D1. One pt never suppressed to the postM range (peak sE2 1227 pg/mL) and was found to have an ovarian cyst after 3 months on amcenestrant, requiring surgery. One additional pt had multiple ovarian cysts (sE2 84 pg/mL). Median age of the 7 pts who had sE2 rebound was 43 years. There was no significant difference in Ki67 at 3 weeks and surgery between pts whose sE2 levels remained suppressed (median Ki67 2.0%) compared to those whose estradiol rebounded into the preM range or never suppressed (median Ki67 1.5%). In the 5 pts whose sE2 rebounded to > 200 pg/mL, all pts had tumor Ki67 < 10% at 3 weeks and surgery. Between 12/2022 and 8/2023, 20 pts were enrolled to AI +/- OFS and 11 pts were preM. Of the 11 preM pts, all pts suppressed sE2 to the postM range. No SOC patients had sE2 levels rebound into the preM range. Conclusions: In this study of neoadjuvant oral SERD with monthly OFS, 7/38 (18.4%) preM pts had sE2 levels remain or rebound into the preM range. sE2 levels did not appear to impact Ki67 suppression on NA ET. Work up for ovarian cysts should be considered in pts with symptoms, or significantly elevated or persistent sE2 levels. Clinical trial information: NCT01042379 .

610 Background: The adverse event (AE) landscape in oncology is changing due to the introduction of immunotherapy and antibody drug conjugates. These AEs come with both short and long-term symptoms that significantly impact patient quality of life. Monitoring for early onset of symptoms could optimize therapy for a particular patient, maximizing potential efficacy while mitigating toxicity. It is also possible that some toxicities are directly associated with drug sensitivity. We sought to identify symptoms associated with pathologic complete response (pCR) using patient-reported outcomes (PROs) in early-stage high-risk breast cancer patients. Methods: Our study population included 288 stage II/III high-risk breast cancer patients enrolled on the I-SPY2 trial from 2021-2024, who received novel neoadjuvant therapies ± standard paclitaxel. pCR was assigned if tumor was absent in breast and nodes at surgery following neoadjuvant treatment. Patients (n = 288, pCR rate = 29%, 89% administered immunotherapy) were sent electronic PROs. 33 patient-reported AEs were measured using NCI's Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE). Each symptom was evaluated using severity, frequency, and interference on a Likert Scale. Presence of early PRO symptoms (cycles 1-3 of treatment) were binarized (at least one of moderate or greater), and odds ratios were computed with pCR as outcome. To assess whether higher grade AEs were enriched in patients that achieved a pCR, we also performed the Wilcoxan rank sum test using maximum (worst) symptom severity. Results: Of 288 patients included in our analysis (median age = 48 years, range = 20-78), 203 (70.5%) were White, 17 (5.9%) were Asian, 33 (11.5%) were Black or African American, and 35 (12.2%) were Hispanic. PRO analysis revealed that patients that had moderate to severe muscle pain (27% vs 10% OR = 3.15, p < 0.05), joint pain (22% vs 8% OR = 3.23, p < 0.05), headache (27% vs 12.5% OR = 2.59, p < 0.05), or mouth/throat sores (16% vs 5% OR = 3.56, p < 0.05) within weeks 1-3 had higher odds of achieving a pCR. When we looked at maximum severity between weeks 1-3, patients that achieved a PCR had higher grade muscle pain (p = 0.04), heart palpitations (p = 0.035), and significantly lower grade numbness and tingling (p = 0.002). Beyond 6 weeks, associations were weaker or insignificant. Conclusions: Our study utilizes an analysis framework that was able to determine sentinel symptoms such as muscle and joint pain, mouth/throat sores and palpitations as early as weeks 1-3 associated with increased efficacy. This may suggest an early immune reaction in patients that eventually respond favorably to treatment. Our work can help provide earlier proactive monitoring to mitigate toxicities, treatment redirection if needed, and a potential symptom-based early understanding to personalize treatment efficacy. A similar analysis is underway to predict immune related AEs. Clinical trial information: NCT01042379 .

TPS2689 Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, existing FDA approved companion diagnostic biomarkers like PD-L1, dMMR/MSI-H and TMB have low accuracy in predicting response. Ex vivo cytokine profiling of live tumor samples has shown promise as an improved means of predicting response to PD-1 blockade (Voabil, et al. Nat Med. 2021), but this approach has been limited to tumor resections given the need for large amounts of tissue. Here we present three clinical trials that leverage a novel approach using limited tissue from a single core needle biopsy (CNB) (20 gauge or larger). A sequential ex vivo treatment strategy is used, eliminating the need for a separate control arm and addressing challenges with tumor heterogeneity, particularly in CNBs where tissue is limiting. Using a specialized instrument, CNBs are cut into live tumor fragments (LTFs) which are viable in culture and retain the native tumor microenvironment, enabling cytokine profiling in response to ICI treatment ex vivo. Methods: ELEPHAS-01 (NCT05478538), ELEPHAS-02 (NCT05520099) and ELEPHAS-04 (NCT06349642) are observational prospective clinical trials initiated to characterize the accuracy of this approach for predicting ICI response. Over 750 patients that are being considered for standard of care (SOC) ICI therapy in the metastatic/relapse or neoadjuvant setting will be enrolled (Table). Fresh live CNBs are collected prior to treatment start and processed within 24 hrs enabling prediction of results within 72 hrs of receipt. LTFs are treated using a strategy where control (IgG) and SOC ICI treatments are performed sequentially on the same tissue in a single well. Changes in the cytokine secretion rates are then compared between ICI and control to characterize immunotherapy response. Additionally, tissue viability and tumor content measurements are used to assess tissue quality. Clinical response is measured using pathologic response in patients receiving neoadjuvant ICI therapy, while RECIST v1.1 is used in all other patients. The primary objective of these trials is to determine the platform’s ex vivo accuracy (e.g., sensitivity, specificity) for predicting clinical response to ICIs and comparing it to the accuracy of PD-L1, dMMR/MSI-H and TMB. Clinical trial information: NCT06349642 , NCT05478538 , NCT05520099 . ELEPHAS-01 (Lung) ELEPHAS-02 (Hoosier) ELEPHAS-04 (Mayo) Setting Metastatic & recurrent Metastatic & recurrent Metastatic, recurrent & neoadjuvant Tumor type Lung Bladder, kidney, colorectal, head and neck, lung, melanoma, endometrial Metastatic/recurrent: lung, skin, esophageal, cervical, endometrial, colon, liver, kidney, bladder Neoadjuvant: breast–TNBC, lung Enrollment as of 1/27/2025 26 44 20 Est. total enrollment 216 216 324 Clinical endpoints RECIST v1.1 RECIST v1.1 RECIST v1.1 & Pathologic response at surgery

e12562 Background: Previous research has suggested that breast cancer (BC) diagnosed during pregnancy or the postpartum period exhibits more aggressive clinical features, possibly due to pregnancy-related hormonal changes, immune modulation, and alterations in the mammary microenvironment compared to nulligravid or women many years out from pregnancy. Emerging data have demonstrated potential worse outcomes for patients (pts) diagnosed in post-partum. This study evaluated the influence of timing of diagnosis in relation to pregnancy history and recency of childbirth on long-term outcomes in a modern cohort of young pts with early-stage BC. Methods: Pts with stage I–III BC age < 40y in the prospective Young Women’s Breast Cancer Study (YWBCS) were categorized at diagnosis as Nulligravid (no prior pregnancy), Nulliparous (prior pregnancy without live birth), Currently Pregnant, or Parous (subdivided by time since last childbirth: within 5 years [≤ 5y PP], and 5–10 years postpartum [5–10y PP]). Baseline characteristics and outcomes were compared across BC subtypes (estrogen receptor+/HER2- [ER+/HER2-], HER2+, and triple-negative BC [TNBC]). Prognostic analyses for distant recurrence-free survival (DRFS) used Cox models. Results: 859 pts were included, 257 (30%) nulligravid, 50 (6%) nulliparous, 37 (4%) pregnant, and 515 (60%) parous (348 [68%] were ≤5y PP, and 167 [32%] were 5–10y PP). Median follow-up was 133 (6–209) months. Median age at diagnosis was lower in nulligravid pts (33 vs. 35–38 years); T1 tumors were most common in pts >5y PP (62%), and N0 status was highest in nulligravid pts (64%) (all p < 0.0001). Pregnant pts had higher rates of TNBC (27%), and T3 tumors (14%), N1 status, N1 (41%), and Grade 3 (81%) tumors compared to other groups (all p < 0.0001). Overall, only tumor size (T2-T4 vs T1, HR 2.03; 95% CI 1.37–3.03) and nodal status (N1 vs N0, HR 2.22; 1.48–3.34; N2/3 vs N0, HR 3.23; 1.96-5.33) were independently associated with worse DRFS; pregnancy history was not: nulligravid + nulliparous pts had no significant differences in DRFS compared to Pregnant (HR 1.46; 0.75–2.86), Parous <5y PP (HR 0.86; 0.58–1.26), and Parous 5–10y PP (HR 0.89; 0.54–1.48). Subgroup analyses by BC subtype (Table) and sensitivity analyses (excluding currently pregnant pts or separating nulligravid and nulliparous pts) demonstrated no significant associations between pregnancy history and DRFS. Conclusions: In this cohort study of very young patients with early breast cancer with contemporary treatment including management of breast cancer during pregnancy, pregnancy history and recency of pregnancy were not independent predictors of long-term disease outcomes. DRFS results by subgroup. Pregnancy Group N (%) HR (95% CI) ER+/HER2- Nulligravid + Nulliparous 173 (38.1) Ref Pregnant 16 (3.5) 0.93 (0.32–2.70) Parous ≤5y PP 177 (39.0) 0.77 (0.45–1.29) Parous 5–10y PP 88 (19.4) 0.78 (0.39–1.53) HER2+ Nulligravid + Nulliparous 77 (30.8) Ref Pregnant 11 (4.4) 3.27 (0.80–13.38) Parous ≤5y PP 113 (45.2) 1.50 (0.60–3.75) Parous 5–10y PP 49 (19.6) 1.45 (0.45–4.66) TNBC Nulligravid + Nulliparous 56 (36.8) Ref Pregnant 10 (6.6) 1.92 (0.61–6.09) Parous ≤5y PP 57 (37.5) 0.68 (0.28–1.63) Parous 5–10y PP 29 (19.1) 1.16 (0.43–3.14)

3008 Background: Numerous studies have demonstrated the prognostic value of ctDNA analysis after neoadjuvant chemotherapy for early-stage high-risk breast cancer. Few studies have characterized ctDNA in pts receiving NET for early-stage hormone receptor positive (HR+)/HER2- BC that is predicted to benefit less from chemotherapy. Methods: Cell-free DNA (cfDNA) was isolated from 432 plasma samples from 108 pts enrolled in the I-SPY2 EOP trial. Pts had Stage 2/3 HR+/HER2-, MammaPrint low or high risk 1 BC. Pts were randomized to one of 7 neoadjuvant-based treatment arms including arms containing AI, Z-endoxifen, Lasofoxifene, vepdegestrant (ARV-471), and Abemaciclib. Pts were treated for 6 months prior to surgery. Blood was collected at baseline (T0), 3 weeks (T1), 12 weeks (T2), and 6 months (T3). A personalized ctDNA test (Signatera) was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The chi-square test was used to assess associations between categorical variables, and the Wilcoxon rank-sum test was used to evaluate differences in medians. Results: ctDNA information was available for 101 patients at baseline (T0) (Table 1). At T0, 36 (35.6%) patients were ctDNA-positive. 23/36 (63.9%) became ctDNA-negative and 13/36 (36.1%) remained ctDNA-positive. At T0, 65/101 patients (64.4%) were ctDNA-negative. Of these, 57 (87.7%) remained negative, while 8 (12.3%) became ctDNA-positive at T1 before reverting to ctDNA-negative. A higher percentage of ctDNA-positive patients at T0 were cN+ compared to ctDNA-negative pts (p = 0.036, 64% vs. 40%). Additionally, ctDNA-positivity at T0 was strongly associated with higher Ki67 (p = 0.03) and larger functional tumor volume by MRI at baseline (p = 0.03). T3/T4 and high-grade tumors at baseline were also associated with having ctDNA positivity at baseline, though this was not statistically significant (p = 0.34 and 0.058, respectively). Conclusions: In this study of pts with Stage 2/3 HR+ HER2- BC with largely MammaPrint low risk signatures, over one-third of pts had detectable ctDNA at baseline. Detectable ctDNA at baseline was associated with cN+ disease, larger FTV, and high baseline Ki67. The majority of pts with positive ctDNA at baseline cleared the ctDNA on NET. Clinical trial information: NCT01042379 . Clinicopathologic characteristics of EOP patients. All Patients(N=101) Age at screening 55 (27-80) years* Clinical N Stage Node+ (cN+) 49 (48.5%) Node- (cN-) 52 (51.5%) SET status High 84 (83.2%) Low 14 (13.9%) Missing 3 (2.97%) MammaPrint (MP) risk** High risk 1 (H1) 15 (14.9%) Low risk 86 (85.1%) *Mean(min-max). **H1: MP score between 0 and -0.57; low: MP score between 0 and 0.355.

4006 Background: Elraglusib (9-ING-41) is a first-in-class inhibitor of GSK-3ß, which may mediate drug resistance, EMT, and damaged DNA and tumor immune response in advanced cancer. In pancreatic cancer models in mice, elraglusib combined with chemotherapy enhanced anti-tumor effects and survival. In a single-arm clinical study, elraglusib/GnP showed antitumor activity and prolonged survival in pts with mPDAC. Methods: Pts with previously untreated mPDAC were randomized 2:1 to GnP plus elraglusib 9.3 mg/kg IV once weekly or GnP in an open-label phase 2 study. The primary endpoint was 1-yr OS in the primary analysis set. Upon study completion, mOS will be the primary endpoint once survival distributions are compared after the 12-month follow-up using log-rank analysis. Secondary endpoints included DCR, ORR, mPFS, and TEAEs/TRAEs. The planned sample size was 207 evaluable pts (130 for elraglusib/GnP and 77 for GnP), assuming 1-yr OS of 55% with elraglusib/GnP and 35% with GnP to achieve 80% power with a chi-square test at a 2-sided 5% α. For OS, nonparametric log-rank test was used with statistical significance at p-value < 0.048. Cytokine/chemokine correlative biomarker assays were performed. The study completed enrollment in February 2024. Results: As of November 15, 2024 (preliminary data cut-off date), the primary analysis set included 155 pts in the elraglusib/GnP arm and 78 pts in the GnP arm, with 52.8% males and 57.5% ECOG PS 1. Median (range) CA 19-9 levels were 1568 U/mL (1 to 381,904 U/mL) in the elraglusib/GnP arm and 1590 U/mL (2 to 501,000 IU/mL) in the GnP arm. The 1-yr OS rate was 43.6% with elraglusib/GnP vs 22.5% with GnP (z-test p = 0.002); the mOS was 9.3 mo with elraglusib/GnP vs 7.2 mo with GnP (HR, 0.63; log rank p = 0.016; see Table). 38.1% of pts on elraglusib/GnP and 19.2% on GnP are censored, with the majority at > 10 months OS. Several biomarkers appear to be predictive for OS including IFNβ and PD-L1. The most common TRAE with elraglusib/GnP was grade 1-2 transient visual impairment in > 60% of patients (vs 9% with GnP). Grade ≥3 TEAEs occurred in 89.7% of pts on elraglusib/GnP and 80.8% on GnP. Most common grade ≥3 TEAEs with elraglusib/GnP (vs GnP) were neutropenia 51.6% (vs 29.5%), anemia 24.5% (vs 29.5%), and fatigue 16.1% (vs 5.1%). Conclusions: The preliminary results showed a statistically significant benefit for 1-yr OS and mOS and favorable trends for ORR and DCR with elraglusib/GnP over GnP, with manageable safety profile. The mOS for GnP is lower relative to MPACT and NAPOLI-3 but comparable to recent real-world meta-analyses, explained by advanced disease burden and higher mortality rate in the first 4 months in our study. Topline analysis (April 2025) and correlative biomarker analysis predictive for OS will be presented. Clinical trial information: NCT03678883 . Preliminary efficacy results. Elraglusib/GnPn=155 GnPn=78 1-year OS, %z-test p=0.002 43.6 22.5 mOS, moHR=0.63; log-rank p=0.016 9.3 7.2 Events, n (%) 96 (61.9) 63 (80.8) mPFS, moHR=0.91; p=NS 5.6 4.9 Events, n (%) 128 (82.6) 70 (89.7) DCR, % 42.6 33.3 ORR, n (%) 43 (27.7) 16 (20.5)

12011 Background: Patients (pts) with high HCT-Comorbidity Index scores (HCT-CI of ≥3), older age (≥65 years), and/or who are frail per gait speed (<0.8 meters/second) have increased morbidity and mortality after allo-HCT compared to younger and healthier counterparts. We report the phase II analysis (PIIA) and interim phase III primary outcome analysis (PIIIA) of a seamless phase II/III prospective, randomized clinical trial conducted at 11 transplant centers to test new approaches to improve quality of life (QOL) in this population. Methods: Phase II compared specialist-administered supportive and palliative care (SPC), patient-administered management of comorbidities (MC, e.g. physical exercise, stress reduction, etc), both (SPC+MC), and usual care (UC) for change in Functional Assessment of Cancer Therapy – Bone Marrow Transplantation (FACT-BMT) QOL scores from baseline to day 90 (D90). Pts deceased prior to D90 were assigned FACT-BMT score=0. The winning phase II arm moved forward versus UC in phase III. Results: PIIA was done after enrolling 35 pts to each of the 4 study arms. Calculating the difference between FACT-BMT scores on D90 minus baseline, excluding missing data, indicated that only SPC resulted in a small improvement in QOL compared to either MC or SPC+MC (Table); hence SPC was the winning phase II arm. The PIIIA was conducted after enrolling 158 SPC pts and 153 UC pts. The SPC and UC arms were well balanced with median age (both 68 years), HCT-CI ≥3 (49% vs 55%), frailty per gait speed (13% vs 12%), female sex (41% vs 34%), non-white race (9.5% vs 11.5%), and Hispanic or unreported ethnicity (7.7% vs 5.7%), respectively. After median follow-up of 362 days, 45 pts had died in each arm. The mean QOL difference between D90 and baseline was 2.83 for SPC and 4.27 for UC (difference of differences, -1.44, 95% CI of difference, -5.03 to 2.14, p=0.43). Fitting a generalized linear model that included baseline, D30, and D90 values and testing the null hypothesis that the slope of scores differs between SPC and UC resulted in p=0.85. Using the Kaplan Meier method, no difference in survival was observed across arms (HR 1.13 [0.75-1.73]). Conclusions: Specialist-administered palliative care showed no meaningful improvement in QOL, nor a survival advantage, compared to usual care in frail, older and comorbid allo-HCT recipients, resulting in the cessation of this Phase II/III trial. Analysis of the whole patient population for primary and secondary outcomes is in progress. Clinical trial information: NCT03870750 . Change in FACT-BMT (D90 value minus baseline value) comparing the 4 arms of phase II. Group Mean difference (sd) Median difference (range) SPC (n=28) -2.93 (28.52) 0.25 (-102 to 38.22) CM (n=18) -18.37 (33.80) -9.50 (-98.33 to 11) SPC+CM (n=27) -15.76 (32.69) -7.67 (-90 to 32)

1015 Background: T-DXd is an antibody-drug conjugate approved for advanced HER2+/low/ultra-low breast cancer and multiple other solid tumors. T-DXd carries a rare but serious risk of ILD (incidence 12-15%), requiring frequent imaging and symptom evaluation. For > grade (G) 2 ILD, guidelines recommend permanent drug discontinuation. For asymptomatic G1 ILD, drug is held with the option for rechallenge (RC) if imaging findings resolve. Limited data exist on outcomes of RC after ILD in diverse real-world patients (pts). Methods: In this multi-center retrospective study, we analyzed pts with T-DXd related ILD treated from 2017-2024. Pts with ILD were identified via chart/ICD code review. Adjudication of T-DXd related ILD was based on treating providers’ assessment and graded via CTCAE v5. We collected pt demographics, T-DXd and steroid dosing, imaging results, and outcomes after RC. Statistical analysis was performed using Wilcoxon rank sum and Fisher’s exact tests. Results: Four centers treated 712 pts with T-DXd, with a 9.1% rate of any grade ILD (n=65). One other center reported only RC data in 18 pts with ILD. In total, 47 pts were RC; 38 after G1 ILD (81%), 9 after G2. Median (med) time to initial ILD was 145 days (d) after 1st dose (interquartile range [IQR] 78-205). Demographics for pts RC are shown in the table. Among 50 pts with G1 ILD, including pts not RC, 28/50 (56%) received steroids for a med of 36d (IQR 27-79). Radiographic improvement was seen at a med of 24d (IQR 19-63) for pts treated with steroids vs 82d (IQR 48-94) without (p<0.01); and a med of 35d (IQR 22-82) for pts RC vs 81d (IQR 68-105) for pts not RC (p=0.01). Among pts with G1 ILD, 38/50 (76%) were RC at a med of 42d (IQR 36-57) from last dose; 23/38 (61%) were dose reduced. After RC, pts remained on T-DXd for a med of 215d (IQR 60-334); 10/38 (26%) developed recurrent ILD (7-G1, 2-G2, 1-G3) at a med of 211d (IQR 47-273) from RC. No statistically significant differences were seen between ILD onset, time to RC, or demographics for pts with recurrent ILD vs not. Of the 9 pts RC after G2 ILD, T-DXd was continued for a med of 129d (IQR 49-171); 2/9 (22%) developed recurrent ILD (1-G2, 1-G3). No G5 toxicity was seen with RC. Conclusions: In this multi-center study, high RC rates were seen after G1 ILD with long duration of clinical benefit. Pts treated with steroids had faster radiographic ILD improvement, highlighting the importance of early steroid use. Among pts RC after G1 ILD, recurrent ILD rates were low, with the majority G1 and no G5 events. Notably, 9 pts with G2 ILD were RC, with a similar rate of recurrent ILD; this must be interpreted cautiously. Our large cohort data further supports the safety of T-DXd RC in diverse real-world settings. RC Pt Characteristics (n=47) n (%) or Median (IQR) Cancer typeBreastGIGyn 43 (91)3 (6)1 (2) Age (yrs) 57 (52-68) Prior # therapy lines in the advanced/metastatic setting 3 (1-5) Renal impairment (CrCl < 60 mL/min) 8 (17)