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Real-world experience with neoadjuvant chemoimmunotherapy in resectable NSCLC: A single academic institution experience.

e20074 Background: Neoadjuvant chemoimmunotherapy has led to significant improvements in outcomes for patients with resectable non-small cell lung cancer (NSCLC), resulting in higher rates of pathological response and improved survival, especially in stage IIIRegarding this, we designed our real-world analysis to investigate outcomes in sigle institution center. Methods: We conducted a single-center, retrospective, real-world analysis of patients with resectable NSCLC who received neoadjuvant chemoimmunotherapy, focusing on pathological response and nodal downstaging. Results: From March 2023 to December 2025, 59 patients with resectable NSCLC completed two to four cycles of neoadjuvant chemoimmunotherapy before surgical evaluation. The median age was 66 years (range, 59-70), and 54% were male. The objective response rate was 97% per RECIST 1.1. Most patients were stage III (IIIA, 53%; IIIB, 24%). Adenocarcinoma was present in 64% (38/59), and squamous cell carcinoma in 29% (17/59). The median time to surgery was 9 weeks (range, 7-12). Pathological assessment of the primary tumor showed complete pathological response in 43% and major pathological response in another 18%. Notably, 15 patients (30%) showed a complete pathological response in both the primary tumor and lymph nodes. Among those with baseline lymph node involvement, 58% experienced nodal downstaging after neoadjuvant chemoimmunotherapy, with 50% achieving complete nodal clearance (ypN0). Additionally, 38% of cN2 patients were downstaged to ypN0. Grade 3 toxicities occurred in 7% of patients (4/59). Conclusions: Pathological response and nodal downstaging are being established as clinically meaningful surrogates for long-term outcomes in patients with resectable NSCLC treated with neoadjuvant chemoimmunotherapy. In our real-world cohort, this approach resulted in high rates of both pathological response and nodal downstaging. Further follow – up is needed to investigate tese finding on event-free survival and overall survival.

A pilot study of autologous tumor-infiltrating lymphocytes (LN-145) in adult patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma.

e23566 Background: Advanced undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLS) are difficult to treat soft tissue sarcomas with response rates to first line systemic therapy between 10-30%. However, both UPS and DDLPS have been shown to have measurable tumor infiltrating lymphocyte (TIL) populations. LN-144 (lifileucel), an autologous TIL product derived from unresectable or metastatic melanoma, was shown to have an overall response rate (ORR) of 36% in heavily pretreated melanoma patients with a median DOR of 19.7 months. We hypothesized that generation and infusion of LN-145, an autologous TIL product from non-melanoma solid tumors, in this case UPS and DDLPS, would be both safe and feasible. Methods: NCT05607095 is a single center multi-cohort pilot trial with Cohort 2 enrolling patients with metastatic or unresectable UPS or DDLS to undergo autologous TIL therapy with LN-145. Eligible patients had to receive at least 1 prior line of systemic therapy, a lesion at least 1.5 cm in size available for TIL harvest, and adequate organ function and performance status (ECOG 0-1). After surgical excision of suitable tumor for TIL expansion, successful LN-145 product generation was determined by characteristics that meet pre-specified criteria in the LN-145 IND. Patients then underwent nonmyeloablative lymphodepletion with cyclophosphamide (60 mg/kg x 2 doses) and fludarabine (25 mg/m 2 x 5 doses). LN-145 was then infused and expanded with intravenous interleukin 2 (600,000 IU/kg up to 6 doses). Primary endpoints of the trial were feasibility, defined as ³6 of 10 harvested pts undergoing LN-145 therapy, and safety, defined by the incidence of Grade ³3 adverse events (AE) as measured by CTCAE v5.0. Key secondary endpoints included estimated LN-145 manufacture rates and efficacy (ORR) utilizing RECIST 1.1. Exploratory endpoints include persistence of LN-145 cells and immune correlates in tissue and peripheral blood and their potential association with objective response and toxicity. Safety and efficacy measures will be summarized using point estimates and a Clopper Pearson exact confidence interval will be used. The final results of the primary feasibility and safety endpoints and secondary feasibility endpoint for the first 10 enrolled patients as well as and preliminary secondary efficacy and exploratory correlative studies through week 12 for 7 treated patients will be reported as late-breaking abstract after data lock on March 1, 2026. Clinical trial information: NCT05607095 .

National trends in inpatient incidence of head and neck cancer and anatomic subsites in the United States, 2018 to 2022.

e23233 Background: Inpatient hospitalizations for head and neck cancer (HNC) reflect severe disease, treatment-related complications, and advanced oncologic care. While population-based cancer incidence is well described, national trends in inpatient HNC incidence, particularly by anatomic subsite across the COVID-19 era, remain poorly characterized. Methods: A survey-weighted analysis of the Healthcare Cost and Utilization Project National Inpatient Sample (NIS), 2018 to 2022, was performed to generate nationally representative estimates. Hospitalizations with a principal diagnosis of HNC were identified using ICD-10-CM codes C00 to C06 (oral cavity), C07 to C08 (salivary gland), C09 to C10 (oropharynx), C11 (nasopharynx), C12 to C13 (hypopharynx), C30 to C31 (sinonasal), C32 (larynx), and C14 or C76.0 (other or ill-defined). Thyroid cancer (C73) was excluded. Inpatient incidence was defined as hospitalizations or discharges. Unweighted NIS counts and survey-weighted national estimates were reported by calendar year and anatomic subsite. Results: From 2018 to 2022, the NIS contained 33,204 unweighted HNC hospitalizations, corresponding to a weighted national estimate of 166,020 hospitalizations (95% CI 158,702 to 173,338). Annual weighted inpatient incidence remained stable, ranging from approximately 31,800 to 34,500 hospitalizations per year. Unweighted annual counts were 6,509 (2018), 6,805 (2019), 6,357 (2020), 6,636 (2021), and 6,897 (2022), with corresponding weighted estimates of 32,545, 34,025, 31,785, 33,180, and 34,485 hospitalizations. By subsite, oral cavity cancer represented the largest inpatient burden, accounting for 40.6% of unweighted cases and approximately 67,260 weighted hospitalizations. Laryngeal cancer was the second most common subsite (21.3% unweighted; approximately 35,145 weighted hospitalizations), followed by oropharyngeal cancer (13.5% unweighted; approximately 22,450 weighted hospitalizations). Less common subsites included salivary gland (6.9%), sinonasal (4.7%), hypopharyngeal (3.6%), nasopharyngeal (2.4%), and other or ill-defined HNC (7.1%). Across subsites, inpatient incidence patterns were generally stable over time, with a modest decline in 2020 followed by recovery in 2021 to 2022. This pattern was consistent for oral cavity, laryngeal, and oropharyngeal cancers. Conclusions: From 2018 to 2022, national inpatient incidence of head and neck cancer remained stable, with a transient decline during 2020 consistent with COVID-19–related healthcare disruption. Oral cavity and laryngeal cancers accounted for most inpatient HNC hospitalizations, highlighting their disproportionate inpatient burden. These findings provide contemporary national benchmarks for inpatient HNC incidence by subsite and emphasize the distinction between inpatient disease burden and population cancer incidence.

A phase 1, first-in-human (FIH), dose-escalation and dose-optimization study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of CBI-1214 T-cell engager in participants with advanced or metastatic microsatellite-stable (MSS)/microsatellite instability–low (MSI-L) colorectal cancer (CRC).

TPS3678 Background: Advanced and metastatic colorectal cancer (CRC) remains an area of significant unmet clinical need, particularly for patients with MSS/MSI-L tumors. In recent years, there have been several advancements in the treatment of solid tumors with T cell engagers. Our ATLAS scRNA-seq based discovery platform identified LY6G6D as a highly-specific tumor-associated antigen in advanced and metastatic CRC. CBI-1214, a CD3 bispecific T cell engager targeting LY6G6D with potent in vitro and in vivo activity even at low LY6G6D expression levels of ~300 copies/cell ( Yigit B et al, AACR 2025 ), is being developed for the treatment of patients with advanced or metastatic MSS/MSI-L CRC. Methods: This ongoing, open-label FIH study (CBI-1214-001) is being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of CBI-1214 and to determine the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) in participants with advanced or metastatic MSS/MSI-L CRC who have exhausted at least one prior line of systemic treatment and do not qualify for available targeted treatment options for actionable genomic alterations. Additional eligibility criteria include: at least 18 years of age, measurable disease (as defined by RECIST v1.1), available archival tumor tissue sample or a fresh tumor sample, ECOG PS 0 or 1, as well as adequate hematologic and organ functions. Patients whose CRC tumor tissues have been identified as dMMR or MSI-H are excluded. The study is conducted in two parts: Part 1 dose escalation, which starts with Part 1a as accelerated dose escalation, followed by Part 1b escalation, which is based on a modified toxicity probability interval (mTPI-2) design, and Part 2, which is designed as a randomized dose optimization study to select the final recommended phase 2 dose (RP2D). For both parts of the study, the study intervention is administered as monotherapy, given as an intravenous (IV) infusion, in 21-day treatment cycles, with a step-up option. After an up-to-28-day screening period, eligible patients receive study medication and are followed for their entire treatment period plus a follow-up period of approximately 90 days. The study is open for recruitment in the United States (NCT07321106). Clinical trial information: NCT07321106 .

Sennoside-functionalized ZrO₂ nanoparticles via Cassia angustifolia: Gram-selective antibacterial and anticancer nanoplatform with green synthesis

Negative Thermal Expansion Material‐Mediated Stress Engineering for Enhancing the Mechanical and Thermal Stability of Flexible Perovskite Solar Cells

ABSTRACT Flexible perovskite solar cells (FPSCs) offer lightweight, high‐efficiency, flexibility, residual stress from substrate‐perovskite thermal expansion coefficients (CTE) /lattice mismatch drives grain‐boundary cracking, defect rise, and delamination, limiting stability and efficiency gains. Substrates with a low CTE limit the lattice contraction of perovskites during the cooling process, which leads to the generation of tensile strain. In this paper, a strategy for regulating the CTE was developed by adding potassium pyrophosphate (KPP) to perovskite precursors. The P─O bonds in KPP not only form coordination bonds with Pb 2+ , but also form hydrogen bonds with FA + , reducing the defect state density and improving the stability of the device. More importantly, KPP with the characteristic of “thermal contraction and cold expansion” can significantly relieve the residual stress in the perovskite thin film. After 100 thermal cycles between 25°C and 100°C, its thermal cycling stability remains at 90%, while that of the control group is only 70.9%. Therefore, the optimized FPSCs achieved a power conversion efficiency (PCE) of 25.41%. In addition, unpackaged devices exhibit mechanical robustness at T 92 > 10 ,000 bending cycles (with a bending radius of 5 mm), operational stability at T 91 >1000 h.

Integrating interventional radiology into melanoma care: A quality improvement initiative to advance intratumoral therapies and multidisciplinary collaboration.

e23312 Background: Despite advances in immunotherapy (IO), management of advanced melanoma after anti-PD-1 progression remains challenging. Intratumoral IO and other interventional radiology (IR)-based approaches are emerging options for select patients, yet their integration into care is limited by inconsistent multidisciplinary collaboration and lack of standardized referral workflows. We implemented a quality improvement (QI) initiative to assess multidisciplinary practice gaps and improve integration of IR-based therapies in melanoma care. Methods: Healthcare professionals (HCPs) involved in melanoma care (N = 133) from 3 academic and 3 regionally tethered community oncology centers completed baseline surveys assessing familiarity with IR, multidisciplinary collaboration, referral workflows, and follow-up. Participating teams engaged in QI exchange sessions to review findings and develop site-specific action plans. Follow-up surveys from site representatives (N = 7) evaluated post-intervention practice changes. Results: At baseline, integration of IR in melanoma care was limited. Although tumor board (TB) participation varied across institutions, only 21% of HCPs reported inclusion of IR in these discussions, and 13% reported not participating in TBs at all. While 44% of HCPs regularly collaborated with IR, only 15% had standardized referral workflows. Top challenges working with IR included limited communication/collaboration between teams (43%), difficulty accessing IR services (41%), and lack of standardized referral workflows (31%). Post-referral communication was also inconsistent: 26% of HCPs reported uncertainty regarding treatments delivered or discussed with patients, 17% reported receiving no follow-up communication from IR, and only 20% reported having direct case-based discussions with IR. These challenges were attributed to unclear handoffs or division of responsibility (34%), patient confusion regarding care management (32%), and difficulty integrating IR recommendations into broader treatment plans (28%). To address these gaps, teams developed action plans focused on identifying IR champions to participate in TBs, standardizing referral workflows, and strengthening partnerships with local IR services. In follow-up surveys, teams reported improvements in confidence, multidisciplinary communication and collaboration, inclusion of IR in treatment planning, and access to IR services. Conclusions: This initiative identified persistent gaps integrating IR into melanoma care, particularly in multidisciplinary engagement, referral standardization, and post-referral communication. Implementation of action plans was associated with improvements in collaboration, confidence, and workflow integration, supporting coordinated delivery of intratumoral therapies.

Perioperative tislelizumab plus chemotherapy versus chemotherapy in MHC-II positive/MHC-II negative locally advanced GC/GEJC: A prospective, randomized, open-label, biomarker-driven, phase 2 trial.

2513 Background: Neoadjuvant immunotherapy achieves major pathologic response (mPR) in 40% of locally advanced gastric cancer (LAGC) patients. Tumor-specific MHC-II expression(tsMHC-II) has been linked to a better enhanced response to immune checkpoint inhibitor therapy. Herein, we conducted a prospective, randomized study to evaluate the effectiveness of chemotherapy combined with anti-PD-1 therapy versus chemotherapy alone as neoadjuvant treatment for tsMHC-II-positive LAGC patients. Methods: Patients with locally advanced GC/GEJC (cT3-4N+M0, CY0, P0) were enrolled according to tsMHC-II expression. Within each stratum, patients were subsequently randomized 1:1 to receive either tislelizumab combined with chemotherapy or chemotherapy alone, including Arm A (tsMHC-II-positive, chemotherapy + tislelizumab), Arm B (tsMHC-II-positive, chemotherapy), Arm C (tsMHC-II-negative, chemotherapy + tislelizumab), Arm D (tsMHC-II- negative, chemotherapy). For experimental group, patients received either 3 preoperative and 3 postoperative cycles of tislelizumab plus SOX/XELOX, followed by 11 cycles of tislelizumab. For control group, patients received either 3 preoperative and 3 postoperative cycles of SOX/XELOX. The primary endpoint was mPR rate (Arm A vs. Arm B). The key secondary endpoint was pCR rate (Arm A vs. Arm B). This clinical trial was registered at Clinicaltrial.gov (NCT06374901). Results: 136 patients (34 per arm) were enrolled from July 2024 to March 2025, with a median age of 65 years (range, 30-75), and 105 (76.64%) were male. The study achieved its primary endpoint. The results revealed that tsMHC-II-positive patients in the tislelizumab plus chemotherapy group achieved a greater proportion of mPR (61.8% versus 26.5%; P = 0.003) and pCR (32.4% versus 8.8%; P = 0.016) than did those in the chemotherapy group, which met a prespecified endpoint. In contrast, this benefit was absent in tsMHC-II-negative patients (mPR: 23.5% vs 26.5%, P = 0.886; pCR: 5.9% vs 8.8%, P = 0.642). There were no significant differences in treatment-related adverse reactions among each group. Conclusions: In conclusion, compared with perioperative chemotherapy alone, the addition of tislelizumab to a given chemotherapy regimen significantly increased the proportion of mPR and pCR in tsMHC-II-positive patients with GAC/GEJAC only, which revealed that tsMHC-II could be a biomarker to guide the selection of appropriate GAC/GEJAC patients for perioperative immunotherapy. Clinical trial information: NCT06374901 .

Early-onset colorectal cancer: 2-year analyses of Georgian cancer registry.

e15645 Background: Incidence of early onset colorectal cancer (EOCRC) is rising. Young patients (age < 50) are often diagnosed with stage IV and aggressive disease. Younger age in stage 3 CRC is negatively prognostic and associated with higher relapse rates and risk of death. Colorectal cancer screening is operating in Georgia since 2011 but referral is low. Incidence and characteristics of EOCRC have not been studied in Georgia. Methods: Data from Georgian cancer registry including 2022-2023 years were reviewed: these includes prospectively collected number of cases, age, sex, location, stage, pathology, grade, treatment. The study aimed to investigate clinicopathologic characteristics, treatment approaches, survival rates of EOCRC compared to Late onset colorectal cancer (LOCRC) (age > 50). Results: A total of 751 patients with CRC were identified. 59 (8%) were < 50 (median age 45). Left sided colon cancer was more common than right sided in both groups (37%vs27% in EOCRC; 62%vs27% in LOCRC). Stage III - IV was most frequent in both groups - stage III 44% in EOCRC vs 33% in LOCRC, stage IV 19% vs 24%. ( p value 0.0214). Adenocarcinomas (ADK) were 74% in EOCRC vs 75% in LOCRC. Rate of mucinous ADK was higher in EOCRC 10% vs 3% (p value 0.001). In both groups 20% were undefined carcinomas and 5% - rare histologies. Young adults with stage II/III rectal cancer had more radiation therapy (RT) (70% vs 19% for stage II; 62% vs 34% for stage III) and with stage II/III colon cancer had more chemotherapy (CT) than elderly (84% vs 41% for stage II; 69% vs 45% for stage III). Median survival was undefined for most comparisons except for EOCRC in Stage IV (24 months) HR- 0.66 (CI - 0.25 - 1.71 p-value 0.08). Data on molecular characteristics, recurrence, cause of death is not included in registry. Conclusions: This study showed that in Georgia patients with EOCRC have higher rates of mucinous ADK. Stage III is most common in EOCRC. Young patients with early-stage rectal cancer have more RT, those with early-stage colon cancer have more CT compared to elderly. Survival data is immature but median survival for stage IV EOCRC is low. Although with limitations this is the first evaluation of EOCRC from the Georgian cancer registry with potential to inform if incidence trends and patients characteristics follow the same patterns as Western countries.

Provider insights and utilization of psychiatric pharmacogenomics for patients with comorbid breast cancer and emotional distress.

e24103 Background: Patients with breast cancer frequently experience anxiety and depression, yet systemic delays in psychiatric care often leave oncologists to manage these conditions. The recent adoption of DPYD genotyping into NCCN guidelines for fluoropyrimidine safety marks a shift toward routine pharmacogenomic (PGx) integrations in oncology. This creates an opportunity to expand PGx to supportive care, specifically for psychiatric comorbidities. While Clinical Pharmacogenetics Implementation Consortium (CPIC) Level A guidelines exist for selective serotonin reuptake inhibitors (SSRIs), little is known about how oncology providers apply psychiatric PGx. This study examines provider perspectives on the utility and clinical decision-making implications of psychiatric PGx testing for patients with comorbid breast cancer and emotional distress. Methods: Breast oncology providers attended an educational seminar focused on the clinical application of PGx guidelines and a 13-gene neuropsychiatric panel (Tempus nP). Knowledge, attitude, and utilization of PGx tests were assessed at baseline (after the seminar). Surveys were also conducted following receipt of each subsequently ordered test for the impact of PGx testing on medication selection. Phenotypic findings from the PGx test reports were also summarized. Results: To date, 11 breast oncology providers (Female = 9, Male = 2; Years in practice = 12.3 ± 10.1) across two centers have enrolled. At baseline, most providers (n = 7, 64%) strongly agreed that PGx provides value in psychiatric medication selection, yet only (n = 3/10, 30%) strongly agreed that they were confident in their ability to understand PGx results independently. Across 25 post-test surveys, 96 % (n = 24) reported that PGx testing had at least a mild impact (increased confidence in medication choice), with 24% (n = 6) of those responses reporting substantial impact (a change in prescribed medication selection or dose). Phenotypic analysis of 35 PGx tests revealed the majority (n = 31, 89%) of patients possessed a non-normal result for CYP2D6, CYP2C19, or SLC6A4 gene, which are commonly involved in response to first-line SSRIs. Conclusions: These early findings indicate that many breast oncology providers report value in using PGx results to increase their confidence in psychiatric medication management, and genomic results highlight that variations in genes that impact response and side effect burden for first line antidepressants are common among individuals with breast cancer experiencing emotional distress. Ongoing data collection will further assess attitudes and perspectives on how psychiatric PGx can affect oncology provider medication decision-making and explore relationships between providers attitudes and genomic results.

Decoding cancers of unknown primary through genomics-driven clustering: A pan-cancer framework for prognostic classification using AACR GENIE data.

e15006 Background: Cancer of unknown primary (CUP) is a heterogeneous metastatic entity lacking an identifiable tissue of origin, limiting evidence-based therapy. Leveraging large-scale genomic data, machine-learning approaches can stratify CUP into biologically informative subgroups. Methods: Using AACR GENIE data, we implemented a machine-learning framework to stratify tumors based solely on genomics. Unsupervised k-modes clustering was applied to single-nucleotide variant (SNV) and copy-number alteration (CNA) profiles from tumors with known primary sites (reference, REF; n = 52,289) to identify molecular subgroups, supported by t-SNE for visualization. A supervised Random Forest classifier trained on REF-derived labels assigned CUP samples (n = 1,637) to these clusters which were evaluated for survival associations. Results: Four distinct molecular clusters were identified in the REF dataset. Cluster 1 (n = 2,376; favorable prognosis) was enriched for APC, PIK3CA, and KRAS mutations, consistent with colorectal- and endometrial-associated biology. Cluster 2 (n = 6,587; poor prognosis) exhibited KRAS- and TP53-driven alterations with frequent SMAD4 mutations, reflective of aggressive pancreatic- and NSCLC-like profiles. Cluster 3 (n = 18,473; intermediate prognosis) showed pervasive TP53 mutations with recurrent EGFR and ERBB2 amplifications. Cluster 4 (n = 24,853; favorable prognosis) displayed wild-type and copy-number–neutral states, with selective enrichment of targetable alterations (VHL, GATA3, SPOP, BRAF, NRAS, CTNNB1). CUP samples exhibited similar overall survival trends to matched REF clusters, albeit with uniformly shorter median survival. Conclusions: This hybrid unsupervised–supervised approach provides a genomics-driven framework for CUP stratification, identifying biologically informative subgroups that may improve prognostication and support treatment decisions independent of tissue-of-origin prediction. Keywords: machine learning, genomics, cancer of unknown primary, precision oncology.

Early implementation of a lung cancer screening program in a safety-net health system.

e22524 Background: Lung cancer screening (LCS) with low-dose CT reduces lung cancer mortality but remains underutilized in safety-net health systems. Barriers extend beyond eligibility criteria and include incomplete tobacco use documentation, fragmented referral workflows, limited care coordination, and challenges ensuring follow-up. We evaluated baseline gaps in LCS identification and early outcomes following implementation of a multi-component ambulatory screening program designed to address these system-level barriers. Methods: We conducted a retrospective observational quality improvement analysis across outpatient clinics within a safety-net health system. Pre-implementation data from 2024 assessed smoking history documentation (pack-years and quit date), potential LCS eligibility per U.S. Preventive Services Task Force criteria, and evidence of prior low-dose CT screening. A multi-component ambulatory LCS program was implemented on November 15, 2025, incorporating enhanced tobacco screening workflows, streamlined electronic referrals, patient navigation, and structured follow-up tracking. Post-implementation outcomes included outpatient visits among patients aged 50–80 years, tobacco use screening documentation, and ambulatory referrals to lung cancer screening from November 2025 through January 2026. Outcomes were summarized descriptively. Results: At baseline, 5,563 current or former smokers were seen, of whom 4,903 met age and smoking recency criteria for potential eligibility. Complete smoking history documentation was present in approximately 40% of patients. Based on available documentation, 665 patients met LCS criteria; 512 (77%) had evidence of prior screening or follow-up. Post-implementation, 43,648 outpatient visits occurred, including 23,857 among patients aged 50–80 years. Tobacco use screening was documented in 18,103/23,857 encounters (75.9%). A total of 140 ambulatory referrals to lung cancer screening were placed, increasing from 19 in November to 53 in January. Conclusions: In a safety-net health system, lung cancer screening was limited prior to program implementation by incomplete smoking history documentation and fragmented screening workflows. Early implementation of a multi-component ambulatory screening program incorporating enhanced tobacco screening, streamlined referrals, patient navigation, and follow-up tracking was associated with improved documentation and increased referral activity. Ongoing evaluation will assess screening completion and adherence across the screening program.

Utilization of risk-reducing interventions among breast cancer patients with pathogenic germline variants across safety-net and academic hospitals.

e22546 Background: Risk-reducing interventions (RRI) reduce cancer risk for patients with pathogenic/likely pathogenic germline variants (PGV) associated with hereditary breast cancer. Uptake varies widely and may be influenced by stage at diagnosis, PGV penetrance, race, and healthcare setting. Data describing RRI utilization by stage and PGV risk, particularly in safety-net systems, remain limited. Methods: We conducted a retrospective cohort study of breast cancer patients with PGV treated at Harris Health System (HHS), a public safety-net hospital, and Baylor St. Luke’s Medical Center (BSLMC), a private academic hospital. Patients diagnosed between October 2009 and September 2019 were included (N = 404; 151 HHS, 253 BSLMC). PGVs were categorized as high-risk (BRCA1, BRCA2, PALB2, PTEN, TP53), or moderate-risk (ATM, CHEK2, other). RRI included risk-reducing breast or gynecologic surgery. Descriptive statistics summarized RRI rates by stage at diagnosis, PGV risk, race, and hospital system. Results: RRI utilization was observed across stages 0 - III, with higher rates among patients diagnosed at earlier stages; no RRIs were observed among stage IV patients. Patients with high-risk PGVs consistently demonstrated higher RRI rates than those with moderate-risk PGVs at all stages. RRI utilization was higher at HHS than at BSLMC, particularly among patients with high-risk PGVs, with variation persisting by stage and PGV risk across hospital systems. Hispanic patients were most likely to undergo RRI and were predominantly treated at HHS. Conclusions: RRI utilization among breast cancer patients with PGVs varies by stage at diagnosis, PGV risk, and healthcare setting. Higher uptake among patients with high-risk PGVs and earlier-stage disease highlights the role of clinical context in RRI decision-making. These findings support further investigation into how access, counseling, and system-level factors influence equitable delivery of risk-reducing care. Percentage of patients utilizing risk-reducing interventions by stage and pathogenic germline variant at safety-net and academic hospital. Overall High-Risk% (Total n) Overall Moderate- Risk% (Total n) Safety-Net High-Risk% (Total n) Safety-Net Moderate- Risk% (Total n) Academic Hospital High-Risk% (Total n) Academic Hospital Moderate- Risk% (Total n) Stage 0 86.67 (15) 23.53 (17) 88.89 (9) 0.00 (2) 83.33 (6) 26.67 (15) Stage I 65.79 (38) 32.26 (31) 75.00 (16) 40.00 (5) 59.09 (22) 30.77 (26) Stage II 70.15 (67) 26.67 (30) 80.49 (41) 50.00 (4) 53.85 (26) 23.08 (26) Stage III 64.71 (51) 31.58 (19) 67.57 (37) 20.00 (5) 57.14 (14) 35.71 (14) Stage 0-1 71.70 (53) 29.17 (48) 80.00 (25) 28.57 (7) 64.29 (28) 29.27 (41) Stage II-III 67.80 (118) 28.57 (49) 74.36 (78) 33.33 (9) 55.00 (40) 27.50 (40) High-risk PGVs include BRCA1, BRCA2, PALB2, PTEN, P53. Medium-risk PGVs include ATM, CHEK2, other.

A sponsor-held platform IND model for personalized immunotherapy.

e23044 Background: Despite strong biological rationale, personalized cancer immunotherapies have struggled to scale beyond clinical trials. A challenge is the mismatch between population-level drug development and therapies intended for individual patients. Additional limitations include drug-centric trial designs, fragmented regulatory oversight, and limited infrastructure for real-world evidence (RWE) generation. These factors have constrained institutional adoption. Methods: We developed a centralized clinical model in which a sponsor provides a platform IND, predefined design and safety rules, centralized pharmacovigilance, and digital infrastructure, while participating oncology centers retain responsibility for patient care. Patient-specific immunotherapies are designed based on tumor and immune profiling and manufactured by sponsor-qualified vendors. Treatment planning is guided by prospective assessment of biological relevance and safety with predefined monitoring rules. Participating institutions enroll patients under the IND and use program-provided tools for coordination, safety reporting, and data capture. Each patient-specific immunotherapy is regulated under 21 CFR 312 with sponsor-controlled release and safety oversight. Results: This model enables institutions to deliver personalized immunotherapy as a structured clinical program. Key features include: (1) site-level participation under sponsor-held IND, (2) centralized safety oversight and regulatory accountability, (3) physician-directed individualized treatment within predefined program rules, and (4) systematic generation of structured RWE suitable for regulatory review and payer engagement. The framework reduces operational burden for clinical sites and enables learning across patients and institutions without altering local standards of care. Conclusions: This platform IND model provides a scalable pathway for personalized immunotherapy within existing regulatory structures. By shifting focus from population-level development to patient-level delivery with centralized oversight, this approach aligns clinical practice, safety monitoring, and evidence generation, potentially facilitating broader adoption and supporting future regulatory and reimbursement pathways. Traditional IND(Population-Level Drug Approval) Platform IND(Personalized Oncology Care) Personalized Oncology Outcomes Population-based drug design Patient-specific therapy design Personalized care beyond standard of care Efficacy and safety assessed at the population level Biological relevance and safety assessment Personalized immunotherapy for all patients Restricted trial eligibility Individual-level eligibility RWE for coverage decisions Static treatment paradigm after approval Structured learning from care delivery Centralized safety oversight and evidence generation

Perioperative chemotherapy or preoperative chemoradiotherapy in patients with esophageal carcinoma: A systematic review and meta-analysis.

e16105 Background: Despite advances in treatment options, esophageal carcinoma remains a disease with poor prognosis with a low 5-year survival rate and a high recurrence rate even after curative resection. RCTs have established that both perioperative chemotherapy (CT) and preoperative chemoradiotherapy (CRT) are superior to surgery alone; however, the optimal approach between CT versus CRT for esophageal carcinoma remains debated. Furthermore, data from recently published high quality trials have not been incorporated in prior quantitative syntheses. This meta-analysis compares the safety and efficacy of CT versus CRT in resectable esophageal and gastroesophageal junction carcinoma including subgroup analyses integrating recently available evidence. Methods: A systematic review and meta-analysis was conducted according to PRISMA guidelines. Electronic databases were systematically searched for eligible randomized controlled trials (RCTs) that enrolled adult patients (aged ≥ 18 years) with histologically confirmed, resectable esophageal or gastroesophageal junction carcinoma, directly compared perioperative CT with preoperative CRT, and reported at least one outcome of interest. Risk of bias was assessed using the Cochrane Risk of Bias Version 2.0 (RoB 2.0) tool across five domains. Meta-analysis was conducted using RevMan 5.4 with a random-effects model. Hazard Ratios (HRs) were pooled for time-to-event outcomes, and risk ratios (RR) for dichotomous endpoints. Statistical heterogeneity was assessed using the Chi-square test and quantified with the I 2 statistic. Results: Eight RCTs comprising 2,277 patients were included. Compared with CRT, CT had significantly reduced R0 resection rates (RR 0.94, 95% CI 0.89, 0.99) and a lower pathologic complete response (RR 0.27, 95% CI 0.13, 0.58). No statistically significant differences were observed in overall survival, progression-free survival, postoperative mortality, surgical complications or severe adverse events. There was a trend toward greater benefit of CRT in squamous cell carcinoma; however, the test for subgroup differences did not attain statistical significance. Conclusions: By incorporating data from the most recent RCTs, our meta-analysis suggests that CRT improves local tumor control by increasing R0 resection rates and complete response rates, but without a clear survival advantage over CT. This meta-analysis further highlights the need for an updated multidisciplinary framework and highlights the importance of biomarker-driven strategies and molecular profiling to identify more effective patient subgroups that may benefit most from either approach in future research.

Neo-adjuvant radiation and intratumoral immunotherapy followed by surgery: The NARIS trial for extremity soft tissue sarcoma.

11566 Background: Patients with STS who failed to respond to standard treatment have limited subsequent treatment options. Radiotherapy combined with immunotherapy has demonstrated efficacy in certain STS subtypes, such as undifferentiated pleomorphic sarcoma (UPS); however, perioperative strategies still require optimization to further improve local control and reduce adverse events, particularly for patients with multiple recurrences yet seeking limb preservation. Methods: Patients with pathologically confirmed extremity STS without metastases were enrolled. Eligible participants received two neoadjuvant cycles administered every three weeks. Each cycle consisted of hypofractionated radiotherapy (a total of 5 Gy × 4 fractions across two cycles) combined with intratumoral injection of a PD-L1 (TQB2450) monoclonal antibody. Results: A total of 15 patients were screened, of whom 11 met the eligibility criteria and provided written informed consent. Except for one patient with disease progression after standard chemoradiotherapy, other patients had recurrent disease following one to three prior curative resections at baseline. The ORR and DCR were 36.4% (95% CI, 10.9–69.2%) and 90.9% (95% CI, 58.7–99.8%), respectively. One patient has not yet undergone surgery. Among the 10 patients who received surgery, one achieved a pCR, and two achieved MPR. All three cases occurred in UPS patients. In the 10 evaluable patients with STS, the median percentage of tumor necrosis and fibrosis was 63.5% (IQR 17.5–88.75%), and the median residual viable tumor percentage was 36.5% (IQR 11.25–82.5%). Subgroup analysis showed that the median percentage of tumor necrosis and fibrosis in UPS patients was 97% (IQR 88–99.25%), compared with 25% (IQR 10–55%) in other histological subtypes. The pCR rate and MPR rate in UPS patients were 25% (1/4) and 75% (3/4), respectively. During the neoadjuvant phase, the main TEAEs were local swelling and decreased lymphocyte counts, which were reversible during treatment intervals. No grade 3 TEAEs or immune-related adverse events were observed. Postoperative complications in the 10 surgical patients were as expected and mainly included local soft tissue edema, pain, local stiffness, and limb numbness. No delayed wound healing or surgical site infections were observed. Conclusions: Compared with current clinical studies in STS that employ conventionally fractionated radical radiotherapy and intravenous immune checkpoint inhibitors, this study utilized a lower total radiation dose delivered in larger fractions combined with intratumoral administration of immunotherapy, achieving comparable disease control with manageable toxicity. It may be clinically valuable for patients with recurrent disease after multiple surgeries or those with prior exposure to local radiotherapy. Clinical trial information: ChiCTR2200060659.

Chemoradiotherapy plus sintilimab versus chemoradiotherapy as neoadjuvant treatment in locally advanced esophageal squamous cell carcinoma (NEOCRTEC2101): A multicenter, randomized, phase III trial.

TPS4248 Background: Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is the current standard of care for resectable locally advanced esophageal squamous cell carcinoma (ESCC). The integration of immunotherapy is now challenging this established therapeutic paradigm. Our previous phase II trial demonstrated that combining PD-1 inhibitor and NCRT yielded an encouraging pathological complete response (pCR) rate with an acceptable safety profile in ESCC. Therefore, this multicenter, randomized phase III trial (NEOCRTEC2101) aims to compare the efficacy and safety of NCRT combined with sintilimab (a IgG4 anti-PD-1 monoclonal antibody) versus NCRT alone in patients with resectable locally advanced ESCC. Methods: This was a multicenter, open-label, randomized, phase III trial. Key eligibility criteria included previously untreated, histologically confirmed, resectable thoracic ESCC clinically staged as T1-4aN1-3M0 or T3-4aN0M0 according to the 8th edition of the UICC staging system, age 18–75 years, Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate hematologic and organ function. Key exclusion criteria included a history of other malignancies, previous antitumor therapy, severe comorbidities, active autoimmune disease, prior non-infectious pneumonitis, or interstitial lung disease. Eligible patients were randomly assigned (1:1) to sintilimab plus NCRT group or NCRT group. All patients received NCRT consisting of concurrent radiotherapy (40 or 45 Gy in 20 fractions) and chemotherapy (paclitaxel 50 mg/m² + cisplatin 25 mg/m² administered on days 1, 8, 15, and 22). Patients randomized to the sintilimab plus NCRT group additionally received sintilimab 200 mg via intravenous infusion on days 1 and 22. Surgical resection was performed 6-8 weeks following the completion of neoadjuvant therapy. The primary endpoint was overall survival, and the secondary endpoints were progression-free survival, pCR rate, R0 resection rate, and treatment-related adverse events. The planned sample size is 422 patients. This study opened to accrual in October 2022 and is currently recruiting patients. Clinical trial information: NCT05357846 .

Impact of prior immune checkpoint inhibition on the clinical efficacy of belzutifan in advanced renal cell carcinoma.

e16547 Background: Hypoxia-inducible factor 2α (HIF-2α) is a transcription factor that plays a central role in the pathogenesis of clear-cell renal cell carcinoma (ccRCC). Loss of the von Hippel–Lindau (VHL) tumor suppressor, which is present in the vast majority of ccRCC cases, leads to constitutive stabilization of HIF-α subunits, particularly HIF-2α. Persistent HIF-2α activity drives oncogenic programs including angiogenesis (via VEGF upregulation), metabolic reprogramming, proliferation, and survival. Belzutifan, a selective HIF-2α inhibitor, targets this core molecular driver and is currently approved for patients previously exposed to both VEGF-targeted therapies and immune checkpoint inhibitors (ICIs). However, in real-world practice, many patients with severe autoimmune diseases are unable to receive ICIs and instead undergo sequential VEGF-targeted TKI therapy. It remains uncertain whether belzutifan requires prior immune “priming” to achieve its therapeutic effect. Methods: A retrospective cohort study was conducted using the TriNetX Global Collaborative Network, including adults ≥18 years with RCC who received belzutifan; patients with Von Hippel–Lindau syndrome were excluded. Two cohorts were compared: those who initiated belzutifan after prior ICI exposure and those who received belzutifan without prior ICI therapy. Propensity score matching was performed on demographic variables, laboratory parameters, prior nephrectomy, and cardiovascular/cerebrovascular/ autoimmune comorbidities. Outcomes were evaluated over 365 days from belzutifan initiation. The primary endpoint was all-cause mortality; secondary endpoints included hospitalization and ICU-level care. Results: Before matching, 369 patients received belzutifan after ICIs, and 241 received belzutifan without prior ICIs. The overall mean age was 65 years, with 70.1 % male patients. After matching, 174 patients remained in each cohort. One-year overall survival was similar between the prior-ICI and no-ICI groups (68.36% vs 69.34%, respectively), with median survival not reached in either cohort. Survival differences were not statistically significant (log-rank p = 0.583; HR 1.127). Rates of hospitalization (55.7% vs 51.1%) and ICU admission (17.2% vs 16.1%) were likewise not significantly different. Conclusions: Belzutifan showed comparable survival and healthcare utilization outcomes regardless of prior ICI exposure, supporting the premise that its efficacy is independent of immune priming. These findings suggest that belzutifan may be an appropriate therapeutic option for ICI-ineligible patients who have received VEGF-targeted TKIs. Prospective studies are warranted to evaluate TKI-to-belzutifan sequences and inform potential expansion of treatment indications.

A prospective study of mpMRI-guided salvage radiotherapy with lesion-directed dose escalation after radical prostatectomy: 10-year follow-up results (MRI Study: UMIN 000009823).

5115 Background: Salvage radiotherapy (SRT) after radical prostatectomy (RP) has traditionally been delivered as uniform dose distribution of the prostate bed without lesion visualization. We prospectively implemented an image-guided salvage strategy integrating high-resolution multiparametric MRI (mpMRI) and lesion-directed dose escalation. Here we report long-term oncologic outcomes of this pioneering approach. Methods: This prospective, single-arm clinical study was registered in the UMIN database in 2013. Patients with biochemical recurrence (BCR, PSA ≥0.2 ng/mL) after RP and no evidence of distant metastasis were enrolled. All patients underwent 3 Tesla mpMRI with an endorectal coil prior to SRT. When a focal recurrent lesion was identified, intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) was delivered (70 Gy to the MRI-defined lesion and 66 Gy to the prostate bed in 33 fractions). Patients without visible lesions received prostate-bed irradiation alone. Treatment failure after SRT was defined as PSA > 0.2 ng/mL. Long-term clinical outcomes were analyzed. Results: A total of 40 patients completed protocol treatment. mpMRI identified focal recurrence sites in 11 patients (27.5%), all of whom received lesion-directed SIB-IMRT. After a median follow-up of 10.6 years, treatment failure occurred in 13 patients (32.5%). Among patients treated with SIB-IMRT, 4 of 11 developed BCR, whereas among 29 patients without mpMRI-detectable recurrence at the time of SRT, 9 developed BCR. There was no statistically significant difference in BCR rates between the two groups. Importantly, no patient developed radiologically evident local recurrence within the irradiated prostate bed, including those treated with SIB in their disease course. All but one patient with treatment failure received subsequent systemic salvage therapy. Distant metastases developed in 3 patients, and 1 patient died from prostate cancer. One patient without SIB experienced grade 3 perforation of the sigmoid colon. During follow-up after SRT, secondary malignancies were diagnosed in 10 patients. Conclusions: In this prospective study with long-term follow-up, mpMRI-guided SRT achieved excellent durable local control. Although second BCR occurred in a subset of patients, the absence of in-field local failures regardless of mpMRI detectability at the time of SRT supports the biological and clinical validity of lesion-directed salvage intensification. Our findings underscore individualized SIB approach and highlight the need for future studies to refine patient selection and treatment intensification strategies in salvage settings, including androgen deprivation therapy and/or elective pelvic nodal irradiation. Clinical trial information: UMIN000009823.

Zidesamtinib efficacy and safety in patients with advanced <i>ROS1</i> -positive solid tumors other than NSCLC in the ARROS-1 study.

3108 Background: ROS1 fusions are oncogenic drivers in various cancers. Multiple ROS1 tyrosine kinase inhibitors (TKIs) are available for ROS1 + non-small cell lung cancer (NSCLC); however, there are limited data on the activity of these agents in patients with other ROS1 + tumors. In patients with advanced ROS1 + NSCLC (TKI pretreated and TKI-naïve), zidesamtinib has demonstrated encouraging clinical activity, including in patients with CNS disease and/or ROS1 G2032R mutation, and a safety profile consistent with its highly ROS1-selective, TRK-sparing design. Here we report the first data on the activity of zidesamtinib in patients with other ROS1 + solid tumors. Methods: The global Phase 1/2 ARROS-1 study (NCT05118789) includes a cohort of patients with advanced/metastatic ROS1 + solid tumors other than NSCLC, whose disease has progressed on any prior therapy. Key endpoints are objective response rate (ORR, RECIST v1.1 by BICR), duration of response (DOR), and safety. Data cut: 22 September 2025. Results: 15 efficacy-evaluable patients with ROS1 + solid tumors (10 non-NSCLC tumor types) received zidesamtinib. Patients received a median of 2 prior anticancer therapies (range 1-6): 60% were ROS1 TKI-naïve, 40% were ROS1 TKI pre-treated (range 1-2), 73% had prior chemotherapy (range 1-4). ORR was 40% (6/15, including 1 PR pending confirmation), with no disease progression by BICR among responders (DOR range 3.9+ – 22.8+ months). Responses were observed across multiple tumor types, including cholangiocarcinoma, colorectal, gastric, inflammatory myofibroblastic tumor, ovarian, and pancreatic. 2 ROS1 TKI pre-treated patients had ROS1 resistance mutations (G2032R and F2004I/F2004V) at baseline and both achieved a PR (1 pending confirmation). Treatment-related adverse events (TRAEs) in ≥15% of patients were increased alanine aminotransferase, increased blood creatine phosphokinase, and dysgeusia (n=3 patients each). No patients discontinued due to TRAEs; 1 pt dose-reduced due to TRAE. Conclusions: Zidesamtinib demonstrated encouraging activity in patients with diverse ROS1 + solid tumors, including those refractory to standard-of-care therapies. Safety was consistent with its ROS1-selective, TRK-sparing design. Enrollment is ongoing. Clinical trial information: NCT05118789 .