Browse Articles

Neoantigen prediction and reactivity of cerebrospinal fluid–human-derived tumor reactive T cells (CSF-TRT cells) in leptomeningeal disease (LMD) from solid tumors.

2030 Background: Leptomeningeal disease (LMD) is a devastating complication of metastases and its incidence is increasing. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) showed complete responses in patients with metastatic melanoma and other solid tumors. To obtain CSF-TRT cells as a source of T cells for ACT, we aim 1) to identify the expansion method that allows higher expansion of tumor reactive TIL; 2) to enrich tumor neoantigen reactive TILs and determine their in-vivo and ex-vivo functional capabilities. Methods: Cells were isolated from 64 CSF collections from melanoma (M-LMD), 9 CSF from breast cancer (B-LMD), and 9 CSF from lung adenocarcinoma (L-LMD) from patients with LMD. Cells were plated following established TIL culture protocols (high-dose IL-2): 1) OKT3, 2) anti-4-1BB-agonist, 3) IL-7+IL-15+IL-21, 4) anti-CD3/CD28-T-activator, 5) anti-CD3/CD28/CD137-T-activator, 6) anti-CD3/CD28-T-expander. After 4-6 weeks, reactivity was assessed with HLA-matched or autologous tumor cells. Additionally, Whole Exome Sequencing (WES) and RNA sequencing were performed in T cells expanded from CSF and pair-matched extracranial tumors from 12 patients with M-LMD for epitope prediction to identify neoantigens that may be targets of immunoediting using computational algorithms. Results: CSF yielded an average of 1.204e5 viable cells for expansion. After culture in IL-2, 53.4% of samples showed increased cell yield with average 165.29-fold expansion. PreREP resulted in 37.6% CD8+ T cells. REP had a 96.8% success rate (mean 589.87-fold expansion). Post-REP flow cytometry revealed expansion of CD4+ T cells. Additional cultures produced similar yields with reduced T cell input requirement and demonstrated the potential to enrich for CD8+ T cells. Out of five samples tested for reactivity to HLA-matched melanoma cell lines, three produced varying levels of IFN-y. T cells expanded from CSF samples from L-LMD and B-LMD had less successful results. L-LMD had a success expansion rate of 11.1% with IL-2 only, 83.3% with T-Activator, 50% with CD127 T Activator, and 50% with T-Expander. B-LMD had a success rate of 22.2% with IL-2 only, 0% with OKT3, 83.3% with T-Activator, 50% with CD137 T-Activator, and 85.7% with T-Expander. One of the CSF samples from L-LMD tested showed reactivity to autologous HLA-matched tumor cells, whereas none of the CSF T cells from B-LMD showed a successful reactivity. Preliminary studies demonstrated CSF TIL reactivity against tumor reactive neoantigens. Ongoing studies will confirm our results. Conclusions: Results demonstrate successful expansion of T cells ex vivo from CSF in M-LMD, raising the potential to use CSF-derived T-cells as therapeutic strategy for LMD. There was a variable success rate with expansion of T cells from CSF from B-LMD and L-LMD and supplementary studies are needed.

Impact of guideline-discordant care for muscle-invasive bladder cancer on preventable survival losses: A national counterfactual analysis of 55,873 patients.

e16586 Background: Guideline-discordant care disproportionately affects racial minorities, uninsured, and underinsured patients, yet prior studies lack quantification of absolute survival time lost. We evaluated equity-adjusted survival penalties from non-adherence to guideline-concordant therapy in muscle-invasive bladder cancer (MIBC). Methods: From the National Cancer Database, we identified patients with non metastatic muscle invasive bladder cancer (cT2 to T4a, N0 or N1, M0). Overall survival was defined from diagnosis to death or last contact. Guideline-concordant therapy was defined as radical cystectomy (± perioperative systemic therapy) or trimodality therapy (definitive bladder radiotherapy with chemotherapy); all other patterns were classified as discordant. Of 55,873 eligible patients, 28,025 received concordant therapy (27,401 cystectomy; 524 trimodality therapy) and 27,848 received discordant careInverse probability of treatment weighting (IPTW) was used to balance demographic, socioeconomic, facility, tumor, and temporal covariates. We analyzed survival using weighted Kaplan-Meier and Cox models censored at 36 and 60 months. Equity-adjusted survival penalties were calculated as the difference between observed survival and counterfactual survival predicted from concordant-only models. Restricted mean survival time losses were extrapolated to years lost per 1,000 patients. Results: Guideline concordance was associated with significantly improved survival (36-month HR 0.64; 60-month HR 0.68; both p < 0.01). Among concordant modalities, radical cystectomy conferred an early survival advantage over trimodality therapy at 36 months (HR 0.23; p < 0.05) which dissipated by 60 months (HR 0.53; p > 0.05). Survival penalties were most severe for vulnerable populations. At 36 months, uninsured patients incurred a 0.90-month survival penalty (75.0 life-years lost per 1,000 patients). By 60 months, penalties widened: uninsured patients lost 1.94 months (161.7 life-years/1,000), Filipino patients lost 1.53 months (127.0/1,000), Medicaid beneficiaries lost 0.97 months (80.8/1,000), and patients at community cancer programs lost 0.21 months (54.1/1,000). Conclusions: In this national cohort of 55,873 patients, guideline concordance reduced the propensity-weighted risk of death by 32% to 36% at 3 and 5 years. However, non-adherence results in substantial absolute survival losses for marginalized groups. By quantifying these "survival penalties," we demonstrate that targeting the factors underlying discordance offers a direct opportunity to reduce inequities and achieve measurable population-level survival gains in MIBC.

Failure-to-rescue after pancreatectomy for pancreatic cancer in the United States: National Inpatient outcomes, 2018–2023.

e23232 Background: Pancreatectomy for pancreatic cancer carries substantial postoperative morbidity. As operative mortality has declined, inpatient outcomes increasingly depend on the ability to recognize and manage major postoperative complications; contemporary national benchmarks for these rescue outcomes remain limited. Methods: A retrospective analysis of the 2018–2023 National Inpatient Sample identified adult pancreatectomy hospitalizations for pancreatic cancer using ICD-10-CM/PCS codes. Major postoperative complications were defined using diagnosis codes, and failure-to-rescue was defined as in-hospital mortality among hospitalizations with ≥1 complication. Survey-weighted logistic regression, restricted to complicated cases, evaluated factors associated with failure-to-rescue while accounting for national weighting, clustering, stratification, patient characteristics, admission factors, hospital features, calendar year, and APR-DRG severity. Results: An estimated 115,385 hospitalizations for pancreatic cancer–related pancreatectomy were identified nationally from 2018–2023. Major postoperative complications occurred in 25.5% of hospitalizations (95% CI 24.9–26.1). Overall in-hospital mortality was 2.3% (95% CI 2.1–2.5). Among hospitalizations with at least one major complication, mortality was 7.7%, corresponding to a failure-to-rescue (FTR) rate of 7.7% (95% CI 7.0–8.4). Across the full cohort, FTR prevalence was 2.0% (95% CI 1.8–2.2). Among complicated hospitalizations, mean length of stay was 12.6 days (95% CI 12.3–12.9). The most common complication domains were acute kidney injury (22.4%; 95% CI 21.2–23.7), respiratory complications (14.5%; 95% CI 13.6–15.6), and infectious or septic complications (13.7%; 95% CI 12.8–14.7). In unadjusted analyses, failure-to-rescue varied by hospital structure, with higher rates at rural and smaller hospitals and lower rates at urban teaching and large hospitals. In adjusted analyses restricted to complicated hospitalizations, increasing age was associated with higher odds of FTR (OR 1.01 per year, 95% CI 1.00–1.02, p = 0.045), while elective admission was associated with lower odds of FTR (OR 0.48, 95% CI 0.38–0.62, p < 0.001). Hospital teaching status, bed size, and geographic region were not independently associated with FTR after adjustment. Conclusions: One-quarter of pancreatectomy hospitalizations were complicated, with a 7.7% failure-to-rescue rate. After adjustment, failure-to-rescue was driven by patient and admission factors rather than hospital structure, establishing contemporary national benchmarks for postoperative rescue after pancreatectomy.

Appendiceal cancer: Historical trends in histological composition and cause-specific mortality based on SEER database analysis.

e16485 Background: Appendiceal cancers are rare malignancies characterized by marked histologic heterogeneity and diverse clinical behavior. Although the incidence has increased over recent decades, long-term population data describing mortality patterns and competing causes of death remain limited. We examined trends in histologic distribution and all-cause mortality among patients with appendiceal cancer using the Surveillance, Epidemiology, and End Results (SEER) Research Plus database. Methods: We conducted a retrospective cohort study of patients diagnosed with primary appendiceal malignancies between 2000 and 2022 using the SEER Plus database. Demographic characteristics, tumor features, stage, and treatment variables were extracted. Histologic subtypes were defined using International Classification of Diseases for Oncology, Third Edition (ICD-O-3) morphology codes and categorized into the following types: colonic type adenocarcinoma, mucinous adenocarcinoma, malignant carcinoid tumor, neuroendocrine neoplasms, and signet ring cell carcinoma. Mortality causes were evaluated using cumulative incidence functions and Fine-Gray subdistribution hazard models, treating non-appendiceal cancer deaths as competing risks. Results: A total of 16,739 patients met the inclusion criteria. Malignant carcinoid tumors were the most common histology (45.6%), followed by mucinous adenocarcinoma (27.6%) and colonic-type adenocarcinoma (18.5%). Linear regression analysis demonstrated significant temporal increases in proportion for malignant carcinoid tumors (R² = 0.824, p < 0.001), with malignant carcinoid tumors surpassing other subtypes to become the predominant histology after 2015. There was a decrease in mucinous adenocarcinoma (R² = 0.824, p < 0.001) and colonic-type adenocarcinoma (R2 = 0.898, p < 0.001) histologies. Appendiceal cancer-specific death was the leading cause of mortality overall. Non-cancer causes, particularly cardiovascular disease, represented an important competing risk during long-term follow-up. In multivariable Fine-Gray models, colonic-type adenocarcinoma and signet ring cell carcinoma were associated with significantly higher appendiceal cancer-specific mortality compared with malignant carcinoid tumors (p < 0.001). Surgical resection was consistently associated with reduced cancer mortality, while advanced age and those who received chemotherapy were associated with higher cancer-specific mortality. Conclusions: Appendiceal cancer exhibits evolving histologic patterns with substantial heterogeneity in cancer-specific mortality. While appendiceal cancer remains the predominant cause of death, cardiovascular disease represents an important competing risk, particularly among patients with indolent histologies and longer survival.

An emerging disparity in young-onset lung adenocarcinoma: Evidence from a SEER analysis.

e20677 Background: Lung adenocarcinoma (LUAD) incidence in younger adults has received limited attention, and stage-specific trends across sex and race/ethnicity remain incompletely characterized. We evaluated the temporal incidence patterns and survival outcomes among patients aged 15–49 years, with a focus on identifying emerging demographic subgroups. Methods: Incidence data for LUAD diagnosed between 2000 and 2021 were obtained from the SEER 17 Registries (November 2023 submission). Age-adjusted incidence rates were calculated using the 2000 US standard population and stratified by age group (15–39 vs 40–49), sex, race/ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian or Pacific Islander [NHAPI], Hispanic), and SEER Combined Summary Stage (2004+; localized, regional, distant). Temporal trends were assessed using Joinpoint regression to estimate annual percent change (APC). The emerging group was defined a priori as NHAPI females; all other patients comprised the non-emerging group. Survival analyses included cases diagnosed from 2004–2016. Five-year cause-specific survival was estimated using the Kaplan–Meier method, with comparisons by log-rank testing. Multivariable Cox proportional hazards models evaluated associations between demographic and clinical factors and survival. Stage distribution at diagnosis was compared using chi-square testing. Results: Among 11,072 patients aged 15–49 years, 776 (7.0%) comprised the emerging group. Joinpoint analyses demonstrated an increase in LUAD incidence among NHAPI females, particularly in distant-stage disease, while most other demographic groups showed stable or declining trends. Five-year cause-specific survival was significantly higher in the emerging group compared with others (median survival 34.0 vs 18.0 months; log-rank p < 0.001). In multivariable Cox regression, emerging group status was independently associated with improved survival (HR 0.73, 95% CI 0.66–0.80). Advanced stage at diagnosis remained the strongest predictor of mortality (regional: HR 3.59; distant: HR 11.89; both p < 0.001). Despite improved survival, the emerging group demonstrated a higher proportion of distant-stage presentation (71.1% vs 66.7%, p = 0.002). Conclusions: Young NHAPI females represent an emerging subgroup with increasing LUAD incidence and distinct stage and survival patterns. Although survival outcomes were more favorable, a higher burden of advanced-stage disease highlights a growing disparity. These findings underscore the importance of disaggregated analyses to identify emerging at-risk populations and inform targeted prevention and early detection strategies.

Impact of mRNA SARS-CoV-2 vaccination on CAR T-cell therapy outcomes in hematologic malignancies: A multi-center real-world analysis.

11001 Background: The clinical landscape of hematologic malignancies has been reshaped by Chimeric Antigen Receptor (CAR) T-cell therapies; however, their administration is intrinsically associated with immune-mediated toxicities, specifically cytokine release syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). The interaction between the immunogenic stimulus of mRNA SARS-CoV-2 vaccines and the systemic inflammatory milieu of CAR T-cell therapy remains undefined in real-world practice. This study aimed to delineate the impact of mRNA vaccination on survival outcomes and immunotoxicity profiles within this vulnerable patient population. Methods: We conducted a retrospective cohort study using the TriNetX global federated health research network. We identified patients with hematologic malignancies who received CAR T-cell therapy using ICD-10 and RXNORM codes. Patients were stratified into two cohorts based on whether they received mRNA-based SARS-CoV-2 vaccines. The cohorts were 1:1 propensity score-matched for age, sex, race, staging, and comorbidities. The primary outcome was all-cause mortality at 3 years, assessed with Hazard Ratios (HR). Secondary outcomes included CRS grade 1/2 and 3/4, and ICANS, both graded per the ASTCT criteria, and assessed with Odds Ratios (OR). Results: A total of 3,199 CAR T-cell patients (222 mRNA vaccine recipients and 2,977 without the mRNA vaccine) were identified. After 1:1 propensity score matching, 218 patients remained in each cohort. The 3-year mortality was significantly lower among mRNA SARS-CoV-2 vaccine recipients as compared to non-recipients (HR 0.608; 95% CI, 0.411 - 0.901). The mRNA vaccine group had a higher rate of CRS 1/2 (OR 1.577; 95% CI, 1.056 - 2.356). However, there were not enough cases of CRS 3/4 to compare the two cohorts. Furthermore, there was no significant difference in ICANS between the two cohorts (OR 0.8262; 95% CI, 0.522–1.37). Conclusions: In this propensity score-matched analysis of real-world data, mRNA SARS-CoV-2 vaccination was associated with a significantly superior long-term survival among CAR T-cell recipients. These findings build on early pre-clinical data related to SARS-CoV-2 mRNA vaccines demonstrating substantial increase in type I interferon, enabling innate immune cells to prime CD8 + T cells. The results provide early real-world clinical evidence and pave the way for prospective validation. Key outcomes in CAR T-cell recipients. Outcome Effect of mRNA Vaccination (95% CI) p Value All-cause mortality (3-year) HR 0.61 (0.41–0.90) 0.01 CRS grade 1/2 OR 1.58 (1.06–2.36) 0.03 ICANS (any grade) OR 0.83 (0.52–1.37) 0.41

Patterns of upper endoscopy use prior to gastric cancer diagnosis among high-risk populations.

11192 Background: Gastric cancer is frequently diagnosed at advanced stages in the United States, contributing to poor survival. Although several populations carry elevated risk, real-world patterns of upper endoscopic evaluation before gastric cancer diagnosis remain poorly characterized. Understanding pre-diagnostic endoscopy utilization may identify gaps in care and inform future evaluation strategies. Methods: A retrospective cohort study using Epic SlicerDicer identified adults ≥18 years diagnosed with gastric adenocarcinoma at Tufts Medical Center between January 2021 and January 2026. Gastric cancer was identified by ICD-10 codes, excluding patients with prior disease. Upper endoscopy (EGD) performed 6–36 months before diagnosis was assessed overall and across high-risk subgroups. EGDs within 6 months were excluded to distinguish pre-diagnostic from index diagnostic procedures. High-risk features were defined by the 2025 AGA Clinical Practice Update and included Asian race, Hispanic ethnicity, interpreter requirement, and prior Helicobacter pylori infection, gastric intestinal metaplasia (GIM), or chronic atrophic gastritis (CAG). Rates of pre-diagnostic EGD utilization were described overall and by subgroup. Results: Among 258 patients diagnosed with gastric adenocarcinoma, 77 (29.8%) presented with metastatic disease. Overall, 118 patients (45.7%) underwent EGD 6–36 months before diagnosis, while approximately half had their first documented EGD at the time of cancer diagnosis. Rates were similar across racial groups: White (45.3%), Asian (46.3%), Black (43.8%), and Other (45.7%). Utilization was higher among Hispanic versus non-Hispanic patients (57.7% vs 46.2%) and among those requiring interpreter services (51.8% vs 47.0%). Patients with gastric precursor conditions (34.1%) had similar rates of pre-diagnostic EGD (52.3%), including prior H. pylori infection (40.0%), GIM (63.3%), and CAG (55.0%). Of 140 patients without pre-diagnostic EGD, 39 (27.9%) underwent colonoscopy alone, indicating access to endoscopic care without concurrent EGD. Conclusions: Most upper endoscopies occurred near the time of cancer diagnosis, suggesting predominantly diagnostic rather than preventive evaluation. Even among patients with recognized risk factors and gastric precursor conditions, only about half underwent prior upper endoscopic assessment. Colonoscopy without concurrent EGD highlights gaps in integrated, risk-based gastrointestinal cancer prevention and an opportunity to improve earlier recognition of gastric cancer in high-risk populations. Upper endoscopy use before gastric cancer diagnosis. High-Risk Feature Total (N) Total (%) % w/ EGD (6–36 mo) Overall population 258 — 45.7 Asian race 67 26.0 46.3 Hispanic ethnicity 26 10.1 57.7 Requires interpreter 56 21.7 51.8 H. pylori infection 35 13.6 40.0 GIM 60 23.3 63.3 CAG 20 7.8 55.0 Any H. pylori , GIM, or CAG 88 34.1 52.3

Separating facts from feeds: An evaluation of social media videos on Barrett’s esophagus.

9043 Background: Esophageal cancer is subdivided into two types based on histopathology, squamous cell carcinoma and adenocarcinoma (ACE). While the former has declined in incidence within the US, the latter has seen a marked increase. The natural history of ACE begins with metaplastic and dysplastic changes, coined Barrett’s esophagus (BE). This pre-malignant condition is treatable if dysplastic changes are detected early. Surveillance endoscopies are recommended every 3-5 years in individuals with BE, yet the adherence to this recommendation remains low. As the incidence of cancer increases in young individuals, clinicians must adapt their methods for disseminating information. In this study, we graded social media videos about BE and compared scores between medical professionals and non-medical professionals. Methods: Utilizing a freshly made account to limit algorithmic tailoring, 106 videos were gathered from TikTok (n=60, 56%) and Instagram (n=46, 44%) using the hashtag “#barrettesophagus.” Inclusion criteria included videos covering the pathophysiology, clinical features, diagnosis, treatment, or surveillance of BE. Exclusion criteria were videos that did not cover those topics or were not in English. Videos were graded utilizing the CHAI rubric, a verified, 10-point grading rubric for online videos, where 10 is an ideal score. The graded categories are credibility, transparency, content accuracy, accessibility, and relevance. Medical professionals (MP) were defined as MD/DOs, PhDs, RNs, PA/NPs, or RDs. Engagement was defined as cumulative total of likes and comments. Each video was graded by two independent reviewers. Statistical analysis was performed utilizing unpaired, Welch’s t-test. Results: Out of the 106 videos, 15 were excluded. From those remaining, 52 videos (49%) were made by MP, and 54 videos (51%) were made by non-MP. This latter group was composed of lay individuals (n=12, 11%), non-medical influencers (n=12, 11%), professional organizations (n=3, 2%), and private groups (n=12, 11%). The average CHAI for videos from MP were 9.7, compared to 7.0 from non-MP (p < 0.01). Screening guidelines were covered in 21 videos (20%), with MP covering 15 of them (71%), while only 6 were covered by non-MP (29%). Average engagement on MP videos was 2674, contrasted to 183 in the non-MP group. No videos explicitly stated that AI was involved in making the content. Conclusions: Medical professionals produced significantly higher-grade content covering BE than non-medical professionals. Additionally, medical professionals were more likely to report on the updated screening guidelines for BE and on average had higher engagement per video. This highlights the benefit of medical professionals within social media and shows the potential of disseminating updated screening guidelines through modern avenues of information sharing.

Effect of induction immunochemotherapy before concurrent chemoradiotherapy on outcomes in limited-stage small cell lung cancer.

e20158 Background: Immunotherapy, chemotherapy, and radiotherapy all play significant roles in the management of small cell lung cancer (SCLC). Combining radiotherapy with chemotherapy followed by immunotherapy shows promise for limited-stage SCLC (LS-SCLC), offering good tolerability and survival benefits. However, there is limited data on whether immunotherapy combined with chemotherapy for LS-SCLC can be performed before chemoradiotherapy. Therefore, we investigated the safety and effectiveness of induction immunochemotherapy followed by concurrent chemoradiotherapy (CCRT) for LS-SCLC. Methods: A retrospective analysis was conducted on 138 patients with LS-SCLC who received chemoradiotherapy between January 2019 and December 2024. This study included 34 patients receiving induction immunochemotherapy and 104 patients receiving induction chemotherapy. All patients underwent 2-4 cycles of induction therapy before CCRT. Clinical outcomes, including survival and toxicity, were compared between groups. Imaging assessments were performed before and 1 month after CCRT. The evaluations included the tumor response to induction therapy, treatment-related adverse events, complications during and after CCRT, tumor response after CCRT, progression-free survival (PFS), and overall survival (OS). Follow-up data were collected through regular check-ups or inpatient records. Results: Compared to the induction chemotherapy group, the objective response rate (ORR) of tumors after induction treatment in the induction immunochemotherapy group was 67.6% (23/34) versus 45.2% (47/104) (P = 0.023). After CCRT, the ORR in two groups was 79.4% (27/34) versus 60.6% (63/104) (P = 0.045). The median follow-up time was 25.3 months for the induction immunochemotherapy group and 28.2 months for the induction chemotherapy group. The median progression-free survival (PFS) for two groups was 21.3 months versus 13.1 months (P = 0.015), and the median overall survival (OS) was not reached versus 41.7 months (P = 0.039). Treatment-related toxicities of grade 1-2 were 64.7% versus 54.8% (P = 0.311), and grade 3-4 toxicities were 41.2% versus 41.3% (P = 0.986). No grade 5 treatment-related toxicities were observed. Conclusions: Induction immunochemotherapy followed by CCRT for patients with LS-SCLC is effective and safe with a high ORR, PFS and OS rate, as well as a tolerable toxicity profile. Larger, randomized controlled trials are required to confirm our findings. Characteristics Induction immunochemotherapy (n=34) Induction chemotherapy (n=104) Best response to induction therapy-n(%) CR/PR 23 (67.6) 47 (45.2) SD 10 (29.4) 52 (51.0) PD 1 (2.9) 4 (3.8) Best response to CCRT-n(%) CR/PR 27 (79.4) 63 (60.6) SD 6 (17.6) 34 (32.7) PD 1 (2.9) 7 (6.7) The median progression-free survival-months 21.3 13.1 The median overall survival-months NR 41.7

Clinical efficacy and tolerability of the selective RET inhibitor soxataltinib (SY-5007) in advanced <i>RET</i> fusion–positive non–small cell lung cancer (NSCLC): Primary findings from a confirmatory phase III trial.

8639 Background: Oncogenic RET gene fusions represent a clinically validated molecular driver occurring in approximately 1–2% of all NSCLC cases, establishing a critical need for targeted therapeutic strategies. Soxataltinib is a novel, orally bioavailable, and highly selective small-molecule inhibitor of RET kinase. Its anti-tumor potency and safety have been previously reported in a phase I/II study. Here we confirmed its clinical value in a pivotal phase III study. Methods: This multicenter, single-arm Phase III clinical trial was designed to evaluate the efficacy and safety of Soxataltinib in patients with RET fusion–positive NSCLC who were previously untreated for advanced disease. The primary endpoint was the confirmed Objective Response Rate (ORR), as determined by Blinded Independent Central Review (BICR) per RECIST v1.1. The secondary endpoints included investigator-assessed ORR, Disease Control Rate (DCR), Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and safety. Results: At the data cutoff (April 10, 2025), the Per-Protocol Population (PPP) comprised 95 patients, 61 of whom were Key efficacy population (KEP) for statistical hypothesis. Soxataltinib demonstrated profound anti-tumor efficacy. The primary endpoint was met. The BICR-confirmed ORR was 90.0% (95%CI: 79.5, 96.2) for KEP and 87.4% (95%CI: 79.0, 93.3) for PPP. The overall DCR was 96.7% (95%CI: 88.5, 99.6) for KEP and 93.7% (95%CI: 86.8, 97.6) for PPP. The median PFS and DOR had not yet been reached, with an estimated 15-month PFS rate of 68.9% (95%CI: 54.3, 79.7) and 65.0% (95%CI: 51.5, 75.6) and 12-month DOR rate of 73.8% (95%CI: 58.2, 84.4) and 69.1% (95%CI: 53.8, 80.1), respectively for KEP and PPP. The OS data remained immature. The safety analysis population comprised 96 patients who received at least one dose of Soxataltinib. The most common Grade ≥3 treatment-emergent adverse events (TEAEs) were hypertension (22.9%), diarrhea (16.7%), Aspartate aminotransferase increased (6.3%), Alanine aminotransferase increased (5.2%), and hyponatraemia (5.2%). These events were predominantly manageable. None of the patients permanently discontinued treatment due to a treatment-related adverse event. No patient died due to TEAE that was definitely related, probably related, or possibly related to Soxataltinib. Conclusions: The primary analysis of this Phase III trial confirmed Soxataltinib as a highly effective and well-tolerated therapeutic agent for patients with RET fusion–positive NSCLC in the first-line setting. This observed high response rates and durable disease control benefit underscored its potential as a best-in-class RET inhibitor. The adverse event profile was predictable and manageable, supporting its feasibility for long-term administration. Clinical trial information: NCT06031558 .

10-year molecular landscape of metastatic colorectal cancer in Latin America: Gender and age-specific mutational patterns in a large Colombian cohort (N=2,543).

e15597 Background: Molecular profiling of KRAS , NRAS , and BRAF is mandatory for anti-EGFR therapy selection and prognostic stratification in metastatic colorectal cancer (mCRC). While well-characterized in Caucasian and Asian populations, large-scale data from Latin America—a region with unique genetic admixture—remain scarce. We aimed to characterize the mutational prevalence, demographic associations, and testing modalities in the largest Colombian mCRC cohort to date, identifying high-risk biological clusters. Methods: We conducted a retrospective analysis of 2,543 patients with stage IV CRC (2014–2023) at a national reference laboratory. Mutations in KRAS/NRAS (exons 2-4) and BRAF (exons 11, 15) were detected via RT-PCR (IVD/CE-marked). Testing was primarily performed on FFPE tissue (≥10% cellularity); plasma cfDNA was utilized since 2019 when tissue was unavailable. Statistical significance was assessed using 𝜒2 and Fisher’s exact tests. Results: The cohort was balanced by sex (49.3% female; 50.7% male; median age 61). FFPE was the predominant modality (11:1 ratio vs. plasma). Mutational Prevalence: FFPE rates were KRAS 3%, NRAS 8.0%, and BRAF 11.0%. Gender Dimorphism: Overall mutational burden was significantly higher in women (p &lt; 0.05). Specifically, BRAF exon 15 (V600) variants were enriched in women (96.0% vs. 85.0% in men, p = 0.008), whereas exon 11 (non-V600) variants were more frequent in men (15.0% vs. 4.0%, $p = 0.01). Age Interaction: In women, BRAF mutations showed a strong association with age &gt; 50 years (p = 0.002), a pattern not observed in men or for RAS Liquid Biopsy Performance: cfDNA showed lower sensitivity for RAS detection compared to FFPE (p &lt; 0.001), primarily due to the failure to capture low-frequency NRAS . Conclusions: This landmark study reveals significant sex- and age-specific biological clusters in Colombian mCRC patients. The BRAF -age-gender nexus (Women &gt; 50y) likely reflects a high prevalence of the Serrated Pathway, identifying a priority group for BRAF-targeted triplets and immunotherapy (MSI-H-linked). Furthermore, the identification of KRAS G12C and atypical BRAF (Exon 11) variants underscores the need for reflex NGS to personalize therapy. While liquid biopsy is expanding, tissue-based testing remains the gold standard for initial molecular staging in this real-world setting. Variable Total Cohort Women (n=1,253) Men (n=1,290) p-value Median Age (Range) 61 (15–95) 62 (18–95) 60 (15–92) 0.08 Specimen Type - FFPE Tissue 91.7% 91.5% 91.9% NS - Plasma cfDNA 8.3% 8.5% 8.1% NS Mutational Status (FFPE) - KRAS Mutated 52.3% 54.1% 50.5% 0.042 * - NRAS Mutated 8.0% 7.8% 8.2% 0.65 - BRAF Mutated 11.0% 12.8% 9.3% 0.015 * BRAF Subtype (Exon) - Exon 15 (V600) 90.5% 96.0% 85.0% 0.008 * - Exon 11 (Non-V600) 9.5% 4.0% 15.0% 0.012 * Age-Specific BRAF+ - Age &gt;50 years - 14.2% 9.5% 0.002 * - Age &lt;50 years - 8.1% 8.9% 0.45

BRIDGe: Barriers to real-world implementation of diagnostic genomics—Quantifying the genomic awareness-access divide in Indian oncology care.

e13604 Background: Uptake and actionability of molecular testing remain suboptimal in low-and-middle-income settings. In this study, we quantify the awareness-to-uptake gap &amp; care-delivery gaps, identifying modifiable barriers to equitable precision oncology, in an urban tertiary oncology center in South India. Methods: Cross-sectional, anonymized survey (Cronbach’s α = 0.7) developed by a 4-member oncology team and piloted in the OPD, conducted between January &amp; December 2025. Along with clinical data, a 7-item factual genomic awareness score (range 0–7; ≥5 = high awareness) assessed knowledge of clinical utility, heritability, methods, facilities and access. Uptake was defined as completion of molecular test. Descriptive statistics and Chi Square were done to identify predictors of test uptake. Results: Participants included 114 patients and 314 caregivers (73.4%); 67.3% were female and 15.8% were medical personnel. Respondents were primarily affiliated with breast (47.6%), gastrointestinal (17.3%) and gynecological (16.8%) cancers. Per indication, 276 respondents underwent pre-test counselling, and only 178 actually underwent molecular testing. Among them, 39.3% were covered by insurance, 32.6% paid out-of-pocket and only 28.1% could utilize patient-assistance. Treatment was modified in 50.6% based on results; while 88/178 (49.4%) had no treatment change (46 with no actionable result; 42 were financially unable to access indicated therapy). Initial exposure to genomic testing was predominantly physician-driven. Despite 73.4% knowing that cancers can be inherited, only 216 respondents identified the role of molecular testing in guiding diagnosis and treatment. Despite high interest (81.8% wished to learn more; 74.8% willing to participate in research), 92.8% perceived testing as unaffordable and only 7.0% were aware of possible insurance coverage. Barriers to testing included lack of awareness (65.0%), cost (25.2%), fear of results (9.8%). 35.5% reported ethical/privacy concerns. Despite an urban/graduate majority, only 24.8% met the criteria for high awareness (Age &lt; 40y, Post graduate education, caregivers, medical background p &lt; 0.05). Mean awareness scores were higher among those tested (4.8±1.5) than the overall population (3.3±1.6). Conversely, high awareness did not translate to high test uptake (p &lt; 0.05). Medical background and postgraduate education were independent predictors of test uptake. (p &lt; 0.05). Conclusions: Despite a tertiary-urban setting, genomic literacy is moderate. Willingness and meaningful clinical impact are undermined by affordability and limited insurance coverage. In LMICs, precision oncology cannot be equitable if genomic awareness outpaces financial and systemic support. Improvement of public education &amp; healthcare policy advocacy can bridge the awareness-to-uptake divide in cancer care.

Phase II study of frontline gemcitabine, 5-fluorouracil/leucovorin, and cisplatin (GemFLP) in advanced urachal and non-urachal urinary tract adenocarcinoma.

4515 Background: Adenocarcinomas of the urinary tract are rare malignancies with limited prospective data. Outcomes of triplet chemotherapy remain poorly defined. Methods: This was a prospective, single-arm, phase II study (NCT00082706) conducted at MD Anderson. Between 2005 and 2010, patients (pts) aged ≥18 years with ECOG 0–2 and metastatic or unresectable urachal (UA) or non-urachal adenocarcinoma (NUA) received frontline GemFLP (5-fluorouracil 200 mg/m² continuous infusion ×5 days with leucovorin 23 mg IV daily ×5; cisplatin 20 mg/m² IV daily ×5; gemcitabine 200 mg/m² IV on days 1 and 5). Best overall response (BOR) was assessed by imaging. Primary endpoints were objective response rate (ORR) and overall survival (OS); secondary endpoint was toxicity. PFS was calculated from treatment initiation and duration of response (DoR) from first CR/PR to progression or death; time-to-event endpoints were estimated by Kaplan–Meier (KM). Post hoc analyses evaluated baseline tumor markers (CEA, CA19-9, CA125, β-hCG) Treatment-related adverse events (TRAEs) were graded per CTCAE v5. Results: Forty-six pts were enrolled (28 UA, 18 NUA). Median age was 58 years; 41% were de novo metastatic, and 78% had visceral metastases. ORR was 44% (20/46). Among responders, median DoR was 8.6 months (95% CI 4.6–30.8). median PFS was 3.3 months (95% CI 2.3–8.4) and median OS (mOS) was 21.0 months (95% CI 15.9–35.3) There was no difference in PFS (p=0.39) or OS (p=0.99) between UA and NUA. Baseline CEA, CA19-9, CA125, and β-hCG were not associated with ORR or PFS. Higher baseline CA125 was associated with inferior OS (HR 1.33, 95% CI: 1.12–1.58; p =0.001) Subsequent systemic therapy was administered to 28 pts (60.9%); median number of subsequent treatment lines was 2 (range 1–5). The most common hematologic TRAEs were anemia (28.1%; grade ≥3 [G3] 12.5%), thrombocytopenia (21.9%; G3 12.5%), and neutropenia (12.5%; G3 9.4%). The most frequent non-hematologic TRAEs were dehydration (21.9%; G3: 6.2%), diarrhea (9.4%; G3 6.2%) and catheter-related thrombosis (9.4%; G3 9.4%). No grade 5 events occurred. Conclusions: In this prospective phase II study, frontline GemFLP achieved a 44% ORR with durable responses (mDoR 8.6 mo) and 21 mo mOS in advanced UA and NUA. Survival did not differ between UA and NUA subtypes. Baseline CA125 was associated with OS. Toxicity was manageable. These data provide a prospective benchmark for this rare disease. Clinical trial information: NCT00082706 . Variable UA (n=28) NUA (n=18) Characteristics Age, median [ICR] 58 [54– 62] 58 [54– 62] 67 [ 62-72] Race, n (%) White 22 (79) 11 61) Black 6 (21) 6 (33) Other 0 1 (6) Prior surgery for localized disease, n (%) 18 (64) 5 (28) Mets at baseline Any 24 (86) 7 (39) Lung 6 (21) 4 (22) Liver 3 (11) 0 Peritoneum 17 (61) 0 Bone 3 (11) 3 (17) Nodal-only mets 1 (3) 2 (10) Outcomes ORR (%) 43.5 35.7 55.6 BOR n (%) CR 4 (14) 2 (11) PR 6 (21) 8 (44) SD 11 (39) 4 (22) PD 6 (21) 3 (17) NE 1 (4) 1 (6)

Enrollment outcomes after screening in phase 1 oncology clinical trials: Real-world evidence from a NCI-designated cancer center.

e13720 Background: Despite many efforts to increase diversity enrollment in Phase 1 trials (Ph1) significant disparities persist among underrepresented minorities (URM). Enrollment patterns for this patient population after initial screening for Ph1 are poorly understood. We evaluated the patients' journey from screening to enrollment for URM to understand the patterns once they have potential access to Ph1. Methods: All patients screened for Ph1 at the John Theurer Cancer Center at Hackensack University Medical Center from 2014-2025 were analyzed. Primary outcomes were enrollment rate, stratification by racial/ethnic group and representation compared to US Census Bureau (2018-2022). Statistical analysis included a chi-square test for differences in enrollment rates, Fisher's exact test for pairwise comparisons, and a Kruskal-Wallis test for age differences. Results: A total of 1,316 patients were evaluated for 140 Ph1. 803 patients were enrolled, yielding an enrollment rate of 61.0%, with URM comprising 33.3% of enrollments. The study cohort was 52.1% female and 47.9% male, median age was 62.5 years (range, 24.7–90.9). Racial/ethnic composition included non-Hispanic White (NHW) 66.2%, Hispanic 19.0%, African American/Black (AA) 7.5%, Asian 6.8%, and Other 0.5%.There were no statistically significant differences in enrollment rates across groups (p=0.225). However, NHW had higher enrollment rates compared to URM. NHW 62.6%, Hispanic 60.8%, AA 56.9%, Asian 52.3%. Pairwise comparisons are shown in Table 1. Comparison with census data demonstrated notable disparities in representation. NHW participants were overrepresented at screening (66.2% vs 47%; ratio 1.42), whereas URM groups were underrepresented, including Hispanic (19.0% vs 20%; ratio 0.95), AA (7.5% vs 14%; ratio 0.52), and Asian individuals (5.6% vs 10%; ratio 0.56). The enrollment rate remained stable over time (2014-2019: 59.6% vs 2020-2024: 63.5%, p=0.907). Mean age in the study cohort varied significantly (Kruskal-Wallis H=62.68, p&lt;0.001): Hispanic 58.5 years, AA 59.5 years, Asian 59.5 years, NHW 64.2 years, with Hispanic being the youngest group to enroll. Conclusions: Enrollment rates among patients screened for Ph1 were comparable across racial/ethnic groups, indicating equitable access after screening. However, substantial demographic disparities were observed at the screening stage with NHW being overrepresented, and AA and Asian patients underrepresented relative to regional demographics. These findings suggest that ensuring access to Ph1 access enables enrollment parity, but that inequities in referral and pre-screening processes persist. Comparison Rates P-valve NHW / Hispanic 62.6% / 60.8% p = 0.606 NHW / AA 62.6% / 56.9% p = 0.282 NHW / Asian 62.6% / 52.3% p = 0.064 Hispanic / AA 60.8% / 56.9% p = 0.550 Hispanic / Asian 60.8% / 52.3% p = 0.204 AA / Asian 56.9% / 52.3% p = 0.559

The association of nutritional factors on disease control and survival in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) treated with anti–PD-1 monoclonal antibody.

6053 Background: Anti-PD-1 mAb therapy is standard of care for systemic treatment for R/M-HNSCC. These patients (pts) also face significant issues with malnutrition. Therefore, we evaluated whether there was any association between outcomes with anti-PD-1 treatment and nutritional markers including BMI, prognostic nutritional index (PNI), and serum albumin. Methods: We collected baseline serum albumin, PNI [(10 × serum albumin (g/dL)) + (0.005 × total lymphocyte count)], BMI, and initial BMI trend (baseline to 3 months), on pts with R/M-HNSCC treated with anti-PD-1 at our institution and evaluated association with disease control (CR/PR/SD vs. PD), PFS, and OS. Baseline BMI was analyzed as a continuous variable and binarily [&lt;18.5 vs. ≥18.5, and median split (23.85)]. Associations of explanatory variables with disease control were evaluated using multivariable logistic regression, reported as odds ratios (ORs) and 95% confidence intervals (CIs) and with PFS and OS using Cox proportional hazards regression, reported as hazard ratios (HRs) and 95% CIs. All analyses were conducted using R version 4.5.2. Results: In our retrospective cohort (n = 124), the median age was 68 and primary sites included oral cavity (39%), larynx (16%), hypopharynx (5%), oropharynx (34%; 64% p16+), and other (6%). 43% of patients received anti-PD-1 for platinum failure and 57% for frontline. On univariate analysis, higher PNI was significantly associated with increased disease control (OR = 1.11; 95% CI: 1.04–1.21; p = 0.007), PFS (HR = 0.96; 95% CI: 0.94-0.98; p &lt; 0.001), and OS (HR = 0.97; 95% CI: 0.95–0.99; p = 0.002). Higher albumin was significantly associated with increased PFS (HR = 0.45; 95% CI: 0.24-0.85; p = 0.014) and OS (HR = 0.25; 95% CI: 0.13-0.48; p &lt; 0.001). Evaluation of baseline characteristics showed platinum failure was significantly associated with worse efficacy and therefore multivariate analysis was conducted, adjusting for platinum failure status. PNI was still significantly associated with increased disease control (OR = 1.09; 95% CI: 1.03–1.18; p = 0.016) and PFS (HR = 0.97; 95% CI: 0.95–0.99; p &lt;0.001). Higher serum albumin was only significantly associated with increased OS (HR = 0.29; 95% CI: 0.14–0.57; p &lt;0.001). Neither baseline nor trend in BMI was associated with efficacy. Conclusions: In our cohort of anti-PD-1 treated R/M-HNSCC pts, higher baseline albumin was associated with increased OS while higher baseline prognostic nutritional index was associated with increased disease control and PFS, including in multivariate analysis. While BMI has been associated with efficacy of anti-PD-1 in other solid tumors, it was not in our cohort. Our data suggests that markers that factor in nutritional and immune status may be more relevant in R/M-HNSCC. Further study is warranted.

Social determinants of health and survival outcomes in metastatic breast cancer (MBC): Retrospective analysis from a major Canadian cancer centre.

e13758 Background: Social determines of health (SDOH), including geography and sociodemographic factors influence cancer outcomes, even in publicly funded healthcare systems. However, evaluation is limited by inconsistent data collection. We examined survival outcomes among patients with MBC across regional health care authorities (HCA) in British Columbia (BC), Canada, focusing on available sociodemographic data, including self-reported race and ethnicity. Methods: We conducted a retrospective cohort study of patients diagnosed with MBC between 2014-2017 across BC HCAs using a prospective provincial cancer database. Sociodemographic variables, including self-reported race and ethnicity, were manually abstracted from clinical intake and consultation records and categorized according to Canadian Cancer Clinical Trials Network (3CTN) guidelines. Endpoints were 5-year breast cancer specific (BCSS) and overall survival (OS), estimated using Kaplan-Meier methods and compared with log-rank tests. Results: Among 1917 eligible patients, 513 (26%) had missing self-reported race and ethnicity data, most commonly due to non-disclosure. Patient demographics reflected the 2021 provincial census, with White and East Asian patients comprising the largest groups (54.7% and 7.4%). No significant differences in BCSS and OS were observed across racial and ethnic groups (p = 0.2), though interpretation was limited by missing data. Survival varied by geography: patients treated in the urban HCA had higher 5-year OS relative to those treated in more remote HCAs (Table 1). No significant differences in BCSS were observed by HCA. Conclusions: Within a large, publicly funded cancer system, urban geography was associated with improved OS in MBC, highlighting geography as a key SDOH. The absence of BCSS differences may reflect standardized treatment delivery and competing non-cancer comorbidities. Although no survival differences by race or ethnicity were identified, substantial missing data limits definitive conclusions. These findings underscore the importance of standardized, prospective collection of sociodemographic and comorbidity data to inform equitable cancer care delivery. Further work is needed to clarify drivers of regional variation, including local treatment availability, clinical trial access and patient-level factors influencing treatment uptake. Five-year breast cancer mortality and overall mortality across regional HCA. 5-year Breast Cancer Mortality (95% CI) 5-year Overall Mortality (95% CI) Health authority 1 (urban) 70.0 (65.5, 74.0) 27.8 (23.9, 32.3) 2 76.0 (71.5, 79.9) 22.3 (18.6, 26.7) 3 76.6 (73.1, 79.7) 19.3 (16.4, 22.6) 4 76.3 (71.4, 80.6) 18.6 (14.8, 23.2) 5 69.8 (59.4, 78.0) 22.9 (15.9, 33.1)

Meaning-centered psychotherapy versus dignity therapy for spiritual well-being in patients with cancer: A systematic review and meta-analysis.

e24118 Background: Meaning-Centered Psychotherapy (MCP) and Dignity Therapy (DT) are frequently employed psychotherapeutic approaches in palliative cancer care. Both are grounded in existential principles and designed to assist patients with advanced cancer. Evidence suggests that both interventions can improve spiritual well-being in this population. To date, no systematic meta-analysis has compared the efficacy of these interventions in enhancing spiritual well-being, and it remains unclear which intervention may be more effective. Implementing these therapies requires substantial resources, and in settings with limited resources, palliative care services must make strategic decisions about which intervention to prioritize. This study examined the comparative effectiveness of MCP and DT for improving spiritual well-being in adults with cancer using an indirect meta-analytic approach. Methods: This systematic review and meta-analysis was registered in PROSPERO (CRD42025642106). PubMed/MEDLINE, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to January 28, 2025, without language or date restrictions. Randomized controlled trials and cohort studies involving adult cancer patients receiving MCP or DT were included. Usual care or palliative care without structured psychotherapeutic intervention served as comparators. The characteristics of MCP and DT were extracted and reported using the Template for Intervention Description and Replication (TIDieR) checklist. The primary outcome was spiritual well-being measured using the Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being (FACIT-Sp). Two reviewers independently screened and extracted data. Random-effects meta-analyses were conducted for MCP and DT versus usual care, with indirect comparison using the Bucher method and heterogeneity assessed by I². Results: Four studies comparing MCP with usual care ( N = 758; 374 MCP, 384 control) and three studies comparing DT with usual care ( N = 412; 214 DT, 198 control) were included.MCP was associated with a statistically significant improvement in spiritual well-being compared with usual care (MD = 3.23, 95% CI 0.82 to 5.64; I² = 74.1%).DT showed no significant difference compared with usual care (MD = −0.11, 95% CI −1.23 to 4.69; I² = 18.2%). Indirect comparison using the Bucher method showed no statistically significant difference between MCP and DT (MD = 3.47, 95% CI −4.13 to 11.07). Conclusions: The indirect comparison found no significant difference between MCP and DT. In the absence of evidence demonstrating the superiority of MCP or DT, these findings raise important considerations for palliative care services. Our results emphasize the need for direct head-to-head trials and economic evaluations to guide service planning and clinical decision-making.

Impact of adjuvant sequential chemoradiotherapy on long-term overall survival in early-stage cervical cancer: Final analysis of the STARS phase III randomized trial.

5527 Background: The STARS trial (NCT00806117) previously demonstrated that adjuvant sequential chemoradiotherapy (SCRT) significantly improved disease-free survival (DFS) compared with radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) in early-stage cervical cancer patients with pathological risk factors. This pre-specified analysis reports the mature overall survival (OS) results. Methods: In this open-label, phase III trial, 1,048 cervical cancer patients with FIGO stage IB1–IIA2 and postoperative pathological risk factors were randomized (1:1:1) to receive RT alone, CCRT (RT with weekly cisplatin), or SCRT (paclitaxel-cisplatin chemotherapy before and after RT). The second endpoint was OS, analyzed by intention-to-treat. Subgroup analyses were performed based on risk stratification: intermediate-risk (deep stromal invasion or lymphovascular space invasion) and high-risk (node-positive or parametrial involvement). Results: With a median follow-up of 90 months, SCRT significantly improved OS compared to both RT (10-year OS 89.0% vs 81.0%; HR 0.54, 95% CI 0.35-0.83; P=0.005) and CCRT (89.0% vs 83.0%; HR 0.64, 0.41-0.98; P=0.040) in intention to treat population. No significant difference was observed in OS between CCRT and RT (HR 0.85, 0.58-1.24; P=0.404). The survival benefit of SCRT was consistent across key subgroups: it was most pronounced in intermediate-risk patients (HR 0.54 vs RT, 95% CI 0.31-0.93; P=0.027) and showed a clinically meaningful trend in high-risk patients (HR 0.61, 95% CI 0.30-1.24). However, CCRT showed no overall benefit in these risk-based populations but was markedly effective in the subgroup with deep stromal invasion without lymphovascular invasion (HR 0.20 vs RT, 95% CI 0.05-0.85; P=0.029) in per-protocol population. SCRT achieved higher protocol completion than CCRT (73.4% vs 62.3%) and was an independent favorable prognostic factor for OS (HR 0.54) in multivariable analysis, along with lymph node metastasis and adenocarcinoma histology. Conclusions: The long-term STARS trial update confirms adjuvant SCRT as the optimal strategy, demonstrating both DFS and OS superiority in early-stage cervical cancer with postoperative risk factors. The significant 10-year survival benefit strongly supports adopting SCRT where radiotherapy access is limited. Clinical trial information: NCT00806117 .

Impact of ILT4 on lipid metabolism of tumor-associated macrophages to drive immunosuppression and tumor progression in NSCLC.

e20598 Background: Tumor-associated macrophages (TAMs), as the most abundant immune cells in the tumor microenvironment (TME), are main mediators impairing anti-tumor immune response of T cells and restrict immune checkpoint blockade (ICB) efficacy. Suppressing reprogramming and enhancing phagocytosis of TAMs represent promising strategies to potentiate ICB efficacy by harnessing the dual immunoregulatory roles of TAMs. However, the key regulators for TAM reprogramming have not been fully elucidated. Immunoglobulin-like transcript 4 (ILT4) is pivotal for the immunosuppressive activity of myeloid cells. However, its critical role and specific mechanisms in reprogramming TAMs within NSCLC are poorly understood. Methods: Transcriptomic sequencing, multicolor immunofluorescence, and integrated bioinformatics analysis of public databases were used to identify the key regulators for TAMs reprogramming. Kaplan–Meier survival and clinicopathological analysis were performed to assess the clinical significance of ILT4 expression in TAMs. The role of ILT4 in TAM reprogramming and tumor progression were elucidated through in vitro and in vivo experiments. Lipidomics, lipidTOX staining, mitochondrial stress test, transcriptomic sequencing, and rescue experiments were conducted to identify the specific mechanism. Mouse tumor models and therapeutic intervention models were employed to evaluate the potential synergy of combining ILT4 knockout (via adoptive transfer of macrophages from ILT4 (PIR-B) knockout mice) with CD47 and/or PD1 antibody blockade. Results: ILT4 was enriched in TAMs of NSCLC tissues, predicting immunosuppressive TME and unfavorable clinical outcomes. Functionally, ILT4 reprogrammed TAMs towards a pro-tumoral phenotype, therefore suppressing T cell immunity and fueling tumor aggressiveness. Mechanistically, ILT4-activated PI3K/AKT signaling upregulated the expression of CD36 and fatty acid synthase (FASN), two key enzymes mediating fatty acid uptake and synthesis, led to triglyceride (TG) accumulation and energy disorder in TAMs, and sustained their pro-tumoral properties. ILT4 inhibition prevented lipid reprogram of TAMs, and reversed TAM-induced immunosuppression and tumor progression. More importantly, ILT4 (PIR-B) knockout enhanced the efficacy of anti-PD1 and anti-CD47 therapy in vivo, while the triple combination therapy showed the optimal efficacy compared to dual or monotherapy. Conclusions: ILT4 is enriched in TAMs infiltrating NSCLC and plays a key role in driving pro-tumoral polarization of TAMs, a process mediated by the PI3K-AKT-CD36/FASN-TG axis. Furthermore, ILT4 blockade synergistically enhances the efficacy of both CD47 and PD-1 antibodies, with the triple combination showing optimal therapeutic activity. These findings establish a theoretical foundation for developing novel clinical strategies.

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