Citations

TPS2673 Background: The main challenge for developing CAR T therapies for solid tumors is the lack of targets that distinguish tumor from normal cells, resulting in on-target, off-tumor toxicity. Tmod logic-gated CAR T therapy addresses this challenge by incorporating 2 CARs on the same T cell: an activator targeting a marker on both tumor and normal cells, and a blocker targeting HLA-A*02 that inhibits CAR T activity against normal cells while allowing activation against tumor cells (with HLA-A*02 LOH), improving tumor selectivity and decreasing toxicity. Early safety results from 3 ongoing phase 1/2 clinical trials of logic-gated, Tmod CAR T therapy (EVEREST-1, EVEREST-2, and DENALI-1) have demonstrated manageable safety and tolerability in patients with advanced solid tumors (Grierson et al, SITC , 2024; Ward et al, SITC 2025; Specht et al, SABCS , 2025). Early efficacy results include the first ever reported complete response in a patient with non-small cell lung cancer following treatment with a CAR T-cell therapy (A2B694). A2B543 is an autologous Tmod CAR T therapy that contains the same Tmod construct as A2B694 with an added membrane-tethered IL-12 (memIL12) booster. Specifically, A2B543 is comprised of autologous Tmod cells transduced with 2 lentiviral vectors: one expressing both the HLA-A*02-targeted blocker and the mesothelin-targeted CAR activator; and a second expressing the memIL12 booster. Interleukin 12 (IL-12) is a potent, pro-inflammatory cytokine that plays a crucial role in inducing antitumor immune responses; however, systemic IL-12 can be prohibitively toxic (Jia et al, Front Immunol , 2022). In A2B543, expression of the memIL12 cassette is under the control of an NFAT promoter and is induced during antigen engagement or T cell activation. This inducible memIL12 is designed to reduce the toxicity associated with systemic IL-12 while enhancing the long-term potency and persistence of Tmod (Zhang et al, J Immunother Cancer , 2025). Methods: EVEREST-2 (NCT06051695) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B543 in adults with recurrent/metastatic mesothelin-expressing cancers with tumor-associated HLA-A*02 LOH, including mesothelioma, colorectal, non-small cell lung, pancreatic, or ovarian cancer. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH via next-generation sequencing and cryopreserves leukapheresis product. Upon progression, A2B543 is manufactured and then administered after lymphodepletion. The phase 1 primary objective is to evaluate the safety and tolerability of A2B543 and identify a recommended phase 2 dose (RP2D). The phase 2 primary objective is to assess overall response rate. Clinical trial information: NCT06051695 .

TPS1679 Background: Cancer care in the United States remains highly centralized, imposing substantial time, caregiver, and financial burdens on patients, particularly those residing in rural and medically underserved regions. While international experience supports the feasibility of home-based cancer therapy delivery, prospective U.S. clinical trial data are limited. The Cancer CARE Beyond Walls (CCBW) program was developed to address these gaps through a decentralized cancer care model integrating virtual oversight, remote monitoring, mobile clinical services, and community-based nursing partners. The study evaluates the feasibility, safety, and patient-centered impact of delivering cancer-directed therapy in patients’ homes or near-home mobile units in the Florida Panhandle, a region characterized by long travel distances to tertiary centers and limited oncology infrastructure. Methods: This is a phase 2, single-arm clinical trial evaluating the delivery of standard-of-care cancer-directed therapy outside of traditional infusion centers. Eligible adult patients (ECOG 0–3) with histologically confirmed malignancies receiving guideline-supported or FDA-approved systemic cancer therapy must demonstrate tolerability of at least one prior in-clinic treatment cycle. Following registration, patients transition to home-based or near-home mobile unit administration for a minimum of 12 weeks, with an option to continue up to 24 weeks. Care delivery is coordinated through a virtual command center providing real-time virtual oversight, remote monitoring, and escalation pathways. Treatment administration is performed by trained local home health nurses, medication shipping, and digital interaction with the electronic health record. A fully equipped mobile unit extends access to rural areas not covered by home health agencies. The primary endpoint is patient preference for treatment location at week 12. Secondary endpoints include safety, avoidable acute care utilization, patient-reported function and global health/quality of life, patient-reported symptoms, and satisfaction with care. Exploratory endpoints assess travel burden, patient perceptions of caregiver experience, and patient perceptions of home versus mobile unit care. Enrollment of 27 patients will provide 80% power to reject a 50% null rate (2-sided exact test, α=0.10), assuming 75% prefer decentralized care or express no preference. This investigator-initiated trial is open to accrual and is supported by a grant from the Florida Cancer Innovation Fund. Clinical trial information: NCT07285044 .

TPS1147 Background: Due to dramatic improvements in neoadjuvant and adjuvant HER2-directed therapy (tx), most patients (pts) with early HER2+ breast cancer are cured. As a result, over half of pts newly diagnosed with HER2+ metastatic breast cancer (MBC) now present with de novo stage IV disease. Anti-HER2 tx has also significantly extended survival for pts with HER2+ MBC, with a subgroup of exceptional responders alive many years (yrs) after diagnosis. However, the paradigm for HER2+ MBC remains non-curative, and pts receive tx indefinitely with significant toxicities and costs. The SAPPHO study is investigating whether an intensification approach of sequential, non-cross resistant anti-HER2 tx followed by tx discontinuation is associated with long-term disease control in pts with HER2+ MBC. Methods: SAPPHO is an open-label, phase II, single-arm trial testing a sequential regimen of non-cross resistant, HER2-targeted tx with curative intent in pts with de novo HER2+ MBC. Eligible pts must have biopsy-proven, de novo MBC with high HER2 expression (3+ by immunohistochemistry). Pts with brain metastases are eligible upon receipt of local tx. Treatment consists of an induction regimen (trastuzumab-pertuzumab-taxane [THP] x 4 cycles, followed by trastuzumab deruxtecan [TDXd] x 6 cycles, followed by trastuzumab emtansine [TDM1]-tucatinib x 4 cycles), followed by a maintenance regimen (HP-tucatinib for 1 yr). Given results from DESTINY-Breast09, the sequence of TDXd-P x 6 cycles followed by THP x 4 followed by TDM1-tucatinib x 4 can be chosen as alternative induction tx per investigator and patient choice. Pts who remain progression-free after completing maintenance will stop all anti-HER2 tx. Endocrine tx will be continued for pts with hormone receptor+/HER2+ tumors. Tumor specimens from breast and a metastatic site are collected at baseline and the end of induction. Serial plasma samples for ctDNA analysis are collected at baseline, during treatment, and during follow-up. The primary endpoint is the probability of being progression-free and off anti-HER2 tx 4 yrs from the start of induction. With a sample size of 72 pts, the study is designed to have 91% power to reject the null hypothesis that the probability of being off anti-HER2 tx and progression-free is less than 24%, with an alternative hypothesis of 40%. Key secondary endpoints are overall survival, overall response rate by modified RECIST 1.1 after induction, and safety. Correlative endpoints include the relationship between ctDNA dynamics and outcomes. Patient-reported outcomes will be analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, distress about cancer progression, perception of benefit and risk of progression. SAPPHO began enrollment in Q3 2024, and the study is open at 4 US sites within the Translational Breast Cancer Research Consortium (NCT05721248). Clinical trial information: NCT05721248 .

TPS10628 Background: Despite advances in cancer treatment, a lack of established population-level cancer screening strategies for early detection across cancer types contributes to cancer-related mortality. Emerging MCED liquid biopsy tests represent a screening approach with potential to enable detection of multiple malignancies at earlier stages in the disease process. We previously showed that an initial classifier based on a genome-wide methylome enrichment platform detected 12 cancer types, including early-stage, low-shedding tumors (Park et al. AACR 2023. Abs 1030). However, clinical performance of the platform has not been evaluated prospectively. Thus, the CAMPERR study (NCT05366881) was designed to train and validate a cell-free methylated DNA immunoprecipitation and high throughput sequencing (cfMeDIP-seq)-based test for detection and differentiation of 20 pre-selected cancer types, representing 93% of annual cancer incidence and 88% of annual cancer deaths. Longitudinal follow-up for a subset of participants with lung cancer will enable training and validation for MRD-based recurrence prognostication. Methods: This case-control study is enrolling participants with 20 different pre-specified cancer types (n=2400) and those without known cancer (n=3900). Eligible participants are ≥40 years of age and not receiving treatment for cancer at the time of enrollment or taking any demethylating/hypomethylating agents. Cases include individuals with newly diagnosed (≤120 days), untreated cancer or recurrence of a cancer originally diagnosed >5 years ago. Cancers of interest are stage I-IV bladder, brain, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatobiliary, leukemia, lung, lymphoma, multiple myeloma, ovarian, pancreatic, prostate, renal, sarcoma, and thyroid. Participants with stage I-III lung cancer will have clinical follow-up and blood draws after completion of first-line treatment, every 3 mo for the first year thereafter, and every 6 mo for an additional 2 years. Eligible control participants have not been diagnosed with invasive cancer in the last 5 years and will have clinical follow-up ≥12 mo from enrollment to evaluate cancer status. Liquid biopsy results will not be returned to clinicians or participants. The primary objective is cancer detection. Secondary objectives include detection of specific cancer types, identification of the tissue of origin, and prognostication of clinical outcomes (eg, recurrence-free survival, overall survival). CAMPERR is currently enrolling at 15 sites. As of December 3, 2025, 2108 of 2400 cancer cases have been enrolled, including prostate (n=225), lung (n=216), colorectal (n=211), breast (n=193), and pancreatic (n=192); controls are fully enrolled. Clinical trial information: NCT05366881 .

TPS10057 Background: Ewing sarcoma (EWS) is an aggressive tumor of the bone and soft tissue primarily affecting adolescents and young adults. For patients with recurrent disease, outcomes remain poor with 5-year survival rates of 10%–15%, highlighting the need for novel approaches. STEAP1 is highly expressed in EWS cell lines, xenograft models, and patient tumor samples 1 and is transcriptionally regulated by EWSR1::FLI1 , the main oncogenic driver in EWS. Xaluritamig, a humanized bispecific XmAb 2+1 T-cell engager targeting STEAP1 and CD3, has demonstrated potent, antigen-dependent T-cell–mediated lysis of STEAP1-expressing EWS cell lines 1 and induced robust in vivo antitumor activity in EWS xenograft models with concomitant CD8+ T-cell activation. In metastatic castration-resistant prostate cancer, another STEAP1-expressing solid malignancy, xaluritamig has shown meaningful antitumor activity and a manageable safety profile 2 supporting its clinical evaluation in R/R EWS. Methods: This ongoing, phase 1b, single-arm, open-label, two-part, multicenter study (NCT07297979) is evaluating xaluritamig in pediatric, adolescent, and adult patients with a histologic diagnosis of EWS and an EWSR1 :: ETS fusion gene locally confirmed by next-generation sequencing. Patients must have R/R EWS following ≥1 line of systemic therapy and Karnofsky or Lansky performance status ≥70. Part 1 (dose confirmation) consists of cohort 1 (age ≥12 years) and cohort 2 (age ≥2 to <12 years), and part 2 (dose expansion) includes patients aged ≥2 years with no upper age limit at enrollment. This study includes a 21-day screening period, a treatment period, a safety follow-up period, and a long-term follow-up period. Patients receive xaluritamig every 2 weeks once reaching the target dose until radiographic disease progression per RECIST v1.1, clinical disease progression, unacceptable toxicity, initiation of other anticancer therapy not permitted per protocol, withdrawal of consent, death, or end of study as determined by the sponsor, whichever is earlier. Primary endpoints are safety, tolerability, and determination of recommended dose(s) for expansion. Secondary endpoints are pharmacokinetics, preliminary antitumor activity, and immunogenicity. Biomarker evaluation as an exploratory endpoint includes assessment of serum cytokines, other pro-inflammatory markers, immune-cell subsets, circulating tumor DNA, STEAP1 protein expression, and tumor genomic profile and their association with safety and efficacy. CRS mitigation plan includes step-up dosing, steroid premedication, and administration of interleukin-6 inhibitors as needed. Site activation commenced in January 2026 and enrollment is ongoing. 1. Nolan-Stevaux O. Cancer Res. 2020;80(16_Suppl):DDT02–03. 2. Kelly WK, Danila DC, Lin CC, et al. Cancer Discov . 2024;14(1):76-89. Clinical trial information: NCT07297979 .

e24198 Background: Even when radiotherapy is delivered outpatient, treatment-related nausea, vomiting, and dehydration can precipitate hospitalization, driving cost and morbidity. National estimates of this burden are limited. Methods: We analyzed the HCUP National Inpatient Sample (NIS) for 2016–2022 to identify hospitalizations with radiotherapy encounters (Z51.0) and concurrent diagnoses of nausea, vomiting, or dehydration using ICD-10 codes. Outcomes included length of stay (LOS), total charges, ICU use proxies, in-hospital mortality, and non-home discharge. Survey-weighted national estimates were calculated, and multivariable regression assessed predictors including cancer site proxies, age, comorbidity burden, insurance status, income quartile, and hospital characteristics. Results: Across 7,842 weighted admissions, mean LOS was 4.6 days (SD 2.1), mean total charges $23,400 (SD $8,700), and ICU-level care proxies were required in 12% of admissions. In-hospital mortality was 0.9%, and 21% of patients required non-home discharge. Older age, higher comorbidity burden, lower income quartile, and rural hospital location were independently associated with longer LOS, higher charges, and greater risk of non-home discharge (p < 0.01). Admissions for gastrointestinal or head/neck malignancies had the highest rates of RINV-related hospitalization. Temporal trends showed stable rates over the 7-year period. Conclusions: Hospitalizations for RINV and dehydration during radiotherapy represent a measurable national burden with disparities by socioeconomic status, tumor site, and hospital location. Clinical Takeaway: Targeted outpatient supportive interventions, particularly for high-risk patients, may reduce hospitalization, costs, and morbidity during radiotherapy.

e22604 Background: Heart, pericardial, and mediastinal tumors are rare neoplasms with potential sex-specific disparities. Despite their clinical significance, long-term temporal trends stratified by sex remain poorly characterized. Methods: We conducted a population-based analysis using data from the Surveillance, Epidemiology, and End Results (SEER) database, evaluating annual case counts from 1975 to 2022, stratified by sex. Temporal trends in total, male, and female cases were assessed using linear regression models. Results: A total of 657 cases were reported over the study period (445 males; 212 females). Total case counts showed a significant upward trend, increasing by 1.25 cases per year (p < 0.001, R² = 0.59). Male cases increased by 0.85 cases/year (p < 0.001), nearly twice the increase observed in females (0.40 cases/year, p < 0.001). Male predominance persisted throughout the study period, with both sexes showing a gradual upward trend, reflecting a consistent sex disparity in these tumors. Conclusions: The occurrence of heart, pericardial, and mediastinal tumors has increased steadily over the past five decades, disproportionately affecting males. These findings highlight persistent sex-based disparities and underscore the need for further sex-specific research to elucidate underlying risk factors and inform targeted surveillance and early detection strategies.

e22593 Background: Pheochromocytoma is a rare neuroendocrine tumor, and population-level data describing long-term temporal trends are limited. Evaluating national patterns over time may improve epidemiologic understanding and clinical awareness. Methods: We performed a retrospective analysis of pheochromocytoma cases recorded in the Surveillance, Epidemiology, and End Results (SEER) database from 1975 through 2022. Annual case counts were examined overall and by race (White, Black, Other, and Unknown). Temporal trends were assessed using Poisson regression, and annual percent change (APC) was calculated to quantify changes over time. Results: A total of 408 pheochromocytoma cases were identified during the study period. Overall case counts increased significantly over time, with Poisson regression demonstrating a consistent upward trend corresponding to an APC of 5.8% per year (p < 0.001). White individuals accounted for the majority of reported cases, while Black and other racial groups had significantly lower case counts compared with the reference population. Visual assessment of decade-level trends suggested a gradual increase from 1975 through approximately 2010, followed by a sharper rise in more recent years. Conclusions: Pheochromocytoma case counts in the United States have increased substantially over the past five decades based on SEER data. These findings suggest evolving epidemiologic patterns in this rare tumor and emphasize the importance of continued surveillance. Observed trends should be interpreted in the context of potential changes in diagnostic practices, imaging utilization, and cancer registry reporting over time.

e19562 Background: Multiple myeloma is a chronic blood cancer in which patients often live for many years, yet the risk of death remains ongoing. While survival has improved over time, population-level studies that combine traditional survival analysis, advanced modeling techniques, and future burden projections are limited. Methods: We performed a population-based retrospective study using the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival was evaluated using Kaplan–Meier analysis and Cox proportional hazards regression. Parametric survival modeling was conducted using Weibull regression to better characterize long-term mortality patterns. Machine-learning survival analysis was performed using random survival forests to assess the relative importance of clinical and demographic factors. Annual case counts were analyzed and projected through 2035 using time-series forecasting methods. Results: The study included 8,627 patients with multiple myeloma. Overall survival declined gradually over long-term follow-up, with approximately one-quarter to one-third of patients surviving at extended time points. Female patients experienced better survival than males. Significant survival differences were observed across racial groups, with Asian or Pacific Islander patients demonstrating the most favorable outcomes and American Indian or Alaska Native patients the poorest. In multivariable analyses, age, sex, race, and year of diagnosis were independently associated with survival. Parametric modeling closely mirrored non-parametric survival estimates and supported a time-dependent pattern of mortality. Machine-learning analysis identified year of diagnosis as the strongest predictor of survival, followed by age and race. Forecasting suggested that the burden of multiple myeloma will remain substantial through 2035. Conclusions: Multiple myeloma is associated with long-term survival but persistent mortality risk and ongoing demographic disparities. Combining traditional survival analysis with parametric and machine-learning approaches provides a more complete understanding of outcomes and highlights the sustained future burden of this disease, with important implications for clinical care and healthcare planning.

e19559 Background: Timely initiation of systemic therapy is critical in multiple myeloma (MM), yet real-world variation in time to treatment initiation (TTI) and its association with clinical outcomes, treatment-related toxicities, and supportive care utilization remain incompletely characterized. Methods: We conducted a retrospective cohort study using the Epic Cosmos database (2015–2025). Adults with MM were identified using ICD-10-CM code C90. TTI was defined as days from MM diagnosis to first exposure to systemic anti-myeloma therapy, including proteasome inhibitors, immunomodulatory drugs, or anti-CD38 monoclonal antibodies. Patients were stratified into TTI < 30 days (n = 90015), 30–60(n = 81190), and > 60 days(119,245). Primary outcomes included mortality, infection (sepsis or pneumonia), AKI within 30 days, DVT/PE, and bone marrow transplant (BMT). Secondary outcomes included hemodialysis initiation, febrile neutropenia, thrombocytopenia, herpes zoster reactivation, and use of bone-protective therapy (zoledronic acid, pamidronate, or denosumab) and antiviral prophylaxis (acyclovir/valacyclovir). Outcomes are presented as unadjusted percentages with 95% confidence intervals. Results: Mortality demonstrated a U-shaped association with TTI, occurring in 22.99%, 21.32%, and 21.32% of patients in the < 30-day, 30–60-day, and > 60-day cohorts, respectively. Infection rates were 16.42%, 17.11%, and 17.30%, while AKI < 30 occurred in 16.01%, 16.38%, and 16.49%. BMT utilization was highest in the 30–60-day cohort (19.14%) compared with < 30 days (18.28%) and > 60 days (18.21%). VTE rates increased modestly with delayed treatment (9.39%, 9.82%, and 10.10%). HD occurred in 3.15%, 3.08%, and 3.07% of patients. Febrile neutropenia occurred in 17.15%, 18.03%, and 17.55%, thrombocytopenia in 13.34%, 13.93%, and 13.86%, and herpes zoster reactivation in 1.21%, 1.29%, and 1.42%. Antiviral prophylaxis use was highest in the 30–60-day cohort (91.25%) compared with < 30 days (88.48%) and > 60 days (88.23%). Bone-protective therapy use was also highest in the 30–60-day cohort (31.68%) versus < 30 days (28.90%) and > 60 days (23.79%). Conclusions: In this large real-world analysis, initiation of systemic therapy within 30–60 days of MM diagnosis was associated with lower mortality, higher transplant utilization, and greater use of guideline-recommended supportive care compared with both earlier and delayed treatment initiation. Patients treated within 30 days appeared to represent a higher-acuity phenotype, while delays beyond 60 days were associated with lower supportive care uptake and higher thrombotic risk. These findings suggest that time to treatment initiation may reflect both disease severity and care delivery quality, and identify a potentially actionable window to optimize treatment pathways and supportive care in multiple myeloma.