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Next-generation ADCs and emerging conjugate platforms in breast cancer: a ClinicalTrials.gov landscape analysis.

e15026 Background: Antibody–drug conjugates (ADCs) are reshaping breast cancer management, yet their rapid proliferation raises concerns regarding therapeutic redundancy. We investigated the 2025 development pipeline to test the hypothesis that current strategies, heavily skewed toward shared targets and payloads, may be creating cross-resistance bottlenecks, thereby underscoring a critical need for novel antigens and alternative cytotoxic mechanisms to ensure viable future sequencing. Methods: We queried ClinicalTrials.gov on December 31, 2025, for interventional “Breast Cancer/Breast Neoplasms” studies with statuses recruiting, not-yet-recruiting, or active-not-recruiting using keywords enriching for next-generation platforms (ADCs, radiopharmaceuticals, PROTACs, immune-conjugates, oncolytic viruses). Terms corresponding to commonly used payloads were excluded. Manual review removed non-breast, diagnostic-only, radiotherapy-only, and ineligible interventions. Basket trials that included the breast cancer cohort were retained. ADCs were classified by payload class (tubulin vs non-tubulin vs novel) and construct architecture (bispecific, biparatopic). Phases were listed as early (phase 1 and 2) and late (phase 3). Results: Of 154 screened trials, 119 met inclusion criteria. ADCs dominated the landscape (62/119, 52.1%), followed by radiopharmaceuticals (16.0%), oncolytic viruses (9.2%), non-ADC antibodies (4.2%), and other modalities (18.5%). Most trials were early-stage (Phase 1 or 2 at 42.0% and 51.3%) and actively recruiting (62.2%). Mean planned enrollment was highest for ADCs (236) compared with radiopharmaceuticals (109) and oncolytic viruses (32). Within ADCs (n = 62), targets were concentrated in HER2 (25) and TROP2 (11), with expansion into HER3 (7), EGFR (6), and Nectin-4 (6). Payloads included Topoisomerase-I (42/62, 67.7%), microtubule inhibitors (17.7%) and structurally novel architectures (14.5%). Latter included bispecific ADCs (EGFR×HER3; n = 2) and biparatopic HER2 ADCs (n = 6). Overall, ADCs comprised 87.5% (7/8) of late phase, with one single non-ADC trial using an endocrine PROTAC degrader. Among non-ADC antibodies (n = 5), bispecifics were prominent (n = 4), targeting PD-(L)1×VEGF (n = 3) and CD28×Nectin-4 (n = 1). Radiopharmaceutical trials (n = 19) frequently utilized 177Lu and explored theranostic 68Ga/177Lu pairing. Conclusions: In a ClinicalTrials.gov landscape enriched for next-generation conjugate constructs, ADCs had predominance of topoisomerase-I payloads (68%) with emerging presence of structurally novel architectures (15%), including bispecific and biparatopic constructs. These data highlight an urgent strategic imperative to diversify payload mechanisms and validate novel surface antigens to prevent therapeutic bottlenecks and secure effective sequencing pathways for future patients.

A phase I/IIa, first-in-human, multicenter, monotherapy and combination therapy with nivolumab dose-finding study of [ ²¹² Pb]VMT01 melanocortin-1-receptor–targeted, image-guided, alpha-particle therapy in subjects with previously treated unresectable or metastatic melanoma.

9525 Background: Melanocortin-1 receptor (MC1R) is a novel target for radiopharmaceutical therapy and is highly expressed on melanoma tumor cells. VMT01 is an MC1R-targeted peptide. 203 Pb is used for patient selection via SPECT imaging. Peptide radiolabeling with 212 Pb delivers alpha-particle therapy. Here, we present data on the treatment of adult patients with MC1R-positive metastatic melanoma receiving [ 212 Pb]VMT01 either as a monotherapy or in combination with the programmed death-1 (PD-1) checkpoint inhibitor, nivolumab. Methods: This is an ongoing phase I/IIa, first-in-human, prospective, multicenter, open-label, radioactive dose-finding and dose-expansion trial. The objectives are to investigate safety, pharmacokinetics, dosimetry, and efficacy. Participants receive up to 3 treatment cycles with either [ 212 Pb]VMT01 3 mCi, 5 mCi, or 1.5 mCi monotherapy, or combination therapy with [ 212 Pb]VMT01 (1.5 mCi) + nivolumab (480 mg, Q4W) or [ 212 Pb]VMT01 (3 mCi) + nivolumab. Participants are evaluated for any DLTs for the first 6 weeks after cycle 1. Efficacy is assessed by RECIST v1.1 criteria by the investigator. Results: As of 24 December 2025, 26 participants (53.8% male; median age: 68 years [range: 27-81]) with MC1R-positive metastatic melanoma were enrolled. The median prior systemic therapies was 4. All 26 enrolled participants received ≥1 dose of [²¹²Pb]VMT01. No DLTs were reported. All SAEs (including one grade 5 SAE) were attributed to disease progression. Most TEAEs were grade 1 (19.2%) and grade 2 (34.6%). Grade 3 TEAEs occurred in 8 participants (30.8%), 5 on monotherapy and 3 on combination therapy (3 mCi + nivolumab). Of the 22 evaluable participants, 1 PR, 9 SD, and 12 PD were reported. Four participants had progression-free survival of ≥6 months. Conclusions: [ 212 Pb]VMT01 as a monotherapy and in combination with nivolumab was generally safe and well-tolerated in 26 enrolled participants, with antitumor activity observed at the 3 mCi dose level. These data may be supplemented with a more complete follow-up at the time of the meeting. Clinical trial information: NCT05655312 .

Phase 1, open-label clinical trial to treat stage IV cancer patients harboring multiple patient-specific mutated cell surface proteins with chimeric antibodies.

TPS2672 Background: Despite the advent of multiple classes of systemic cancer treatments, tumor recurrence and subsequent resistance to systemic therapy remain a persistent challenge. Thus, newer treatment strategies are needed for metastatic cancer refractory to extant therapies. Leveraging the vast landscape of targetable tumor-specific mutated peptides (TSPs) on the surface of malignant cells offers an opportunity for individualized antibody therapy. These surface TSPs arise due to genetic instability and progressive accumulation of random missense mutations in cancer cells, resulting in dozens to hundreds of substituted amino acids in proteins at the cancer cell surface. We refer to surface proteins harboring substituted amino acids as Mutated cell Surface Proteins (MSPs). Antibodies generated against short TSPs preferentially bind to the mutated peptide compared to the nonmutated peptide. Notably, most cancers harbor several distinct MSPs. For instance, of 100 colon cancer cases, 96% harbored ≥10 MSPs, with similar findings in lung cancer (97%), melanoma (93%), lymphoma (92%), bladder cancer (85%), and stomach cancer (84%). While the presence of many MSPs is common, each patient harbors a unique set of MSPs. Study sponsor has developed a means of preparing custom antibodies against the TSPs present in multiple MSPs to inhibit cancer growth in several preclinical models, prompting a pan-tumor Phase I study evaluating the safety and feasibility of such therapy in refractory cancer patients. Methods: This is a phase I first-in-human study aiming to enroll up to 12 eligible subjects. Primary objective: Safety and tolerability. Secondary objectives: Feasibility of producing and administering the protocol-directed treatment to the patient population; progression-free survival; response rate. Key Inclusion Criteria: a) Stage IV refractory cancer (breast, colon, esophageal, kidney, lung, ovarian, bladder urothelial, stomach, or pancreatic cancers, melanoma, or lymphoma); b) availability of tumor and matched normal tissue sequence data. Treatment: Custom-manufactured chimeric antibodies are being used to target a minimum of 2 to 8 MSPs per patient. An interval of 4- to 6-month antibody production interval is required from initial consent to the start of treatment. The dose-limiting toxicity (DLT) period is 4 weeks; thereafter, in addition to antibody treatment, subjects can receive standard of care [immunotherapy, targeted therapy or hormonal therapies]. Treatment schedule: Week 1, 100 mg i.v.; week 2, 200 mg i.v.; week 3 400 mg; and then 400 mg i.v. every other week for total of 10 doses. We have enrolled 3 subjects and have completed treatment of Subject #1 (bladder cancer), with no DLT to date. The study is ongoing since 12/2025. Clinical trial information: NCT06674538 .

Quantitative assessment of tumor shedding using AI-derived radiographic tumor burden and quantified liquid biopsy in advanced gastrointestinal cancers.

3063 Background: Radiographic imaging remains the clinical standard for assessing cancer treatment response; however, it lacks sensitivity to detect early biological shifts and spatially heterogeneous tumor behavior. Methylated circulating tumor DNA (mctDNA) provides a complementary molecular measure of disease burden, yet the quantitative relationship between radiographic tumor burden and DNA shedding remains poorly characterized. In this cohort study, we evaluated whether early changes in shed rate predict progression-free survival (PFS) and overall survival (OS) in patients with advanced gastrointestinal (GI) cancers. Methods: Patients with advanced GI malignancies receiving systemic therapies underwent paired longitudinal radiographic and liquid biopsy assessments. Radiographic tumor burden was quantified (OSCAR AI platform). Tumor contours were independently blinded reviewed by two radiologists. Up to 15 target lesions per organ were selected, and the total tumor burden was calculated analogous to longitudinal RECIST assessment. Tumor Methylation Score (TMS) from the Northstar Response assay quantified mctDNA. Tumor shed rate (TSR) was defined as the ratio of TMS to the AI-derived radiographic tumor volume and calculated at baseline and at the first on-treatment landmark using the closest-paired CT scan and blood drawn within 120 days. Fold-change in TSR from baseline was compared with PFS and OS. Undetectable tumor volume cases were excluded. Results: Forty patients were evaluable, with both baseline and landmark timepoints available within the 120-day window. TSR ranged from a min of 0 methylated molecules per mm 3 (m4) to a max of 1.0 m4 with a median of 0.06 m4. TSR significantly differed between tumor types (p=0.013, ANOVA), with CRC having the highest median shed rate (0.13 m4) and EGA and pancreatic having the lowest median shed rates (0 m4). TMS was significantly associated with tumor volume at baseline (Rsq=0.15,p=0.01, Deming) and on-treatment (Rsq=0.6, p<0.001, Deming). An increased TSR was associated with OS (HR=5.8, 95% CI 1.7-19.2, <0.01) and PFS (HR=3.5, 1.4-8.6, <0.01). Conclusions: TSR represents a novel, multidimensional integration of AI-driven volumetrics and liquid biopsy. Our findings suggest that an increasing shed rate is a predictor of PFS and OS, potentially serving as a lead-time indicator of tumor-host homeostatic decompensation. Future analysis will determine if TSR captures critical transitions in tumor biology that precede and perhaps drive radiographically detectable progression.

Efficacy and safety of HER2-targeted tyrosine kinase inhibitors in <i>HER2</i> -mutant non–small cell lung cancer: A systematic review and meta-analysis.

e20772 Background: HER2-targeted tyrosine kinase inhibitors (TKIs) represent a new oral targeted therapy class in HER2-mutant non–small cell lung cancer (NSCLC), a rare molecular subset with historically poor outcomes. In 2025, zongertinib and sevabertinib each received FDA accelerated approval for HER2 TKD-mutant NSCLC after prior systemic therapy, expanding precision treatment options. Methods: A systematic search of major databases was conducted to identify studies evaluating HER2-targeted tyrosine kinase inhibitors in HER2-mutant non–small cell lung cancer; pooled analyses were performed using Stata version 18.0, and risk of bias was assessed using the ROB 2.0 tool. Results: A total of five studies were included, comprising 335 patients with advanced or metastatic HER2-mutant NSCLC. Of these, 209 patients received sevabertinib and 126 received zongertinib. Among sevabertinib-treated patients, 73 were treatment-naïve, 81 were previously treated but HER2-TKI–naïve, and 55 had prior HER2-directed ADC exposure. Among zongertinib-treated patients, 75 had previously treated TKD-mutant disease, 31 had prior ADC exposure, and 20 had non-TKD HER2 mutations. Relative to a historical ORR benchmark of 30%, sevabertinib demonstrated significant efficacy in treatment-naïve patients (OR 5.58, 95% CI 3.44–9.06) and previously treated HER2-TKI–naïve patients (OR 4.08, 95% CI 2.55–6.53), with reduced activity post-ADC (OR 1.43, 95% CI 0.78–2.61). Zongertinib showed robust efficacy in previously treated TKD-mutant disease (OR 5.58, 95% CI 3.50–8.90) and retained post-ADC activity (OR 2.14, 95% CI 1.11–4.12). Grade ≥3 adverse events were significantly reduced with sevabertinib (HR 0.65, 95% CI 0.51–0.82) and zongertinib (HR 0.36, 95% CI 0.21–0.60). Treatment discontinuation was lower with sevabertinib (HR 0.12, 95% CI 0.05–0.28), and no interstitial lung disease was reported. Conclusions: Both selective HER2-targeted TKIs demonstrated significant efficacy, with sevabertinib showing broader activity in treatment-naïve and HER2-TKI–naïve patients and zongertinib exhibiting superior tolerability with retained post-ADC efficacy; overall risk of bias across included studies was low.

Comprehensive genomic landscape of osteosarcoma: Systematic review and analysis of 1,058 patients across 20 studies with therapeutic implications from the Fight Osteosarcoma Through European Research (FOSTER) Consortium.

10032 Background: Osteosarcoma exhibits profound genomic complexity, complicating biomarker discovery. Although advances in multi-omics profiling have improved biological understanding, genomic data remain fragmented across heterogeneous cohorts, and actionable alterations are rarely reported. Methods: A systematic review identified 20 studies published between 2005 and 2022, spanning heterogeneous sequencing technologies (whole-genome/exome/RNA sequencing, methylome, and targeted gene panels) and reporting genetic drivers and/or potentially actionable mutations. Mutation data were manually extracted from the published results (e.g., tables, figures, oncoplots) and integrated into a binary Mutation Annotation Format - like matrix (1,041 samples, 471 genes) to provide a comprehensive overview of variants reported to date. Results: 1058 patients were included, with tissue derivation (primary, metastatic, recurrent) described in about 10% of the cases. 3816 germlines or somatic SNVs, CNVs or structural alterations were reported in 471 genes. TP53 (40%), RB1 (18%), and CDKN2A/B (17%) were the most frequently altered genes, alongside with recurrent changes in cell cycle regulators ( CCND family) and angiogenesis-related genes ( VEGFA ). Potentially actionable variants were less common: MYC (13%, all amplifications), CDK4 (10%), PDGFRA (8%); single agent activity against such targets is either lacking or not yet available. Potentially actionable epigenetic targets were rarely identified: TET2 (0.2%), IDH2 (0.3%), DNMT3A (0.7%). TCGA-based pathway analysis revealed consistent involvement of TP53, cell cycle, RTK-RAS, PI3K, and MYC signaling. Co-occurrences detected were TP53 with MAP2K4 , RICTOR , PTPRD and RB1 genes, and structural rearrangements affecting RTK-RAS and PI3K pathways. There was relative exclusivity between mutations of RB1 and CDK4 . Conclusions: The analysis identifies a small number of recurrently mutated genes and a large number of rarely affected, though potentially actionable, mutations, encoding proteins involved in cell surface, nuclear and epigenetic interactions. Lack of harmonization in data processing, mutation calling and definition of ‘over’ and ‘under’ expression, together with absent descriptions of tissue derivation hamper effective large scale analysis and phenotypic subgrouping. TP53 mutation co-occurrences such as RICTOR or RB1 were also identified, with potential therapeutic implications including WEE1 and mTOR inhibitors. Tumors with overactive CDK4/6 typically have functional RB1 and might be sensitive to CDK inhibitors. Harmonization of multi-omic methods and collaborative international analyses are essential to advance precision medicine in osteosarcoma and to inform future trials.

Validation and enhancement of the PROACCT model for predicting 30-day acute care events following outpatient systemic therapy using granular health care utilization variables.

e23243 Background: Acute care events within 30 days of outpatient systemic therapy (ACE30)are common, costly, and potentially preventable. Stein et al. (JOP, 2023) developed thePROACCT Model #2 using nine demographic and treatment variables, achieving apositive predictive value (PPV) of 0.23. Our prior work (He, ASCO 2024) demonstratedminimal improvement using advanced machine-learning methods with the same inputs.We hypothesized that incorporating granular pre-chemotherapy healthcare utilization,vital signs, and laboratory data would improve identification of patients at high risk forACE30. Methods: We analyzed outpatient systemic therapy administrations among 12,231 uniqueadult patients treated at Orlando Health between February 2012 and April 2021. Theoriginal PROACCT Model #2 was validated in this cohort. We then evaluated 133candidate variables and developed enhanced models using 56 variables, includingdetailed acute care utilization history (prior hospitalizations with or without emergencydepartment [ED] visits, prior direct admissions, etc.), pre-chemotherapy vital signs, andlaboratory values. L1-penalized logistic regression, XGBoost, and neural networks weretrained using a 70/30 split. For comparability, patients in the top decile of predicted riskwere classified as high risk. Results: Validation of the PROACCT Model #2 achieved AUC 0.62, sensitivity 0.16,specificity 0.92, and PPV 0.37 in the high-risk decile. The enhanced L1-penalizedlogistic regression model demonstrated superior performance with AUC 0.68, sensitivity0.21, specificity 0.93, and PPV 0.47. Using identical risk thresholds, the enhancedmodel identified 172 ACE30 events among 367 high-risk administrations, comparedwith 135 events using the original model. The strongest predictors of ACE30 includedprior hospitalization with ED visits, prior ED visits without hospitalization, prior directadmissions, metastatic disease, and head and neck cancer, while endocrine therapyclass and breast cancer diagnoses were associated with lower risk. Conclusions: Incorporating granular healthcare utilization history substantiallyimproved precision for identifying patients at high risk for acute care events aftersystemic therapy. These findings suggest that prior acute care utilization captures clinicallymeaningful vulnerability beyond demographic and treatment variables, enabling moreefficient targeting of supportive interventions and care navigation resources. Futurestudies should evaluate whether utilization-informed risk stratification reduces avoidableacute care use.

Early toxicity and temporal mortality patterns following bispecific T-cell engager therapy: A real-world multicenter analysis.

e23336 Background: Bispecific T-cell engagers are increasingly used across hematologic malignancies and, more recently, solid tumors. Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are hallmark toxicities that typically occur early after treatment initiation, yet real-world data describing severe events and downstream outcomes across clinically relevant time windows remain limited. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network. Adult patients (≥18 years) with small cell carcinoma, B-cell non-Hodgkin lymphoma, multiple myeloma, or acute lymphoblastic leukemia who received at least one bispecific T-cell engager (tarlatamab, teclistamab, epcoritamab, mosunetuzumab, glofitamab, or blinatumomab) were included. The index date was defined as first bispecific exposure. Patients with myeloid malignancies, non–small cell lung cancer, selected solid tumors without approved bispecific therapies, or prior chimeric antigen receptor T-cell (CAR-T) therapy were excluded. Outcomes included all-cause mortality, grade ≥3 CRS, grade ≥3 ICANS, Tocilizumab use and early high-acuity supportive care utilization (ICU admission, vasopressors, mechanical ventilation, shock). Outcomes were assessed at 7-, 30-, and 90-day post-index. For supportive care outcomes, patients with the outcome prior to the time window were excluded to capture incident events. Results: A total of 3,642 patients were included. All-cause mortality occurred in 0.7% at 7 days, 3.5% at 30 days, and 9% at 90 days, corresponding to survival probabilities of 99.3%, 96.5%, and 91%, respectively. Severe CRS (grade ≥3) was infrequent and occurred predominantly early, with incidences of 0.5% at 7 days, 0.8% at 30 days, and 1.0% at 90 days. Similarly, severe ICANS (grade ≥3) occurred in 0.4% at 7 days, 0.9% at 30 days, and 1.3% at 90 days. Tocilizumab was administered in 6.7% at 7 days, 9.0% at 30 days, and 9.8% at 90 days. Incident high-acuity supportive care utilization was observed in 4.3% at 7 days, 9.8% at 30 days, and 17.0% at 90 days among patients at risk, whereas hospitalization status was common and reported at 53.0%, 58.4%, and 61.9%, respectively. Conclusions: In this large real-world cohort of patients treated with bispecific T-cell engagers, coded severe CRS and ICANS events were uncommon and plateaued early, whereas mortality and healthcare utilization continued to accrue over time. Given the known under-capture of immune-related toxicity in real-world data, these findings suggest that ongoing risk over follow-up likely reflects a combination of treatment-related toxicity and underlying disease progression, highlighting the need for standardized toxicity ascertainment and strategies to identify patients at highest risk for early clinical deterioration.

Pan-cancer prevalence, molecular landscape, and prognostic impact of <i>CCNE1</i> amplification across 76,046 malignancies.

3125 Background: CCNE1 amplification ( CCNE1 amp) is an oncogenic driver that confers synthetic-lethal vulnerability to agents targeting cell cycle and replication stress. While CCNE1 amp is a poor prognostic marker in some solid tumor types, pan-tumor data are limited. We used the MSK Clinical Sequencing Cohort to characterize its pan-tumor prevalence, molecular landscape, and prognostic impact. Methods: We analyzed data from consented patients with solid tumors sequenced by MSK-IMPACT between July 2014 and August 2025. CCNE1 amp was defined as an amplification or gain per clinical report. Tumor-level prevalence was calculated and reported for histologies with ≥10 CCNE1amp tumors. Co-occurring alterations were evaluated using the first CCNE1 amp sample per tumor type in each patient, with Fisher’s exact test and Benjamini-Hochberg correction. Overall survival was measured from the date of first sequencing to death or last contact. Results: Among 76,046 tumors, the prevalence of CCNE1amp was 2.7% (n = 2,036). Our CCNE1 amp cohort comprised predominantly ovarian (21%, n=435), uterine (15%, n=301), non-small cell lung (11%, n=231), esophagogastric (10%, n=206), and breast cancers (8%, n=168). Prevalence rates were highest in uterine carcinosarcoma (25.6%); ovarian carcinosarcoma (20%); uterine serous carcinoma (16.2%); high-grade serous ovarian carcinoma (15.4%); osteosarcoma (11.9%); gallbladder adenocarcinoma (9.7%); and esophageal adenocarcinoma (9.1%). Prevalence rates in breast cancer were 2.1% and in non-small cell lung cancer 2.6%. Among 67 patients with paired pre- and post-treatment samples of purity ≥30%, CCNE1 amp was reported in all samples in 42% of patients. The most frequently co-mutated genes were TP53 (87%), PIK3CA (12%), KRAS (8%), and RB1 (7%). Most common amplifications included the 19q neighbors CEBPA (31%), KMT2B (22%), and AKT2 (22%); as well as MYC (14%); and ERBB2 (13%). The most significant co-occurrences (q&lt;0.05) were TP53 mutations (OR 11.5) and MYC amplifications (OR 3.5); CCNE1amp was mutually exclusive with PTEN (OR 0.37) and KRAS mutations (OR 0.55). CCNE1amp samples had a higher median fraction of genome altered (median 0.35 vs. 0.12; p&lt;0.001). CCNE1 amp was associated with worsened overall survival in a multivariate Cox model stratified by cancer type and adjusted for age, stage and TP53 status (adjusted HR 1.25; 95% CI 1.17-1.33). Its adverse prognostic impact was more pronounced in TP53 wt (HR 1.62; 95% CI 1.38-1.91) vs. TP53 mut tumors (HR 1.19; 95% CI 1.11-1.27; p for interaction &lt;0.001). Conclusions: CCNE1 amplification defines a pan-cancer genomic subset associated with poor prognosis, genomic instability, and few co-occurring actionable alterations, supporting its relevance as a therapeutic target. Discordance between paired samples suggests that a single negative biopsy may not rule out CCNE1amp.

Body mass index–stratified outcomes with first-line immunotherapy in metastatic RCC: A real-world analysis.

e16507 Background: Obesity is a known risk factor for renal cell carcinoma (RCC) yet paradoxically has been linked to better survival once the disease develops. This “obesity paradox” has been described in patients receiving immune checkpoint inhibitors (ICIs), though data in RCC remain limited. Methods: We conducted a retrospective cohort study using TriNetX, including patients diagnosed after January 2015. Inclusion criteria were adult patients with metastatic RCC, a recorded baseline body mass index (BMI) within six months of diagnosis, and receipt of first-line ICI therapy (nivolumab, ipilimumab, or pembrolizumab) within six months of diagnosis. Patients were stratified into two groups based on BMI (≥25 kg/m² vs 18.5– &lt; 25 kg/m²). To reduce confounding, 1:1 propensity score matching was performed using demographic characteristics, comorbidities, and baseline hemoglobin, LDH, and albumin. Outcomes included all-cause mortality and healthcare utilization (emergency department [ED] visits, hospitalizations, and ICU admissions). In subgroup analyses, the BMI ≥25 kg/m² cohort was further stratified into overweight (25–29.9 kg/m²) and obese (≥30 kg/m²) groups. Effect estimates are reported as hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 64,160 patients with metastatic RCC, 2,471 met inclusion criteria in the BMI ≥25 kg/m² group and 1,623 in the BMI 18.5– &lt; 25 kg/m² group. After matching, 1,390 patients were included in each cohort. Median follow-up was 12 months in both groups; mean age at ICI initiation was 65 years, and 73% were male. Patients with BMI ≥25 kg/m² had lower 1-year all-cause mortality compared with those with BMI 18.5– &lt; 25 kg/m² (31% vs. 35%; HR 0.86, 95% CI 0.75–0.99). At 3 years, mortality remained numerically lower in the higher-BMI group (50% vs. 53%), although this difference did not reach statistical significance (HR 0.90, 95% CI 0.80–1.01). Rates of emergency department visits, hospitalizations, and ICU admissions were similar between groups at both 1 and 3 years. In subgroup analyses among patients with BMI ≥25 kg/m², those with obesity (BMI ≥30 kg/m²) had lower all-cause mortality than overweight patients (BMI 25–29.9 kg/m²), with reduced 1-year mortality (27% vs. 32%; HR 0.82, 95% CI 0.70–0.96) and reduced 3-year mortality (HR 0.87, 95% CI 0.76–0.97). Healthcare utilization outcomes were comparable between these subgroups. Conclusions: In this matched real-world cohort of ICIs-treated metastatic RCC, higher BMI was associated with lower 1-year mortality, though this effect was not maintained at 3 years. Among patients with BMI ≥25 kg/m², obesity was associated with better survival than overweight status. Healthcare utilization was similar across BMI groups. These findings are hypothesis-generating and suggest that body composition and metabolic–inflammatory factors may influence outcomes. Future studies should address these factors.

Outcomes and factors associated with first line chemoimmunotherapy (ChemoIO) or immunotherapy (IO) in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).

e18095 Background: IO alone or with chemotherapy, is standard first-line therapy for recurrent/metastatic HNSCC. This study investigates real-world outcomes and clinical factors associated with survival in patients (pts) receiving first-line chemoIO or IO alone. Methods: Pts with recurrent/metastatic HNSCC treated with first-line IO +/- chemotherapy between 2013-2024 were included in this IRB approved retrospective study. Nasopharyngeal and salivary gland cancers were excluded. Progression free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods and compared using log-rank test. Cox proportional hazards regression was used to identify factors associated with OS. Results: The cohort comprised 267 pts with median age 65 (range 28-98), and 215 (80.5%) male. Of these, 210 (78.7%) had distant metastatic disease and 102 (38.2%) were platinum refractory. Most received IO alone (215, 80.5%). Median follow up was 10 mos (0-121). Median PFS for the cohort was 4.3 mos, with longer PFS in pts receiving chemoIO (6.6 vs. 3.8 mos; p = 0.14). PD-L1 status was available for 181 (67.8%) of the pts. Median PFS stratified by PD-L1 was similar: 6.6 (CPS &lt;1), 4.2 (CPS 1–19), and 5.6 mos (CPS ≥20; p = 0.04). Pts with bony disease had significantly worse PFS compared to those with either visceral disease alone or locoregional disease (mPFS 2.6 vs. 5.1 vs 6.6 mos; p&lt;0.05). Median OS was longer in pts receiving chemoIO than IO alone; 13.9 vs. 10.0 mos (p = 0.06). Median OS stratified by PD-L1 was similar: 12.5 (CPS &lt;1,); 12.8 (CPS 1–19), 14.2 mos (CPS ≥20) (p = 0.59). Pts with bony and visceral disease had significantly worse OS compared to those with visceral disease alone or locoregional disease (mOS 4.5 vs. 11.1 vs. 13.8 mos; p&lt;0.05)Clinical factors associated with worse OS on UVA included platinum refractory at time of treatment start, [HR 1.59, 95%CI 1.20-2.08]; presence of bony and visceral disease compared to locoregional [HR 1.64, 1.06-2.54] or visceral disease only [HR 1.94, 1.34-2.81]; extensive metastatic burden (≥6 metastases vs. ≤5 or locoregional disease) [HR 1.46, 1.11-1.93]; and higher platelets [HR 1.01, 1.001-1.003 (p&lt;0.05 for all). Higher KPS was associated with better OS [HR 0.96, 0.94-0.97]. On multivariable analysis, lower KPS [HR 1.05, 1.03–1.06], platinum-refractory disease [HR 1.72, 1.28-2.33], higher baseline platelet count [HR 1.002, 1.001–1.003], and extensive metastatic burden [HR 1.52, 1.12-2.08] were independently associated with worse OS (p&lt;0.05 for all). Conclusions: In this real-world cohort, first-line chemoIO or IO demonstrated outcomes consistent with KEYNOTE 048 with trends toward improved PFS and OS in chemoIO. Performance status and disease burden were key determinants of survival. Further studies are needed to refine biomarkers and pt selection for IO alone in recurrent/metastatic HNSCC.

Pre-progression discontinuation and off-treatment progression-free interval after enfortumab vedotin–based therapy among patients with clinical benefit in advanced urothelial carcinoma: A single-institution experience.

e16593 Background: In routine practice, enfortumab vedotin (EV) ± pembrolizumab (EVP) may be discontinued before progression due to toxicity, cost, or patient preference. We quantified (1) the frequency and reasons for pre-progression discontinuation (PPD) among patients with clinical benefit and (2) off-treatment progression-free interval (OT-PFI) after stopping, including descriptive EV vs EVP comparisons where feasible. Methods: Single-center retrospective cohort of advanced urothelial carcinoma treated with EV or EVP. Clinical benefit (CB) was best response CR/PR/SD on the EV/EVP-containing line. PPD was any recorded non-progression discontinuation reason (toxicity, cost, patient decision, including EV-component discontinuation within EVP). OT-PFI was measured from EV/EVP end date to PD or death, censored at last follow-up (Kaplan–Meier). EV vs EVP results are descriptive. Results: Among 101 EV/EVP-treated patients, 81 achieved CB (EV 39; EVP 42). PPD occurred in 31/81 (38.3%), higher in EVP than EV (20/42 [47.6%] vs 11/39 [28.2%]). PPD reasons (as % of CB population) were toxicity 17/81 (21.0%; neuropathy 11, skin toxicity 3, pneumonitis 2, general weakness 1; EVP included EV-component discontinuation n = 3), cost 6/81 (7.4%), and patient decision 8/81 (9.9%). Deep response (CR) was more frequent in PPD vs ongoing/until PD (6/31 [19.4%] vs 2/50 [4.0%]). Median cycles (available data) were lower in PPD vs ongoing/until PD: overall 5 (n = 16) vs 6 (n = 33); EV 3 (n = 7) vs 5 (n = 21); EVP 5 (n = 9) vs 7 (n = 12). Subsequent systemic therapy after the EV/EVP line was initiated in 1/31 (3.2%) in PPD vs 21/50 (42.0%) in ongoing/until PD (EV: 1/11 vs 13/28; EVP: 0/20 vs 8/22). OT-PFI was evaluable in 16/31 PPD patients with documented end dates (EV 7; EVP 9; 2 events). Six-month OT-PFI was 59.3% overall (EV 75.0%; EVP 66.7%); median OT-PFI was not reached. Conclusions: In real-world practice, more than one-third of CB patients had recorded discontinuation of EV-based therapy before progression, most commonly due to toxicity. In the evaluable subset, OT-PFI after stopping was frequently prolonged, suggesting that a drug-free interval may be feasible in selected responders. EV vs EVP comparisons are exploratory due to limited events and incomplete stop-date documentation.

A phase II study of amivantamab hyaluronidase in <i>MET</i> amplification–positive stage IV or recurrent non–small cell lung cancer (Lung-MAP Sub-Study).

TPS8680 Background: MET amplification is a known oncogenic driver in non-small cell lung cancer (NSCLC), estimated to occur in approximately 3-4% of non-squamous (nsq) and squamous (sq) cases. While targeted therapies such as tyrosine kinase inhibitors (TKIs) have demonstrated activity in this population, with objective response rates (ORR) approximating 30%, there is a need for novel therapeutic approaches, particularly for patients who have progressed on standard systemic therapies. Amivantamab hyaluronidase is a fully human bispecific antibody targeting EGFR and MET co-formulated with recombinant human hyaluronidase (rHuPH20) for subcutaneous administration. The mechanism of action involves the inhibition of EGFR and MET signaling, receptor degradation, and the induction of antibody-dependent cellular cytotoxicity. S1900J is evaluating the efficacy of this subcutaneous formulation in specific histological cohorts. Methods: S1900J is a 2-stage, single arm phase II biomarker-driven Lung-MAP sub-study. The study includes 2 cohorts of Stage IV or recurrent NSCLC, based on histology (non-squamous and squamous NSCLC). Biomarker eligibility requires documentation of MET amplification as primary driver via tissue or ctDNA NGS. Participants must have received at least one prior line of systemic therapy; notably, patients who have received prior MET TKI therapy (e.g., crizotinib, capmatinib) or harboring other actionable alterations are excluded. Participants receive amivantamab hyaluronidase via subcutaneous injection weekly during Cycle 1 (Days 1, 8, 15, 22) and every 2 weeks thereafter (Days 1, 15). Dosing is weight-based: 1,600 mg amivantamab/20,000 units hyaluronidase for participants &lt; 80 kg, and 2,240 mg amivantamab/28,000 units hyaluronidase for patients ≥80 kg. The primary endpoint is response. with a goal of 40 evaluable participants per cohort. The study design has 90% power to rule out a 15% ORR at the 1-sided 5% level, if the true ORR is 35%. Secondary objectives include progression-free survival, duration of response, and response rates in the subset with MET amplification by FoundationOne CDx assays. Correlative studies of interest include the evaluation of concordance between tissue-based and liquid biopsy (ctDNA) next-generation sequencing for the detection of MET amplification. S1900J opened to accrual on 9/27/2024 and is actively enrolling patients. Clinical trial information: NCT06116682 .

Breast cancer survivorship program: Assessing and addressing patients’ needs.

e13795 Background: Breast cancer (BC) survivors face diverse physical and psychological challenges, often due to treatment (Tx) side effects and possible premature menopause. A structured survivorship program may enable prompt need detection, health education, and provision of recommendations to address patients’ concerns and offer comprehensive, personalized care. This study documented survivors’ symptoms and needs, and their oncologist’s recommendations in a recently-implemented BC survivorship program in Mexico. Methods: Patients with BC who have completed chemotherapy (CT) or are receiving endocrine therapy (ET) at Hospital Zambrano Hellion TecSalud are invited to the survivorship program. In the waiting room, they answer the Menopause Rating Scale (MRS) (score 0-none to 4-very severe) and 2 questions exploring lymphedema symptoms and interest in nutritional advice. During their consultation, the oncologist reviews their results and offers education materials, Tx and/or practical recommendations, or specialty referrals accordingly. Results: From Sep-Dec 2025, 127 survivors had received care through the program. Their median age was 53 years (IQR 48-61). Clinical stage distribution was: 0 (5%), I (39%), II (37%), III (15%), IV (4%). Most patients had undergone mastectomy (53%), sentinel lymph node biopsy (75%), radiotherapy (74%), CT (57%), and were receiving ET (80%). Most (73%) survivors had at least 1 concern, mainly regarding nutrition/weight control advice (46%), vaginal dryness (30%), and arthralgias (23%). Oncologists’ most frequently recommended physical exercise (42%), vaginal lubricants (29%), and antidepressants (27%). No associations were found between the type of cancer Tx received and having particular needs or experiencing multiple needs. Conclusions: This initial assessment of a BC survivorship program confirms a high prevalence of unmet needs, particularly related to lifestyle and menopausal health, irrespective of patients' prior cancer Tx. These findings support the value of dedicated survivorship care with systematic assessments to enable oncologists to provide timely, personalized recommendations to address the ongoing needs of BC survivors. Survivors’ needs and provided recommendations. N=127 (%) Score ≥3 Medical Tx Recommendation Referral Hot flushes 9 (7) 16 (13) Non-pharmacological Tx: 1 (1) Gynecology: 2 (2) Insomnia 26 (21) 31 (24) Exercise: 2 (2)Sleep hygiene: 1 (1)Mindfulness: 1 (1) Psychology: 4 (3) Depressive mood, irritability, or anxiety 18 (14) 13 (10) Mindfulness: 1 (1) Psychology: 6 (5) Fatigue 19 (15) - Exercise: 11 (9)Mindfulness: 1 (1) Psychology: 6 (5) Sexual problems 26 (21) - - Sexology counseling: 4 (3) Vaginal dryness 38 (30) 37 (29) - Gynecology: 12 (9) Arthralgias 29 (23) 12 (9) - Acupuncture: 5 (4) Lymphedema 10 (8) - Compression sleeve: 1 (1) Rehabilitation: 4 (3) Nutrition advice (Yes/No) Yes: 58 (46) - Exercise: 32 (25) Nutrition/Endocrinology: 8 (6)

Baseline skeletal muscle index as an independent prognostic factor in locally advanced head and neck squamous cell carcinoma: A post hoc analysis of the REACH trial.

6088 Background: The prognosis for locally advanced squamous cell carcinoma of the head and neck (LAHNSCC) is heterogeneous. A low skeletal muscle mass index (SMI) assessed by computed tomography reflects sarcopenia and is associated with a poor prognosis. However, evidence-based data on HNSCC remain scarce. Moreover, the prognostic value of SMI in patients treated with radiotherapy combined with different systemic treatments remains unclear. Methods: This is a post hoc analysis of the REACH trial (NCT02999087), conducted between 2017 and 2020, which treated LAHNSCC in two cohorts. Patients eligible (fit) for cisplatin were randomized between radiotherapy with cisplatin and radiotherapy with cetuximab-avelumab; those ineligible for cisplatin (unfit) were randomized between radiotherapy with cetuximab and radiotherapy with cetuximab-avelumab. Baseline SMI was assessed on a C3 vertebral slice using radiotherapy planning computed tomography and analyzed as a continuous variable. Associations of SMI with disease-free survival (DFS) and overall survival (OS) were assessed using Cox proportional hazards models, with multivariable adjustment for performance status, age, stage, p16 status, treatment and cisplatin fit/unfit status. Model performance was internally validated using bootstrapping. Results: Among the 694 patients included in REACH, SMI analysis was available for 623 patients (90%). Only the analyses performed for the 507 men are presented. Among them, 312 (62%) were eligible for cisplatin and 195 (38%) were ineligible. Median SMI was 47 (range 32-66) kg/m 2 , with no difference according to the fit/unfit status and treatment received. A higher SMI was observed in patients with ECOG 0 (vs 1, p&lt;0.0001), younger patients (&lt;65y, p=0.01) but not according to tumor stage (III vs IV). There was a linear relationship between SMI and DFS with a better DFS as SMI rises in both univariate (HR 0.81 every 5 SMI units, p&lt;0.0001) and multivariate analyses (HR 0.88/5 units, p=0.013). Comparable results were observed for OS, with a significant linear relationship between SMI and OS (HR of death 0.76/5 units, p&lt;0.0001, univariate analysis; HR 0.86/5 units, p=0.015, multivariate analysis). Other independent factors associated with improved OS were a p16+ oropharynx tumor, ECOG 0 (vs 1), Stage III tumor (vs IV) and eligibility for cisplatin. The prognostic impact of SMI was consistent across fit/unfit cohorts and treatment arms, with no significant interaction detected. Conclusions: Baseline SMI determined on C3 is a strong and independent prognostic factor for DFS and OS in patients with LAHNSCC treated with radiotherapy with cisplatin, radiotherapy with cetuximab, or radiotherapy with cetuximab and avelumab. The association between SMI and clinical outcomes is linear, arguing against the use of arbitrary prognostic thresholds for SMI.

Utilization of a psychosocial oncology consult service pre-post a one-session educational intervention.

e24115 Background: Psychosocial oncology consultation services (POCS) address the psychosocial needs of hospitalized patients with cancer and are associated with improved outcomes; however, utilization and referral appropriateness remain variable. Provider knowledge gaps and lack of familiarity with referral indications may contribute to underutilization or non-specific consults. This study evaluated whether a one-time educational intervention was associated with changes in provider knowledge and utilization patterns of POCS. Methods: A single-site educational intervention focused on indications for POCS was delivered to Internal Medicine residents and attending physicians at an urban academic medical center. Anonymous surveys assessed providers’ familiarity and intent to utilize POCS pre- and post-intervention. In parallel, consult data were extracted for the 3 months pre- and post-intervention focused on units staffed by Internal Medicine. Consultation reasons were coded as one or more of the following: (1) Psychiatric, (2) General Coping, (3) Specific Cancer-related Coping, (4) Care Engagement, and (5) Non-specific/Other. Primary outcomes were change in provider knowledge, consult volume and specificity. Pre–post differences were analyzed using Chi-square and Mann Whitney U tests. Results: Surveys were completed by 24 providers pre-intervention and 15 post-intervention, the majority were residents. Prior to educational intervention, 46% were not aware of the POCS. Following intervention, providers demonstrated increased familiarity with POCS (p &lt; .001) and greater intention to consult (p &lt; .001)During the pre-intervention period, 70 consults were placed [M age = 58.3 (SD = 14) 29% Black, 19% Hispanic, 66% female], compared with 83 post-intervention [M age = 61.3 (SD = 14%), 36% Black, 20% Hispanic, 68% female], representing an 18.6% increase in consult volume. Table 1 shows pre-post changes in consultation reason proportions. There was a non-statistically significant increase in consults for general and specific cancer-related coping concerns. Conclusions: A one-time educational intervention was associated with improvements in familiarity with and intention to consult POCS, as well increased consult volume. While not statistically significant, there was a higher proportion of appropriate and cancer-specific consult reasons post-intervention. While educational intervention may feasibly improve familiarity and utilization of POCS, a one-time intervention may have limited reach. Future work could evaluate the benefits of a “higher dose” educational intervention. Pre- and post-intervention consultation reasons. Consultation reason Pre % (n) Post % (n) p-value Psychiatric 37.1 (26) 24.1 (20) .973 General Coping 24.3 (17) 48.2 (40) .994 Cancer-related Coping 47.1 (33) 59 (49) .580 Care Engagement 14.3 (10) 10.8 (9) .357 Non-specific/Other 7.1 (5) 14.5 (12) .291

Association between low muscle mass assessed by bioelectrical impedance analysis and clinical outcomes in hospitalized cancer patients.

11034 Background: Low muscle mass is an independent prognostic marker associated with increased clinical risk, functional impairment, and mortality in patients with cancer. Conventional indicators such as body mass index (BMI) may fail to identify individuals at nutritional and functional risk. Bioelectrical impedance analysis (BIA) offers a feasible bedside method for body composition assessment, particularly in resource-constrained hospital settings. This study aimed to evaluate body composition using BIA, determine the prevalence of low muscle mass, and examine its association with clinical, laboratory, and functional parameters in hospitalized oncology patients. Methods: This observational study included 104 adult cancer patients admitted to a tertiary public hospital between January and October 2025. Baseline assessments at hospital admission included BMI, skeletal muscle mass index (SMI), appendicular muscle index, phase angle, fat mass percentage, handgrip strength (HGS), calf circumference (CC), urea-to-creatinine ratio, length of hospital stay, and in-hospital outcome (discharge or death). Low muscle mass was defined according to established cutoffs for SMI and appendicular muscle index. Comparisons were performed between patients with and without low muscle mass, and correlations between appendicular muscle index and functional and nutritional parameters were analyzed. Results: Low muscle mass was identified in 29.8% of patients at admission. Compared with patients without low muscle mass, those affected had significantly lower BMI (23.3 vs 27.6 kg/m², p=0.001), appendicular muscle index (6.20 vs 7.61, p&lt;0.001), phase angle (3.6° vs 5.1°, p&lt;0.001), total muscle mass (25.1 vs 29.4 kg, p&lt;0.001), HGS (30.0 vs 37.0 kgf, p=0.041), and CC (32.5 vs 37.0 cm, p&lt;0.001). Length of hospital stay did not differ significantly between groups. In-hospital mortality was higher among patients with low muscle mass (18.5% vs 7.0%), although this difference did not reach statistical significance (p=0.133). Appendicular muscle index showed moderate to strong positive correlations with BMI, phase angle, HGS, CC, and SMI. Conclusions: BIA proved to be a feasible and informative tool for identifying low muscle mass and functional impairment in hospitalized cancer patients. Appendicular muscle index and SMI were superior to BMI in detecting patients at increased nutritional and functional risk. Given its low cost and bedside applicability, BIA represents a valuable strategy for early risk stratification and supportive care planning in resource-limited oncology settings.

Pigment mediated biosynthesis of crystalline silver nanostructures: Structural characterization and enhanced multifunctional bioactivity

Enabling Sodium‐Ion Batteries Over 180 Wh/kg via Organic‐Salt‐Driven Sodium Replenishment

ABSTRACT Compensating for the substantial sodium ion deficit inherent in P2‐type layered sodium metal oxide cathodes represents a promising strategy for advancing high‐performance sodium‐ion batteries. However, current approaches still fail to reconcile the trade‐off between pre‐sodiation dosage and energy density. Herein, we introduce a soluble sodium compensator, sodium tetraphenylborate (NaBPh 4 ), rationally discovered through a combined unsupervised and supervised machine‐learning screening of boron‑centered anions, which can release sufficient sodium ions to replenish the entire sodium deficit of P2‐type oxides. In P2‐Na 0.67 Ni 0.08 Ti 0.12 Mn 0.8 O 2 || hard carbon full cells, this compensator endows the full cell with an ultra‐long cycle life exceeding 3700 cycles, while a 5 Ah pouch cell achieves a remarkable energy density of 184 Wh kg −1 at 0.1C. This work establishes a versatile strategy for addressing high sodium‐deficiency systems, thereby expanding the research scope and practical application potential of sodium‐ion full cells.

From Bio‐Interface Materials to Neural Integration: The Next‐Generation Brain–Machine Interfaces Powered by Hydrogels

ABSTRACT Brain–machine interfaces (BMIs), which serve as revolutionary tools for neural recording, modulation, and rehabilitation, are highly dependent on the biocompatibility and mechanical suitability of their electrode materials. Although traditional metal electrodes possess excellent conductivity, their inherent rigidity causes a substantial mechanical mismatch with soft neural tissue, leading to chronic inflammatory responses and poor long‐term stability. The emergence of hydrogel electrodes has provided a breakthrough solution to this fundamental limitation. Hydrogels, characterized by their softness, high ionic conductivity, and tissue‐like compliance, offer a viable solution to mitigate these issues. This review systematically explores the material properties of hydrogel‐integrated BMIs, providing an in‐depth investigation of key hydrogel characteristics, including toughness, adhesion, conductivity, and biocompatibility. Additionally, hydrogel‐based BMIs are categorized into non‐invasive and invasive systems, each defined by its characteristic operational principles and signal‐acquisition mechanisms. The study further reviews critical issues, including surgical implantation strategies, multimodal data fusion, integration of artificial intelligence, as well as system integration and clinical translation. From a therapeutic perspective, this work highlights the application of BMIs in treating neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, neuropathic pain, and depression. Furthermore, this review critically examines the persistent challenges faced by hydrogel‐based BMIs and proposes innovative strategies for future development. Ultimately, it outlines a developmental roadmap for next‐generation hydrogel‐based biotherapeutic technologies aimed at achieving high‐fidelity, stable and clinically translatable BMI systems.