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The tetravalent death receptor 5 (DR5) agonist ozekibart (INBRX-109) in conventional chondrosarcoma (CS): Secondary efficacy endpoints from the randomized, registrational, phase 2 ChonDRAgon study.
11504 Background: Clinical outcomes for unresectable/metastatic CS are poor. There are no approved therapies, and systemic treatment options are limited. Ozekibart (INBRX-109), a novel tetravalent DR5 agonist, was evaluated in ChonDRAgon (phase 2; NCT04950075), the largest randomized, placebo (PBO)-controlled trial in advanced conventional CS. ChonDRAgon met its primary endpoint: ozekibart significantly prolonged median progression free survival (PFS) vs PBO (5.52 vs 2.66 mo; stratified HR, 0.479; 95% CI, 0.335-0.684; P <.0001) (Jones et al. CTOS 2025). We present additional efficacy data. Methods: Eligible patients (pts) were ≥18 y with unresectable/metastatic conventional CS; those ≥65 y required a BMI <30 kg/m 2 . Pts with liver conditions associated with increased risk of hepatotoxicity were excluded. Pts were randomized 2:1 to ozekibart 3 mg/kg IV Q3W or PBO and stratified by grade (2 vs 3), IDH mutation status, and prior systemic therapy (No vs Yes). Pts could cross over from PBO to open-label ozekibart upon progression. The primary endpoint was PFS per RECIST 1.1 assessed by real time central independent radiology review (CIRR) in the intention-to-treat population; inter-arm comparison used a stratified log-rank test. The study was powered to detect a HR of 0.571 (90% power; 1-sided family-wise α, 0.025). Secondary efficacy endpoints included overall survival (OS), overall response rate (ORR) per CIRR, quality of life (QOL; EORTC QLQ-C30 pain symptoms and physical functioning scales), duration of response (DOR), and disease control rate (DCR; response, stable disease ≥84 days, non–complete response/non–progressive disease). Results: Overall, 137 pts were randomized to ozekibart and 69 to PBO; median duration of follow-up was 10.2 and 9.0 mo at the primary analysis (data cutoff: Sep 30, 2025). Median age for ozekibart and PBO was 54.0 y (range, 20-82 y) and 50.0 y (19-91 y), respectively; 70.1% and 60.9% of pts were male. Most pts had grade 2 CS (ozekibart, 70.1%; PBO, 69.6%) and ≈40% received prior systemic therapy (42.3%; 40.6%). 18.2% of pts in the ozekibart arm and 4.3% in the PBO arm remain on treatment. Ozekibart demonstrated a manageable safety profile (Jones et al. CTOS 2025) and led to a significantly greater DCR than PBO (54.0% vs 27.5%; P =.0005). ORR was 5.8% (8/137; all partial responses) with ozekibart and 0 with PBO ( P =.0433); median DOR was 11.1 mo. OS data were immature. Ozekibart significantly delayed QOL deterioration vs PBO, in both pain (median time to deterioration, 2.76 vs 1.41 mo; HR, 0.605; P =.0033) and physical functioning (2.56 vs 1.41 mo; HR, 0.561; P= .0007). Conclusions: In addition to a PFS benefit, ozekibart significantly improved DCR and delayed QOL deterioration vs PBO in advanced CS. Ozekibart has the potential to become the first standard of care for a population with high unmet need. Clinical trial information: NCT04950075 .
The COMPLETE-CRC screening initiative: Increasing colonoscopy completion after positive stool-based colorectal cancer screening.
e23288 Background: Timely completion of colonoscopy after a positive colorectal cancer (CRC) screening test is essential to reduce CRC-related morbidity and mortality. Despite increased use of stool-based tests (SBTs), real-world follow-up colonoscopy rates remain suboptimal. Methods: This is a quality improvement study of patients aged 45–75 years with a positive SBT between 8/1/2023 and 8/1/2024 within the Cleveland Clinic health system. Eligible patients were identified using an internally validated natural language processing algorithm. Patients without colonoscopy within 360 days were contacted by a patient navigator via phone and MyChart to provide education, facilitate scheduling, and document barriers. Multivariable logistic regression identified factors associated with colonoscopy completion following outreach. Results: Among 2,548 patients with a positive SBT, 803 (31.5%) had not completed diagnostic colonoscopy within 360 days. Of 737 patients eligible for outreach, 456 were successfully contacted. Among contacted patients, 33 completed colonoscopy and 26 scheduled procedures. Reported barriers included limited knowledge or awareness (31.9%), transportation challenges (31.9%), prior negative experiences (10.6%), fear or anxiety (8.5%), cost concerns (4.3%), and communication failures (6.4%). On univariable analysis, increasing age was associated with lower odds of colonoscopy completion (OR 0.94, 95% CI 0.90–0.98; p=0.003). In multivariable analysis adjusted for age, contacted patients had significantly higher odds of colonoscopy completion than those not contacted (OR 4.99, 95% CI 1.95–16.9; p<0.001). Conclusions: Patient outreach was associated with higher odds of colonoscopy completion after a positive SBT, while increasing age was associated with lower completion rates. Overall completion remained suboptimal, underscoring the need for earlier follow-up strategies. Univariate logistic regression of colonoscopy completion. Characteristic N OR 95% CI p-value Outreach Status 737 Not contacted — — Contacted 5.40 2.12, 18.3 0.002 Age 737 0.94 0.90, 0.98 0.003 Sex 737 Female — — Male 1.14 0.58, 2.21 0.7 Race 737 White — — Black 0.63 0.10, 2.15 0.5 Others 1.80 0.42, 5.40 0.4 Unknown/Declined 0.53 0.03, 2.59 0.5 Ethnicity 737 Hispanic — — Not Hispanic 0.79 0.27, 3.36 0.7 Unknown/Declined 0.92 0.16, 5.19 >0.9 Smoking History 737 Never — — Former 0.45 0.18, 1.00 0.060 Current 1.09 0.06, 5.94 >0.9 Unavailable 0.50 0.19, 1.15 0.12 Mychart Status 737 Activated — — Inactivated 0.39 0.11, 1.00 0.079 Unavailable/Declined 0.90 0.05, 4.56 >0.9 ADI Quartile 737 Q1 — — Q2 0.71 0.28, 1.77 0.5 Q3 0.40 0.12, 1.12 0.093 Q4 1.02 0.44, 2.41 >0.9 Unknown 0.00 >0.9 Medical Coverage 737 Commercial — — Medicaid 0.68 0.11, 2.36 0.6 Medicare 0.39 0.11, 1.00 0.079 Unavailable 1.81 0.41, 5.54 0.4 CCI Score 737 0 — — 1 or 2 0.94 0.42, 2.04 0.9 >=3 1.30 0.56, 2.89 0.5
Molecular profiling and survival outcomes in colorectal cancer in Egypt: Implications for precision oncology in real-world practice.
e15703 Background: Colorectal cancer (CRC) is a molecularly heterogeneous disease, and biomarker-guided treatment has become integral to modern management. However, in many low- and middle-income countries, including Egypt, access to molecular diagnostics and standardized testing strategies remains variable, and real-world survival data are limited. We aimed to describe the prevalence of key molecular alterations in Egyptian patients with CRC and to assess their association with overall survival (OS) in routine clinical practice. Methods: We conducted a retrospective cohort study of PCR-tested patients with CRC (stages I–IV) treated at a tertiary center in Egypt. Molecular alterations of interest included KRAS, NRAS, and BRAF mutations, as well as microsatellite instability (MSI) status. OS was calculated from the time of metastatic diagnosis when applicable. Results: A total of 111 patients with molecularly tested CRC were included. The mean age at diagnosis was 49.7 ± 13.6 years, and 58% were female. Any molecular alteration was detected in 34.2% of patients (38/111). KRAS mutations were the most frequent (30%, 27/90), followed by MSI-H (17.5%, 10/57), NRAS mutations (5.2%), and BRAF mutations (1.48%). No statistically significant difference in OS was observed between patients with and without any molecular alteration (median 32 vs 26 months, p = 0.06). In contrast, KRAS-mutant patients demonstrated significantly longer OS compared with KRAS wild-type patients (32 vs 26 months, p = 0.03). The prevalence of molecular alterations did not differ significantly according to age ( < 45 vs ≥45 years), sex, primary tumor location, initial stage, or nodal status. Conclusions: In this real-world Egyptian cohort, KRAS mutations were associated with unexpectedly longer overall survival, in contrast to conventional prognostic expectations derived from clinical trial populations. This finding likely reflects local real-world factors, including treatment selection patterns, limited access to biologic therapies, very low prevalence of poor-prognosis subtypes such as BRAF mutations, and a relatively short follow-up period. Together with the high prevalence of KRAS mutations and MSI-H, these results highlight the importance of expanding equitable access to molecular diagnostics and tailoring precision oncology strategies to the realities of routine clinical practice in resource-constrained settings.
Social risk factors and treatment preferences for patients with breast cancer.
e23139 Background: Physicians often overestimate their understanding of patient preferences. While patient preferences are influenced by their values, social risk factors (i.e., social conditions associated with worse health) can constrain patients’ treatment choices. Disparities in breast cancer outcomes persist and may be influenced by social risk factors. By directly measuring both treatment preferences and social risk factors, we sought to determine the influence of social risk factors on stated preferences about a breast cancer treatment decision. Methods: From December 2024 to June 2025, we administered surveys to female patients with breast cancer. Patients were eligible if they were diagnosed with any type or stage of breast cancer within 5 years or on active treatment at the University of Chicago. Patients responded to a sample of 8 of 12 randomly selected hypothetical treatment decision scenarios with their preference for 6 versus 12 months of adjuvant treatment. Scenarios had varying efficacy, toxicity, and out-of-pocket costs. Preferences were elicited as a choice probability (percent chance they would choose 6 months) and a discrete choice (6 vs 12 months). Social risk factors of financial toxicity (COST item 12), prior discrimination in healthcare (BRFSS), limited cancer health literacy (CHLT-6), and limited reading ability (SILS-1) were dichotomized based on published cutoffs. Multivariable regression models clustered standard errors at the patient level and adjusted for sociodemographic factors, clinical factors, and scenario attributes. Results: Of the 248 participants, the mean age was 57 (SD 13), 34% were Black, and 38% were living without a partner. Patients had a median of 0 social risk factors (IQR 0-1). Twenty-one percent of patients had financial toxicity, 10% reported prior discrimination in healthcare, 10% had limited cancer health literacy, and 20% had limited reading ability. While neither the presence of any social risk factor nor the number of social risk factors were significantly associated with elicited choice probability or discrete choice, the specific social risk factor of limited cancer health literacy was associated with lower odds of choosing 6 months (aOR 0.28, p=0.005). Conclusions: While social risk factors generally were not associated with treatment preferences, women with limited cancer health literacy were more likely to choose a longer duration of adjuvant therapy when evaluating efficacy and toxicity tradeoffs. This may be due to those with limited cancer health literacy perceiving more treatment as better. When seeking patient treatment preferences, it is important to assess patient understanding of the information provided. Screening for cancer health literacy and then providing tailored information could help ensure accurate preference elicitation when engaging in shared decision-making.
Systematic review of non-oncologic interventions for neoplastic fever.
e24060 Background: Neoplastic fever (or “tumor fever”, TF), is a rare and challenging condition, notable for debilitating night sweats, psychological distress, and extensive efforts to rule out other causes of fever. While treating cancer is critical, these efforts may take time and not be successful. To inform clinical practice and future trial design, we conducted a systematic review and meta-analysis evaluating pharmacologic, non-cancer-related treatments for TF. Methods: See Prospero registration 1124707. CINAHL, PubMed, Web of Science and Cochrane databases were searched from inception to August 19, 2025 for studies of any type with human subjects of any age that included: 1. Primary data, 2. Current cancer diagnosis, 3. Fever of cancer origin, and 4. A non-cancer directed, pharmacologic interventions. We excluded studies: 1. In languages other than English, 2. Addressing fever of any other origin, and 3. With <5 subjects. References for included studies were searched. Trained abstractors performed screening, data extraction, and risk-of-bias assessment using RoB 2, and GRADE assessments, with conflicts resolved by consensus. The primary outcome was “complete response rate (CR)”, as defined by each study. Duration of response, adverse events including gastrointestinal toxicity, bleeding, and other complications were pre-specified secondary outcomes. Results: 3,752 articles were identified. After removing duplicates and reviewing relevance, 98 full-text articles were reviewed, resulting in 26 articles. 24 were case-studies and 2 were prospective clinical trials. 14 were conducted in the United States, 2 in the last 5 years. Defining and reporting of primary and secondary outcomes was lacking, limiting meta-analysis. Most studies were subject to bias and of low certainty. Most studies evaluated non-steroidal anti-inflammatory drugs (NSAIDs); more recent studies investigated dronabinol and tocilizumab. Of the agents that could be synthesized, meta-analysis demonstrated a complete response rate of 86.4% for naproxen (95% CI: 82.2%-90.0%) and 80.0% for indomethacin (95% CI: 70.5%-87.5%). Secondary outcomes were not presented or synthesized due to lack of study reporting. Conclusions: Current evidence for non-cancer directed pharmacologic treatment of neoplastic fever is limited and largely based on low-quality case studies focused on NSAIDs, which show high apparent response rates. Rigorous, prospective trials are needed to evaluate existing and novel agents for standardized primary and secondary outcomes.
Real-world evidence on definitive chemoradiotherapy following neoadjuvant chemoimmunotherapy in locally advanced head and neck squamous cell carcinoma.
6094 Background: Real-world evidence regarding the efficacy and safety of neoadjuvant chemoimmunotherapy (NACI) in the treatment of curable head and neck squamous cell carcinoma (HNSCC) is currently limited. This multi-center study aimed to evaluate the outcomes of NACI in China. Methods: This retrospective study examined stage II-IVB HNSCC patients who underwent NACI followed by radical surgery (Group A) or definitive concurrent chemoradiotherapy (CCRT) (Group B) at four medical centers in China from 2019 to 2025. Propensity score matching was employed to balance baseline covariates between the groups. The primary endpoint was progression-free survival (PFS), while key secondary endpoints included complete pathological response (pCR), major pathological response (MPR), overall survival (OS), and treatment-related adverse events (TRAEs), which were graded according to the CTCAE v5.0 criteria. Survival analyses were conducted using Kaplan-Meier/log-rank tests and Cox proportional hazards models. Results: After matching (n=756), baseline characteristics were well-balanced (|SMD|<0.1). Group A (NACI + surgery, n=457) showed a 67% radiological response and MPR rate, with a 38% pCR, while Group B (NACI + CCRT, n=299) achieved a higher 76% radiological response rate. Regimens were similar (taxane-platinum-immunotherapy), but Group A received fewer chemotherapy cycles (3-4 cycles: 66% vs. 90%). Post-NACI progression was lower in Group B (0.7%). Group B demonstrated significantly longer PFS (hazard ratio [HR] 0.68; p=0.036) and markedly improved OS (HR 0.20; p<0.001). Multivariate analysis confirmed NACI + CCRT (Group B) as a significant independent predictor of improved OS (HR=0.20, 95% CI 0.07–0.59; p=0.003), considering factors such as betel nut use, tumor location, and T and N staging. Common grade 3-4 TRAEs were neutropenia and transaminase elevations; among grade 3 immune-related AEs, thyroid dysfunction predominated. Conclusions: This multicenter real-world study highlights that the combination of NACI and CCRT (Group B) results in significantly better PFS and OS outcomes compared to the NACI and surgical intervention (Group A), despite a pCR rate of 38% in Group A. These findings support the potential benefit of concurrent chemoradiotherapy as a consolidative approach following NACI. However, it is important to recognize that the observational nature of this study prevents definitive conclusions about causality. Therefore, prospective randomized controlled trials are essential to confirm these findings and to ascertain the optimal consolidative strategy. Additionally, further investigation into biomarker-driven patient selection is vital for enhancing treatment precision and effectiveness.
Sedative-hypnotic use peri-chemotherapy and short-term fall and fracture risk in older adults with cancer.
e13765 Background: Falls and fractures are high-impact geriatric adverse events during chemotherapy. Sedative-hypnotics are potentially modifiable yet frequently used around treatment initiation. We evaluated whether early sedative-hypnotic exposure after chemotherapy start is associated with short-term falls and fractures in older adults with cancer. Methods: We performed a retrospective cohort study using the TriNetX Global Collaborative Network (de-identified EHR data) from January 1, 2015 through December 31, 2025. During this period, 1,520,192 adults aged ≥65 years with a broad range of solid and hematologic malignancies initiating first-line systemic chemotherapy were identified. Exposure was defined as benzodiazepines and/or Z-drugs recorded within 0–7 days on/after chemotherapy initiation, with no documented sedative-hypnotic use prior to chemotherapy. Comparators had no sedative-hypnotic use before chemotherapy and none within 0–7 days after chemotherapy. The index date was chemotherapy initiation. Outcomes were falls and fractures assessed over a 90-day follow-up period from day 8 through day 98 post-index. Propensity score matching was performed using baseline demographics, malignancy category, osteoporosis, chronic kidney disease, neuropathy, dementia, anxiety/depression diagnoses, and baseline opioid and systemic corticosteroid use. Patients with outcomes documented prior to the follow-up window were excluded. Results: In the matched analytic cohorts, falls occurred in 1.2% of exposed patients (1,027/84,402) versus 0.86% of unexposed patients (744/85,824) (absolute risk difference 0.35%, RR 1.404, 95% CI 1.278–1.542, p < 0.0001). Fractures occurred in 0.51% of exposed patients (450/86,826) versus 0.42% of unexposed patients (372/87,429) (absolute risk difference 0.093%, RR 1.218, 95% CI 1.062–1.397, p = 0.0047). Conclusions: Among older adults with cancer initiating chemotherapy, sedative-hypnotic exposure in the first week after chemotherapy initiation was associated with increased risks of falls and fractures during the subsequent 90 days of follow-up. Sedative-Hypnotic use screening in older adults with cancer should be incorporated into pre-chemotherapy evaluation in order to mitigate short-term falls and fractures. Clinicians should consider non-pharmacologic alternatives for sleep/anxiety symptoms and, when medications are necessary, use the lowest effective dose and shortest feasible duration during the peri-chemotherapy period. Association of peri-chemotherapy sedative-hypnotic exposure with risk of falls and fractures. Outcome Peri-chemotherapy sedative-hypnotic exposure No peri-chemotherapy sedative-hypnotic exposure Risk of Falls RR 1.404 (95% CI 1.278–1.542), p < 0.0001 Reference Risk of Fractures RR 1.218 (95% CI 1.062–1.397), p = 0.0047 Reference
Long-term associations between ambient PM₂.₅ and PM₁₀ and lung cancer hospital admissions.
e20092 Background: Air pollution is a significant environmental health threat worldwide and an important modifiable risk factor for respiratory diseases. This study investigated the association between ambient concentrations of air pollutants (PM₂.₅ and PM₁₀) and hospital admissions with a primary diagnosis of lung cancer, used as an indicator of severe disease burden over a 17-year period. Methods: Air quality data for PM₂.₅, PM₁₀, and Air Quality Index was gathered from up to 38 fixed monitoring stations in Tehran from January 2009 to January 2026, according to the Tehran Municipality's website. Information on lung cancer patients was obtained from Masih Daneshvari Hospital (a referral center for respiratory diseases in Tehran). During this timeframe, 3321 patients of lung cancer were documented. The research population included 2033 individuals diagnosed with lung cancer and residing in Tehran. Pollutant concentrations at the city level were derived from daily station readings; sensitivity analyses were conducted for determining the robustness of exposure estimates to the inclusion criteria for monitoring stations. Associations between air pollutants and lung cancer admissions were evaluated using negative binomial regression with distributed lag models. Results: Over the 17-year study period, there was a significant association between increased PM₂.₅ and lung cancer hospital admissions, suggesting that fine particulate matter may play a more important role in severe lung cancer burden than coarser particles. Among other characteristics, it is highly probable that these hospitalizations were typically higher among males, reflecting their higher smoking and occupational exposures. The most common months with high AQI are December, January, and November. The month with the greatest patient count is often not the same as the month with the highest AQI. A delayed effect is a more reasonable explanation because lung cancer develops gradually over time. Significant associations were observed between PM₂.₅ (IRR = 1.077, p < 0.03) and lung cancer hospitalizations, whereas PM₁₀ (IRR = 0.991) and AQI (IRR = 0.976) showed weak inverse, non-significant associations. Air pollution peaked in winter, with strongest lagged effects 6–8 years post-exposure (peak at 7 years). Sensitivity analyses indicated that annual exposure estimates were robust to monitoring station inclusion, with variations generally within ±10% across pollutants and years. Conclusions: This 17-year study provides evidence that air pollution may affect the timing or severity of clinical presentations in lung cancer patients; however, it does not establish a causal effect on lung cancer incidence. Nonetheless, these findings underscore the importance of monitoring and mitigating fine particulate pollution to reduce the health impacts of lung cancer and reinforce PM₂.₅ as a key target for public health interventions.
Rethinking the role of tumor size in bladder preservation: Comparing survival outcomes of radical cystectomy (RC) and tri-modality therapy (TMT).
4621 Background: TMT (maximal TURBT followed by chemoradiation) is typically reserved for bladder cancer (BC) patients with solitary tumors less than 6 cm, no extensive carcinoma in situ, and no or unilateral hydronephrosis. The National Comprehensive Cancer Network (NCCN) guidelines specify that optimal candidates for bladder preservation with chemoradiotherapy have tumors less than 6 cm; larger tumors are less likely to be completely resected and have poorer local control and survival outcomes with bladder-sparing approaches. We aimed to analyze outcomes of BC patients receiving multimodal therapy and further categorizing outcomes of RC versus TMT based on tumor sizes. Methods: We analyzed patients with T1–T4, N0–N3, M0 urothelial carcinoma of the bladder using the NCDB (2010–2022). Patients were grouped as: RC, neoadjuvant chemotherapy (NAC) plus RC, RC followed by adjuvant chemotherapy (AC), and TMT. Overall survival (OS) was estimated with Kaplan–Meier methods and multivariable Cox regression adjusted for common confounders for these four groups. We also further analyzed the role of tumor size for patients who received either RC or TMT. Tumor size was divided in three groups; less than 3cm, 3 to 6cm, and more than 6cm. Results: Among 33,836 patients (median age 68y), treatment groups were as follows: RC alone (34%), NAC-RC (23%), RC-AC (21%) and TMT (22%). BC specific prognostic factors like tumor size more than 6cm vs 3cm (HR 1.70 (1.62–1.77) (p < 0.001)) and lymphovascular invasion (LVI) (HR 1.94 (1.87–2.00), p < 0.001)) were independently associated with poor OS. In our analysis, NAC-RC (HR 0.67 (0.64–0.70, p = 0.001) followed by RC-AC (HR 0.72 (0.69–0.75, p = 0.001) conferred the heaviest OS benefit. When tumor size was investigated as a prognostic factor comparing RC versus TMT, multivariate analysis showed that for both tumors less than 3cm (HR = 1.27 (1.16–1.39), p = 0.001) and 3cm to 6cm (HR 1.08(1.03–1.14), p = 0.003), RC was significantly superior in terms of OS. Interestingly, for tumors more than 6cm (HR = 0.97 (0.88–1.06), p = 0.468), the analysis revealed no significant difference in OS between RC and TMT. Conclusions: Despite NAC-RC offering the greatest overall survival (OS) benefit and being the standard of care, it is frequently underutilized as many patients are not candidates for chemotherapy. Consequently, bladder preservation strategies (BPS) are essential. Our analysis shows tumor size may dictate the optimal curative approach. For smaller tumors (< 3 cm and 3cm to 6cm), Radical Cystectomy (RC) is significantly superior to TMT in terms of OS. Conversely, for large tumors (> 6cm) RC provided no significant OS benefit over TMT. This suggests that the inherent aggressiveness of large lesions overrides any surgical advantage. Therefore, BPS must be strongly considered for tumors > 6cm when other TMT contraindications (e.g., hydronephrosis) are absent.
Cell-free DNA (cfDNA) methylation-based multi-cancer early detection (MCED) assay to enable subtyping of lung cancer, breast cancer, and non-Hodgkin lymphoma (NHL).
3047 Background: Given that distinct pathological and molecular subtypes of most cancers correspond to different treatment strategies, accurate cancer subtyping is clinically critical. Currently, pathological and molecular subtyping relies primarily on tissue biopsy—a procedure that is not always clinically feasible. Additionally, tumor heterogeneity may compromise the accuracy of subtyping via this approach. Prior studies have shown that cfDNA methylation-based detection is tissue-independent and outperforms mutation-based assays in cancer subtyping. Here, we employed a previously developed targeted methylation MCED assay to further classify the subtypes of lung cancer, breast cancer, and NHL. Methods: Pretreatment blood samples from lung cancer, breast cancer, and NHL patients enrolled in a MCED study were analyzed via the targeted methylation assay. Only samples with detected circulating tumor DNA (ctDNA) were included. The training cohort comprised lung cancer (n=529: 227 adenocarcinomas, 191 squamous cell carcinomas, 111 small cell carcinomas), breast cancer (n=359: 92 triple-negative breast cancers [TNBC], 267 non-TNBC cases), and NHL (n=157: 145 B-cell lymphomas, 12 T-/NK-cell lymphomas). The validation cohort included lung cancer (n=194: 87 adenocarcinomas, 82 squamous cell carcinomas, 25 small cell carcinomas), breast cancer (n=87: 26 TNBC, 61 non-TNBC cases), and NHL (n=60: 48 B-cell lymphomas, 12 T-/NK-cell lymphomas). cfDNA methylation profiles were analyzed to further classify the subtypes of these three malignancies. Results: In the validation cohort, the lung cancer classification model exhibited high overall accuracy 91.8% (178/194), with subtype-specific accuracies of 94.3% (82/87) for adenocarcinoma, 89.0% (73/82) for squamous cell carcinoma, and 92.0% (23/25) for small cell carcinoma. The breast cancer model achieved an overall accuracy of 80.5% (70/87), including 65.4% (17/26) for TNBC and 86.9% (53/61) for non-TNBC. For NHL, the model yielded an overall accuracy of 96.7% (58/60), with 97.9% (47/48) for B-cell lymphoma and 91.7% (11/12) for T-/NK-cell lymphoma. Conclusions: The cfDNA methylation-based MCED assay facilitates accurate subtype prediction for common malignancies without the need for invasive tissue biopsy procedures. This assay achieves high accuracy in lung cancer and NHL, whereas relatively lower accuracy is observed for breast cancer, particularly TNBC, owing to its reliance on molecular subtyping. Future studies will validate this assay in larger cohorts and extend its utility to a broader spectrum of cancer types.
Ultrasensitive circulating tumor DNA detection and molecular clearance as a prognostic and predictive marker in advanced renal cell carcinoma.
4551 Background: Renal cell carcinoma (RCC) is characterized by exceptionally low levels of circulating tumor DNA (ctDNA), often falling below the limit of detection for conventional liquid biopsy assays. This low-shedding environment creates a significant unmet need for ultrasensitive strategies to detect molecular residual disease (MRD), improving patient stratification, and enabling longitudinal monitoring of disease evolution in a clinical setting. Methods: ctDNA was profiled using NeXT Personal, a tumor-informed WGS-based assay tracking up to ~1,800 patient-specific variants with a limit of detection (LOD) of ~1 part per million (PPM). Baseline and longitudinal (n = 165) plasma from 37 advanced RCC patients were analyzed. The primary analysis evaluated baseline plasma (n = 36) across clinical variables. Prognostic value for progression-free survival (PFS) and overall survival (OS) was assessed in patients treated with immunotherapy or TKIs (n = 35). Results: Baseline ctDNA was detected in 84% (31/37) of patients. Notably, 13% (4/31) of these detections occurred in the ultrasensitive range below 100 PPM. Baseline ctDNA PPM levels significantly correlated with IMDC risk group (median PPM: favorable 10.9, intermediate 244.2, poor 2437.0; P=0.005), presence of histological high-risk features (median PPM: low-risk: 40.6 vs high-risk: 1528.0; P=0.025) and stage at diagnosis (median PPM: I-III 35.1 vs IV 1548.3; P=0.006). Median ctDNA levels were significantly lower in patients with surgical site recurrence (5.5 vs. 937.2 PPM; P=0.038). Molecular ctDNA clearance (mCR), defined as ctDNA-negative status at any point during first-line therapy, was highly prognostic. mCR correlated significantly with best overall response (P=0.007), with 100% specificity for disease control; no patients with progressive disease achieved clearance. Patients not achieving mCR had dramatically worse PFS (HR=8.69; P=0.001) and OS (HR=4.70; P=0.044). Among patients with a best response of stable disease (SD) by imaging, mCR provided critical differentiation; those who cleared ctDNA had 100% PFS/OS at 2 years, whereas those who remained ctDNA-positive saw PFS drop to 0% and OS to 33% by year 1. Additionally, achievement of mCR was significantly associated with clinical disease control (PR+SD, 92.3% vs PR+SD, 50.0%; OR 12.0 [95% CI 1.32–108.8], p=0.013). Conclusions: Ultrasensitive ctDNA profiling effectively overcomes the low-shedding challenge of advanced RCC, and could provide additional prognostic clarity that complements standard-of-care imaging and IMDC risk models. mCR serves as an effective biomarker for long-term survival, identifying patients with durable responses even among those with radiographically stable disease. These findings support integrating ctDNA monitoring to guide treatment intensification or de-escalation strategies.
Fraction genome altered to predict survival in early-stage non–small cell lung cancer.
8042 Background: Patients with stage I-III non-small cell lung cancer (NSCLC) often have very different outcomes, even when they share the same anatomic stage. This suggests that tumor biology plays an important role in prognosis. Fraction genome altered (FGA), a measure of chromosomal instability derived from next-generation sequencing (NGS), is already used in clinical practice but its prognostic value in early-stage NSCLC is not well established. Therefore, we evaluated whether FGA is associated with overall survival (OS) in early-stage NSCLC and whether it provides prognostic information beyond standard clinical factors and tumor mutation burden (TMB). Methods: We performed a retrospective analysis of 7,722 patients with NSCLC using clinical-grade targeted NGS with available copy-number data (MSK CHORD 2024). Disease stage was categorized as stage I-III versus stage IV. FGA was analyzed in quartiles, with high FGA defined as the top quartile. OS was assessed using Kaplan-Meier and multivariable Cox proportional hazards models adjusting for age, sex, smoking history, histology group, sequencing panel, stage, and log-transformed TMB. Incremental prognostic value was evaluated using concordance (C-index) and likelihood ratio testing (LRT). The results were validated using several sensitivity/statistical analysis. Results: After quality control, 7,722 patients were included (3,934 deaths), including 4,343 with stage I-III disease (1,559 deaths). In early-stage NSCLC, increasing FGA was associated with progressively worse OS across quartiles (log-rank χ² = 199.6, p < 0.0001). 5-year OS declined from 65.6% in the lowest FGA quartile to 39.6% in the highest quartile. Patients with high FGA had significantly inferior survival compared with low-FGA patients (5-year OS 39.6% vs 63.0%, p < 0.0001). In multivariable models restricted to stage I-III, high FGA remained independently associated with mortality (Hazard-Ratio = 1.60, 95% CI: 1.42-1.82, p < 0.0001). Adding FGA to clinical models improved survival prediction (C-index = ~0.70) and overall model performance (LRT = 125.9, p < 0.0001), and this improvement was greater than that seen with TMB. When both biomarkers were included, FGA continued to provide strong prognostic information, whereas TMB did not improve prediction once FGA was already in the model. We found our results to be consistent across internally validated analysis. Conclusions: FGA was strongly associated with OS in stage I-III NSCLC. FGA identified a subgroup of early-stage patients with substantially worse outcomes despite similar anatomic stage, indicating important underlying biologic differences. Since, FGA can be obtained from routine targeted NGS already used in clinical practice, it presents a practical biomarker that may improve risk stratification beyond standard clinical factors and TMB, and help guide surveillance and perioperative trial selection.
Diabetic ketoacidosis and hyperosmolar hyperglycemic state as high-acuity phenotypes in U.S. cancer hospitalizations: National Inpatient Sample, 2018–2022.
e23197 Background: Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are uncommon but high-acuity events that may occur during cancer hospitalizations. National estimates describing their association with inpatient physiologic severity, critical illness, mortality, and resource utilization in oncology hospitalizations remain limited. Methods: A serial cross-sectional, hospitalization-level analysis of the 2018 to 2022 Healthcare Cost and Utilization Project National Inpatient Sample (NIS) was performed using discharge-level survey weighting with hospital clustering and stratification to generate nationally representative estimates. Adult hospitalizations with a principal diagnosis of malignancy were identified using ICD-10-CM codes C00 to C97 and D45 to D47. Hyperglycemic crises were defined using any-diagnosis ICD-10-CM code families for diabetic ketoacidosis (DKA; E10.1, E11.1, E13.1, E08.1, E09.1) and hyperosmolar hyperglycemic state (HHS; E10.0, E11.0, E13.0, E08.0, E09.0). Outcomes included All Patient Refined Diagnosis Related Group (APR-DRG) severity of illness subclass, with extreme severity defined as APR-DRG level 4, in-hospital mortality, length of stay, hospitalization cost, and ICU proxies including mechanical ventilation and shock. Survey-weighted multivariable models adjusted for demographics, payer, socioeconomic status, admission characteristics, cancer type, and hospital characteristics. Results: Among 961,848 unweighted cancer hospitalizations representing 4,809,239 hospitalizations nationally, DKA occurred in 0.11%, HHS in 0.02%, and any hyperglycemic crisis in 0.12%. Compared to hospitalizations without crisis, hyperglycemic crisis admissions had higher mean APR-DRG severity (3.52 vs 2.56), longer length of stay (10.80 vs 6.63 days), and higher cost ($35,491 vs $22,792). Hyperglycemic crises were also associated with higher rates of extreme severity (10.41% vs 3.45%), in-hospital mortality (14.15% vs 4.37%), mechanical ventilation (9.99% vs 2.58%), and shock (7.24% vs 1.38%). After adjustment, hyperglycemic crisis remained independently associated with higher inpatient severity (β 0.72, 95% CI 0.64 to 0.80), extreme severity (OR 4.79, 95% CI 3.62 to 6.35), in-hospital mortality (OR 2.80, 95% CI 2.35 to 3.33), mechanical ventilation (OR 3.50, 95% CI 2.89 to 4.25), and shock (OR 4.65, 95% CI 3.71 to 5.83). Conclusions: Although uncommon, hyperglycemic crises create a high-acuity subset of cancer hospitalizations with profound increases in extreme physiologic severity, critical illness, mortality, length of stay, and cost. These findings support hyperglycemic crises as high-priority inpatient risk phenotypes with implications for early recognition, escalation planning, and ICU resource utilization in hospitalized oncology populations.
CLDN18.2–targeting antibody-drug conjugate BA1301 in advanced solid tumors: Results from a phase I clinical trial.
4031 Background: Aberrant expression of claudin18.2 (CLDN18.2) has frequently been observed in various solid tumors, making it a promising therapeutic target for those aggressive cancers. BA1301 is an ADC consisting of a fully humanized anti-CLDN18.2 monoclonal antibody conjugated to monomethyl auristatin E, a potent cytotoxic agent via site-specific glycol conjugation and a cleavable linker with a drug-to-antibody ratio of 4. Here we reported the results from a phase 1 dose escalation and dose expansion study of BA1301. Methods: Eligible pts failed or intolerant to standard therapy were enrolled. BA1301 was intravenously administered with accelerated titration (0.1/0.4 mg/kg Q3W) and traditional 3+3 design (1.2/2.0/2.5/3.0mg/kg Q3W). Dose expansion was evaluated at 1.6/2.0/2.5mg/kg Q3W. CLDN18.2 was test by immunohistochemistry [IHC] Claudin18.2 (EPR19202-244) Assay developed by Medx. Moderate to high expression of CLDN18.2 defined as IHC membrane staining intensity ≥2 in ≥40% of tumor cells. Endpoints were safety and efficacy per RECIST v1.1. Results: As of Dec 22, 2025, a total of 91 patients with advanced cancers (gastric cancer [59, 64.8%], biliary tract cancer [14, 15.4%], pancreatic cancer [11, 12.1%], gynecologic cancers [3, 3.3%] and other 4 tumor types) were enrolled, 49 (53.8%) patients had received ≥2 systemic therapies (median 2, range 1-7). In dose escalation (n = 24), No DLTs were observed.80 (87.9%) patients had at least one treatment-related adverse events (TRAEs), and 33 (36.3%) had grade 3 or 4 TRAEs. The most common TRAEs were corneal disorder (51, 56.0%) and anemia (30, 33.0%). 3(3.3%) pts discontinued treatment due to TRAEs, and no treatment related death reported. Among patients with CLDN18.2 moderate to high expression (N=76), 69 at the ≥1.6 mg/kg dose level had at least one post-baseline tumor assessment. Key efficacy outcomes are presented (Table). Conclusions: BA1301 was well-tolerated with a manageable safety profile and demonstrated promising anti-tumor activity in patients with CLDN18.2 moderate to high expression. The findings support further development of BA1301 as a new therapeutic approach to treat CLDN18.2-positive solid tumors. The trial (NCT06927349) is ongoing in China. Clinical trial information: NCT06927349 . Cancer Type ORR n (%) [95%CI] DCR n (%) [95%CI] Gastric cancer (N=49) 14 (28.6）[16.6, 43.3] 35 (71.4) [56.7, 83.4] Biliary tract cancer (N=10) 3 (30.0) [6.7, 65.2] 6 (60.0) [26.2, 87.8] Pancreatic cancer (N=7) 1 (14.3) [0.4, 57.9] 5 (71.4) [29.0, 96.3] Gynecologic cancer (N=3) 1 (33.3）[0.8, 90.6] 3 (100.0) [29.2, 100.0] In total (N=69) 19 (27.5) [17.5, 39.6] 49 (71.0) [58.8, 81.3]
Do mental health disorders modify cytokine release syndrome risk in immune effector cell therapy? Full-cohort analysis with tarlatamab validation.
e19002 Background: Cytokine release syndrome (CRS) is a common immune effector cell (IEC) therapy toxicity. Host psychiatric effects on immunotoxicity are underexplored. The stress-immune axis or pre-existing neuro-inflammatory states common in mental health disorders (MHDs) may impact IEC toxicity. We therefore evaluated whether pre-treatment MHDs affect CRS risk, with an independent tarlatamab cohort for validation. Methods: This was a retrospective, single-center study of adults receiving commercial/investigational IECs (CAR-T or bispecific T-cell engagers; N=105). The primary exposure was a documented pre-treatment MHD (anxiety, depression, bipolar, or PTSD). The primary outcome was any-grade CRS per ASTCT criteria. Multivariable logistic regression with stepwise adjustment (therapy alone; therapy+gender+ECOG) was used. Sensitivity analyses included log-transformed baseline CRP adjustment and stabilized inverse probability of treatment weighting (IPTW). Validation was performed in a tarlatamab subgroup (N=33). Secondary outcomes included CRS (grade ≥2), ICANS, and treatment response. Results: Among 105 IEC recipients (MHD+ n=53, MHD− n=52), CRS occurred in 18/53 (34.0%) compared to 34/52 (65.4%; Absolute Risk Reduction [ARR] 31.4%). In the primary adjusted model (n=79), MHD+ remained significantly protective (Odds Ratio [OR] 0.33; 95% CI 0.11–0.98; p=0.046). Sensitivity analyses confirmed this protective association: CRP-adjusted OR 0.31 (95% CI 0.10–0.97); IPTW OR 0.35 (95% CI 0.15–0.79). In the tarlatamab validation cohort, CRS risk was notably lower at 18.2% vs 54.5% (ARR 36.3%; OR 0.18; 95% CI 0.03–0.91). Grade ≥2 CRS trended lower in the MHD+ group, but MHD was not associated with ICANS or peak CRP levels. Importantly, efficacy was preserved (response OR 2.03; p=0.401). Conclusions: Pre-treatment MHD was consistently associated with a lower CRS risk across all statistical models and in the independent tarlatamab validation, without compromising anti-tumor efficacy. Further prospective validation of these novel findings is highly warranted to confirm the clinical implications. Analysis outcomes (MHD+ vs MHD−). Analysis N Rate (+/−) OR (95% CI) P CRS – Unadjusted 105 34.0%/65.4% 0.27 (0.12–0.61) 0.0016 CRS – +Therapy 105 34.0%/65.4% 0.38 (0.16–0.90) 0.0284 CRS – Adjusted 79 30.2%/63.9% 0.33 (0.11–0.98) 0.0463 CRS – CRP adj 81 41.0%/71.4% 0.31 (0.10–0.97) 0.0441 CRS – IPTW 105 34.7%/60.6% 0.35 (0.15–0.79) 0.0119 Tarlatamab – CRS 33 18.2%/54.5% 0.18 (0.03–0.91) 0.0381 CRS (≥Gr2) 79 9.4%/28.8% 0.27 (0.07–1.06) 0.0604 Response 65 74.3%/83.3% 2.03 (0.39–10.62) 0.401 OR<1 indicates lower odds in MHD+ vs MHD− for CRS endpoints; OR>1 indicates higher odds of response in MHD+.
Survival and treatment patterns of patients with metastatic urothelial cancer in France: Results of a cohort study using the French National Healthcare database (SNDS).
4610 Background: Despite the increasing number of available treatment options, metastatic urothelial cancer (mUC) remains a challenging disease, characterized by high mortality and substantial rates of undertreatment worldwide. In this study, we aimed to describe treatment patterns and survival among patients with mUC in France. Methods: This retrospective study included adult patients with incident mUC between January 2017 and December 2023. The overall study cohort was divided into two subcohorts: treated, defined as initiating any systemic treatment within 120 days after index date and untreated (defined as not initiating any treatment within 120 days after index date). The index date was defined as diagnosis (first recorded ICD-10 code for metastasis) or start of systemic anticancer treatment. Overall survival (OS) was estimated using Kaplan-Meier method, calculated from the index date for the overall cohort and untreated subcohort, and from the initiation of first line (1L) treatment for the treated subcohort. Baseline characteristics including sex, age, and age-adjusted Charlson Comorbidity index (CCI) were compared between treated and untreated subcohorts using χ2 and Wilcoxon tests. Results: The study included 24,912 patients, male (77.8%), mean (SD) age was 75 (11) yrs, and median (IQR) age-adjusted CCI was 4 (2-5). Median (IQR) follow-up was 2.5 (1-10) months. Mortality was 90.8%, primarily due to malignant tumors (88.6%) among the recorded causes of death. Overall, 1L treatment was initiated in 10,562 pts (42.4%), with increasing annual rates from 2017 (38%) to 2023 (47%). Chemotherapy was the predominant 1L treatment (75.4%) followed by immune-oncology (IO) agents (24.5%). Of 7,960 pts receiving 1L chemotherapy, 4,193 (53%) did not receive any further treatment, and 2,184 (27%) patients received chemotherapy, 1,359 (17%) IO, and 224 (3%) antibody-drug conjugates in second line. Mean (SD) time from index date to 1L initiation was 18 (25) days and mean (SD) duration of 1L was 101 (155) days. Median OS was 2.5 (95% CI 2.4-2.6), 7.6 (7.4-7.8) and 1.1 (1.1-1.1) months for the overall cohort, treated and untreated subcohorts, respectively. It decreased with higher CCI scores: from 3.99 months for patients with CCI 0 to 1.54 months for those with CCI ≥5. Sex, age and CCI were significantly different between treated and untreated patients (p<0.0001). Conclusions: This nationwide population-based study showed that more than half of patients with mUC treated in real-world clinical practice in France did not receive 1L systemic treatment. Untreated individuals were mainly elderly, male, comorbid, and experienced poor survival. These findings underscore the importance of the early utilization and optimization of available therapies to improve outcomes, especially among untreated patients with mUC.
Phase I trial of trastuzumab deruxtecan in combination with stereotactic radiosurgery for brain metastases from HER2-positive breast cancer.
TPS2093 Background: Brain metastases (BM) develop in nearly 40-50% of patients with HER2-positive breast cancer. Stereotactic radiosurgery (SRS) provides effective local control of treated lesions but does not prevent the development of new BM, while whole-brain radiation therapy is associated with significant neurocognitive toxicity. Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody-drug conjugate (ADC) that has demonstrated significant systemic and intracranial activity in patients with HER2-positive breast cancer. Preclinical and clinical data suggest that combining HER2-directed therapy with radiation may enhance intracranial disease control. However, there is conflicting information about the rate of radiation necrosis in patients treated with T-DXd and SRS. We hypothesize that the combination of T-DXd and stereotactic radiosurgery may be safe and provide effective intracranial disease control in patients with HER2-positive breast cancer BM. Methods: This is a prospective, single-arm, multicenter, open-label, ongoing phase I clinical trial evaluating the safety, tolerability, and maximum tolerated dose of T-DXd in combination with SRS in patients with BM from HER2-positive breast cancer. Eligible participants are adults (≥18 years) with histologically confirmed HER2-positive breast cancer, Eastern Cooperative Oncology Group performance status of 0–2, adequate organ function, and 1–10 newly diagnosed BM who are candidates for SRS. Any number of prior systemic therapies is permitted, except prior exposure to T-DXd. Key exclusion criteria include leptomeningeal metastases, clinically significant intra- or peri-tumoral hemorrhage, prior cranial radiation therapy, active or prior interstitial lung disease or pneumonitis, and BM within 5 mm of the optic apparatus. Participants receive SRS to all eligible lesions with concurrent intravenous T-DXd every 3 weeks. A standard 3+3 dose de-escalation design is used, starting at 5.4 mg/kg with planned de-escalation to 4.4 mg/kg and 3.2 mg/kg. Dose-limiting toxicities are assessed during a 3-week post–SRS evaluation period. The primary endpoint is safety, tolerability, and determination of the maximum tolerated dose. Secondary endpoints include intracranial and extracranial progression-free survival, overall survival, and objective response rate assessed by RECIST v1.1. Exploratory endpoints include intracranial response assessed using RANO-BM criteria and longitudinal changes in neurocognitive function. Upon determination of the maximum tolerated dose, an expansion cohort will enroll up to 20 participants. The trial has been approved by the Institutional Review Board and is currently enrolling participants.
Association of facility type with overall survival in older adults with angioimmunoblastic T-cell lymphoma: A National Cancer Database analysis.
e19074 Background: Angioimmunoblastic T cell lymphoma (AITL) is a distinct and aggressive subtype of peripheral T cell lymphoma characterized by immune dysregulation and frequent presentation with advanced stage disease. Predominantly affects older adults and is associated with inferior survival outcomes compared with many B cell lymphomas, despite advances in clinical practice. Although therapeutic advances and supportive care strategies have improved outcomes across lymphoma subtypes, patients aged ≥75 y remain underrepresented in clinical trials, resulting in limited real world data to guide management in this population. Advanced age is often accompanied by higher comorbidity burden and barriers to specialized care that may influence outcomes independently of disease biology. The impact of treatment facility type on outcomes in elderly patients with AITL is not well defined. Methods: We conducted a retrospective analysis of patients aged ≥75 y diagnosed with AITL in the US between 2004-2022 using the National Cancer Database. Demographic, socioeconomic, clinical, treatment, and survival characteristics were compared between patients treated at Academic Cancer Programs (ACP) and Community Cancer Programs (CCP). Kaplan-Meier and Cox regression analyses were used to compare overall survival (OS) between the two cohorts. Variables used for adjustment included age, ethnicity, insurance status, distance from hospital, and Charlson-Deyo comorbidity score. Results: A total of 2,117 patients aged ≥75 y with AITL were identified including 1,112 treated at ACP and 1,005 treated at CCP. Median age was 80 y in both cohorts, and most patients presented with advanced stage. The majority were insured through Medicare, and baseline comorbidity burden was substantial and similar across treatment settings. Patients treated at ACP were more likely to receive treatment, while a high proportion of patients treated at CCP (45%) had no treatment given or had unknown treatment status. Time from diagnosis to initiation of chemotherapy was significantly shorter at ACP compared with CCP.OS favored patients treated at ACP, with higher two year (37% vs 30%), five year (24% vs 17%), and ten year (11% vs 5%) survival compared with CCP. Conclusions: In this national cohort of patients aged ≥75 y with AITL,OS differed significantly by treatment facility type, with a statistically significant and clinically meaningful survival advantage observed among patients treated at ACP. These findings underscore persistent disparities in treatment delivery and early mortality in this vulnerable population and support efforts to strengthen referral pathways to ACP or develop structured partnerships between CCP and ACP. Such strategies may facilitate timely access to specialized care, multidisciplinary expertise, and clinical trials for older adults with aggressive T-cell lymphomas.
Rituximab pre-conditioning in a phase I study of CARv3-TEAM-E for recurrent glioblastoma (GBM): The INCIPIENT trial.
2059 Background: Chimeric Antigen Receptor (CAR) T cells for glioblastoma (GBM) have been limited by the challenge of targeting a single tumor antigen in a heterogeneous disease. To address this barrier, we generated a novel engineered T-cell product (CARv3-TEAM-E) that targets the EGFRvIII antigen while also secreting T-cell-Engaging Antibody Molecules (TEAMs) against wild-type EGFR. Methods: The INCIPIENT clinical trial is a first-in-human study of CARv3-TEAM-E in patients with GBM (NCT05660369). Patients with recurrent GBM were treated with intraventricular CARv3-TEAM-E T cells (10E6 cells per infusion) and one of three pre-treatment regimens: no lymphodepletion (N=3), lymphodepleting chemotherapy with cyclophosphamide and fludarabine (LDC) (N=7), or cyclophosphamide, fludarabine, and rituximab (LDC+R) (N=3). The primary objective was safety and tolerability. Immune cells were profiled in the cerebrospinal fluid (CSF) and peripheral blood by flow cytometry. Results: CAR T manufacturing was successful for all patients. There were no dose-limiting toxicities (DLT). Three patients were treated without LDC; all developed anti-CAR and/or anti-TEAM antibodies (i.e., anti-therapy antibodies) after a single infusion of CARv3-TEAM-E. Subsequently, 7 patients were treated with LDC prior to CARv3-TEAM-E, 5 of which underwent serial infusions (range 2-5 infusions). Four patients had reinfusions after which CAR T cells were not detected in the CSF. We therefore added rituximab to the LDC regimen. In the 3 individuals pre-treated with LDC+R, CAR T cells were detected in CSF not only after initial infusion (range 21-28 days) but also following repeat infusion in all patients (range 3-15 days post-reinfusion). Anti-therapy IgG was not detected in patients treated with LDC+R, as compared to 9/10 patients who developed an antibody response when rituximab was not administered. As of 12/15/2025, 10/13 patients are alive 6-30 months after first infusion, with 7 alive >14 months. Conclusions: Intraventricular CARv3-TEAM-E infusions were well-tolerated after LDC+R pre-conditioning and no DLTs were noted. The addition of Rituximab abrogated anti-therapy antibody formation and prolonged CAR T-cell persistence in 3/3 patients. Survival data reflect continued promise of CARv3-TEAM-E in patients with recurrent glioblastoma. Clinical trial information: NCT05660369 .
RAD-SG: Adaptive radiation therapy with concurrent sacituzumab govitecan for bladder preservation in patients (pts) with muscle invasive bladder cancer (MIBC).
e16614 Background: Concurrent chemoradiotherapy (CRT) is a bladder-preserving option for patients (pts) with MIBC but is limited by systemic radiosensitizer toxicity from conventional chemotherapy agents. Novel agents with improved tolerability and efficacy are needed to be able to combine with RT. Sacituzumab govitecan (SG) is a Trop-2–directed antibody drug conjugate (ADC) with activity in metastatic urothelial carcinoma. RAD-SG is a single-arm phase I trial evaluating concurrent SG with adaptive radiation therapy (RT) in localized MIBC. Methods: Key eligibility include pts with MIBC (T2-T4aN0M0), including variant histology, ECOG PS Score 0-2, normal organ/marrow function, cr cl ≥ 30 mL/min, TURBT within ≤ 60 days prior to treatment. Pts with bilateral hydronephrosis and prior pelvic RT were excluded. Pts receive SG 7.5 mg/kg IV every 21d starting prior to RT then 2 cycles with concurrent adaptive RT over 6 wks (64 Gy) and undergo a mid-treatment cystoscopy evaluation. The primary endpoint is safety, tolerability, and feasibility of TMT with concurrent SG and adaptive RT. Secondary endpoints are bladder intact event-free survival (BI-EFS) defined as time from treatment to first occurrence of residual/recurrent MIBC, nodal or distant metastases, RC, or death from any cause. Correlative objectives include genetic and microenvironmental correlatives, characterization of tumor clonal dynamics, immune repertoire editing, and imaging changes following TMT. Planned enrollment is 20 pts. Results: The study has accrued 14/20 patients at Cleveland Clinic. Treatment was generally well tolerated with common grade 1–2 treatment-related adverse events (TRAEs) being alopecia (77%), anemia (69%), fatigue (62%), and lymphopenia (54%). Grade 3-4 TRAEs included lymphopenia (31%), anemia (8%), proteinuria (8%), and neutropenia (8%). DLT was seen in 2 pts, each with grade 3 neutropenia which recovered without G-CSF. No treatment-related deaths occurred. Four pts experienced recurrence; 2 required salvage RC and 1 developed metastatic disease. Enrollment is ongoing. Conclusions: SG with adaptive RT is feasible and safe in localized MIBC; efficacy and correlative analyses are ongoing. This is the first study to combine an ADC with RT in bladder cancer. Clinical trial information: NCT05833867 .