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Association of prior prostate cancer screening with stage at diagnosis in a US EHR cohort, 2018–2025.
e17071 Background: The US Preventative Service Task Force recommends prostate-specific antigen (PSA)-based screening for men aged 55–69 years and generally discourages routine screening over the age of 70. In addition, the American Cancer Society recommended discussing screening beginning at 40 for patients at high-risk of developing prostate cancer. We evaluated whether evidence of prior PSA screening is associated with earlier stage at first prostate cancer diagnosis. Methods: Using a subset of electronic health records from Truveta Data, we identified adults aged ≥40 years with a first-recorded prostate cancer diagnosis in 2018–2025 (index date). Stage at diagnosis was extracted from clinical notes within 90 days of the index date and categorized as early (I–II) versus late (III–IV). To capture prior screening behavior rather than diagnostic workup for the index diagnosis, we defined prior PSA screening as any PSA screening recorded three years to six months before the index. Patients were required to have ≥1 outpatient visit in the year before the index date and ≥1 outpatient visit in years two or three before index. Patients were excluded if they had any chemotherapy or cancer treatment before index. We compared stage distributions overall and by age group (40–54, 55–69, ≥70). Multivariable logistic regression estimated the association between prior PSA screening and early-stage diagnosis, adjusting for age group, race, ethnicity, rural/urban, Elixhauser comorbidity index, and diagnosis year. Additional logistic regression models were conducted for each age group. Results: Among 1,038,594 patients with prostate cancer, 7,497 met the strict criteria to be included (mean age 73 years). Prior PSA screening was present in 2,163 (55.3%) patients. Early-stage disease was more common among those with prior PSA screening (43.8% vs 39.3%, p < 0.001). Prior PSA testing was associated with higher odds of early-stage diagnosis (adjusted OR 1.49, 95% CI 1.34-1.66). Across age strata, prior PSA testing was consistently associated with higher early-stage proportions (ages 40–54: OR 2.06, 95% CI 0.84-5.03; ages 55–69: OR 1.37, 95% CI 1.14-1.65; ages ≥70: OR 1.54, 95% CI 1.35-1.76). Conclusions: Prior PSA screening was associated with higher odds of earlier-stage at first diagnosis across age strata. The association was observed even among men in age ranges in which routine PSA screening is not generally recommended. Prior routine PSA screening may reflect greater engagement with preventive care or early evaluation of prostate health. The findings of this study support policies and practice workflows that promote timely, risk-informed screening discussions and equitable access in ages 55–69, and individualized decision-making for younger (40–54) and older (≥70) adults to balance the potential benefit of early-stage diagnosis with harms of overdiagnosis.
Plasma small extracellular vesicle microRNAs as non-invasive biomarkers for the diagnosis of pancreatic ductal adenocarcinoma.
4227 Background: Current non-invasive approaches for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) exhibit inherent limitations in accuracy. Consequently, there exists an urgent and unmet need for novel non-invasive biomarkers exhibiting high sensitivity and specificity to enable PDAC diagnosis. Methods: We employed small RNA sequencing to detect microRNA (miRNA) expression in small extracellular vesicles (sEVs) isolated from plasma samples of study participants (n = 208). A diagnostic model was developed (n = 140) and validated (n = 68) to discriminate between patients with PDAC and non-malignant controls (healthy individuals, chronic pancreatitis, intraductal papillary mucinous neoplasms, serous cystadenomas, solid pseudopapillary tumors, pancreatic cysts, and pancreatic abscesses). Results: The small RNA sequencing analysis of plasma sEV miRNA identified 32 differentially expressed sEV miRNAs between non-malignant controls and PDAC patients. The diagnostic model with the best performance was constructed using 17 sEV miRNAs. The diagnostic model achieved an area under curve (AUC) of 0.939, a sensitivity of 93%, and a specificity of 90% in the training cohort and an AUC of 0.951, a sensitivity of 95%, and a specificity of 83% in the test cohort. We identified the distinct characteristics of plasma sEV miRNAs among non-malignant controls compared to PDAC patients. Moreover, nine negative miRNAs and one positive miRNA were found significantly associated with the death risk of PDAC (all p < 0.05). Conclusions: Our findings demonstrates that plasma sEV miRNA exhibits a highly discriminative biomarker for distinguishing non-malignant group from malignant group, making it a promising tool for the diagnosis of PDAC.
Role and mechanism of CMTM6 in radiosensitivity of breast cancer cells.
e12600 Background: To further investigate the role of CMTM6 in breast cancer radiosensitivity, this study employed lentivirus-mediated gene overexpression/knockdown techniques to construct breast cancer cell lines with CMTM6 overexpression or knockdown. The effects of different CMTM6 expression levels on breast cancer cell proliferation, migration, and invasion capabilities were validated, along with its impact on radiosensitivity and underlying mechanisms. The aim is to explore the molecular mechanisms of CMTM6 in breast cancer radiosensitivity, identify new therapeutic targets, and provide more effective treatment strategies for breast cancer patients. Methods: Firstly, we established and validated CMTM6-overexpressing/knockdown breast cancer cell lines, and investigated the effects of CMTM6 overexpression/knockdown on the proliferation, migration, and invasion of breast cancer cells, as well as on these cellular behaviors after irradiation. After treating control and CMTM6-knockdown MDA-MB-231 cells with 4 Gy irradiation, Western blot assays were conducted to explore the effect of CMTM6 on DNA damage in breast cancer cells after irradiation. Respectively, followed by Western blot analysis to detect the expression levels of proteins related to the JAK2/STAT3 signaling pathway, aiming to elucidate the mechanism of CMTM6 in breast cancer cell radiosensitivity. Results: The protein expression level of CMTM6 in CMTM6-knockdown MDA-MB-231 cells was significantly lower than that in the non-knockdown group. Meanwhile, qRT-PCR detection revealed that the mRNA expression level of CMTM6 was significantly reduced in CMTM6-knockdown MDA-MB-231 cells. In contrast, the protein expression level of CMTM6 was significantly increased in CMTM6-overexpressing MCF7 cells compared to the empty vector group. CMTM6 knockdown inhibited the proliferation, migration, and invasion abilities of breast cancer cells after irradiation. Conversely, CMTM6 overexpression promoted the proliferation and migration of irradiated cells and reduced the radiosensitivity of breast cancer cells. Knocking down CMTM6 may enhance the radiosensitivity of MDA-MB-231 cells by inhibiting the activation of the JAK2/STAT3 signaling pathway. Conclusions: This study demonstrates significant differences in CMTM6 expression levels across different breast cancer cell lines. CMTM6 plays an important role in breast cancer proliferation, migration, invasion, and radiosensitivity. Modulating CMTM6 expression can influence the biological behavior of cancer cells: knockdown of CMTM6 significantly inhibits the proliferation, migration, and invasion abilities of MDA-MB-231 cells, while overexpression of CMTM6 significantly promotes the proliferation and migration of MCF7 cells. Furthermore, knockdown of CMTM6 may enhance the radiosensitivity of breast cancer cells by inhibiting the activation of the JAK2/STAT3 signaling pathway.
Post-operative ctDNA-detected molecular residual disease in resected non-small cell lung cancer: A systematic review and meta-analysis of prognostic accuracy.
e20043 Background: Non-small cell lung cancer (NSCLC) continues to be the most common cause of cancer-related deaths globally, contributing to 85% of all lung cancer cases. Recurrence rates remain high despite complete surgical resection in patients with stage I to III NSCLC, despite appropriate postoperative therapy, occurring in 30-55% of patients. Thus, there is an urgent need for biomarkers like ctDNA to detect molecular residual disease (MRD). In light of the increasing but heterogeneous literature, there is a need for a comprehensive analysis of the prognostic performance of postoperative ctDNA-detected MRD in resected NSCLC. Methods: We searched PubMed, Embase, Scopus, ScienceDirect, and Cochrane from inception to January 2026, identifying 438 records. Eligible RCTs and observational studies reported postoperative ctDNA prognostic accuracy (sensitivity, specificity, NPV, PPV, AUC) and DFS HRs (ctDNA+ vs ctDNA-) in resected NSCLC. Data were pooled using RevMan 5.4 with random-effects models (P<0.05). Results: Across 38 pooled studies (n=4794 resected stage I–III NSCLC), postoperative ctDNA positivity was strongly predictive of recurrence and inferior survival outcomes. The pooled recurrence rate among ctDNA-positive patients was 72.4%, compared with 18.7% among ctDNA-negative individuals. Meta-analysis demonstrated a pooled sensitivity of 0.76 (95% CI, 0.68–0.83), specificity of 0.88 (95% CI, 0.81–0.93), and AUC of 0.90 for predicting recurrence. Postoperative ctDNA positivity was associated with significantly shorter disease-free survival (HR = 3.45; 95% CI, 2.51–4.72; p < 0.001) and overall survival (HR = 2.82; 95% CI, 1.95–4.07). Pooled 2-year DFS rates were 38.1% for ctDNA-positive versus 82.6% for ctDNA-negative patients. Subgroup analyses across stage IB–IIIA disease, adjuvant-treated versus untreated cohorts, and assay type (tumor-informed vs tumor-naïve) demonstrated consistent hazard estimates, with no significant heterogeneity (I² < 40%). Collectively, postoperative ctDNA detection identifies molecular residual disease with high prognostic accuracy and serves as a robust biomarker for early recurrence risk stratification after curative-intent resection. Conclusions: Postoperative ctDNA serves as a reliable biomarker for molecular residual disease in resected NSCLC. ctDNA positivity predicts early recurrence whereas ctDNA negativity predicts durable remission, supporting postoperative surveillance.
Impact of population-specific <i>KRAS</i> alterations on therapeutic vulnerabilities in cholangiocarcinoma: Evidence from a global meta-analysis.
e16494 Background: Cholangiocarcinoma (CCA) exhibits marked molecular heterogeneity with significant geographic variation, limiting the generalizability of therapeutic strategies. While multiple genomic studies have characterized CCA, a comprehensive cross-country synthesis of patient-level mutational and clinically actionable alterations remains limited. We performed a meta-analysis integrating global sequencing datasets to define the genomic landscape, pathway dysregulation, and therapeutic relevance of somatic mutations in CCA. Methods: A systematic literature search of PubMed and Google Scholar identified sequencing-based CCA studies published within the last five years. Studies with patient-level clinical and mutational data were included, while those lacking detailed annotations were excluded. Somatic mutation data from 11 eligible studies across 9 countries were curated and integrated with publicly available MSK and TCGA CCA cohorts. Co-occurrence and mutual exclusivity were evaluated using Fisher’s exact test with Benjamini-Hochberg correction (q < 0.05). Pathway enrichment analysis was conducted using Enrichr with the Panther 2016 gene set. Therapeutic actionability was assessed using OncoKB classification. Results: A total of 1,613 CCA samples were analyzed. TP53 (39%) and KRAS (22%) were the most frequently mutated genes across all cohorts. Significant country-specific differences were observed, with TP53 (40%) and KRAS (22%) mutation frequencies in the Indian cohort being significantly higher than those in the MSK ( TP53 : 18.16%; KRAS : 10.45%) and TCGA cohorts ( TP53 : 9.68%; KRAS : 10.45%). Additionally, population-specific KRAS variants (p.G12R, p.G12V, p.G12D) observed exclusively in Indian patients and classified as Level 2 actionable alterations. Compared with the Indian cohort ( IDH1 : 14%; SMAD4 : 8%), the MSK dataset showed a higher IDH1 mutation frequency (22.89% vs 7%, p < 0.01) and a lower SMAD4 mutation frequency (2.49% vs 12%, p < 0.01). Distinct co-occurrence and mutual exclusivity patterns were observed between intrahepatic and extrahepatic CCA, with KRAS showing mutual exclusivity with IDH1 , BRAF , and BAP1 , particularly in iCCA. Conclusions: This comprehensive meta-analysis highlights significant geographic heterogeneity in CCA genomics, with KRAS emerging as a dominant and clinically relevant driver in the Indian population. The distinct KRAS mutation spectrum observed in Indian patients underscores the need for region-specific precision oncology strategies and supports the evaluation of KRAS -directed therapies in this population.
Reporting of propranolol use in studies of beta-blockers in colorectal cancer.
e23378 Background: Beta-adrenergic blockers have been investigated for potential therapeutic and prognostic effects across multiple malignancies, including colorectal cancer (CRC). Propranolol, a non-selective beta-blocker with proposed anti-tumour and anti-angiogenic properties, has received growing interest in oncology. However, the extent to which propranolol use has been specifically reported in studies of beta-blockers in CRC is unclear. Methods: A structured search of PubMed was conducted for the terms beta-adrenergic blockers and colon cancer, identifying publications from 1 January 1970 to 31 December 2025. Only full-length original research articles were included; reviews, abstracts, and letters were excluded. In studies reporting multiple cancer types, data from CRC-specific cohorts were extracted if these were identifiable. Extracted variables included total study population, number of beta-blocker users, and number of propranolol users. Studies were grouped according to whether propranolol use was explicitly reported. Descriptive statistics (medians, interquartile ranges [IQRs], and proportions) were calculated. No inferential analyses were performed. Results: The search (conducted 24 January 2026) yielded 66 publications; 38 were excluded as non-relevant or secondary literature. One target-trial emulation study in colorectal polyps was excluded. Two additional eligible studies were identified through reference screening, resulting in 30 included publications. Only 27% (8/30) reported data on propranolol exposure. Among these studies, the median number of propranolol users was 10 (IQR, 5–49). Studies reporting propranolol use were generally smaller than those that did not report drug-specific exposure, despite broadly similar reporting of beta-blocker use. Conclusions: Although several decades of published research have examined beta-blockers in CRC, explicit reporting of propranolol exposure is uncommon. The limited and inconsistent capture of propranolol use may constrain interpretation of existing evidence and hinders evaluation of this agent’s specific oncologic relevance. Improved granularity in reporting individual beta-blockers is needed to inform future repurposing studies and clinical trial design. Summary of propranolol use in papers of beta blocker use in colorectal cancer. Type of paper Number of papers (%) Number of people in study, median [IQR] Number of people taking beta blockers, median [IQR] Number of people taking propranolol, median [IQR] Propranolol users counted 8 (27%) 1001 [51 to 3801] 286 [15 to 1159] 10 [5 to 49] Propranolol users not counted 22 (73%) 3770 [1213 to 22891] 1236 [468 to 8663]* Not specified Total 30 (100%) 3329 [584 to 20248] 840 [194 to 8049] - *in three studies the number of people taking beta blockers was not specified.
Systemic anticancer therapy in patients with de novo metastatic pancreatic adenocarcinoma: A real-world analysis.
e16383 Background: Metastatic pancreatic adenocarcinoma (mPDAC) is associated with poor prognosis and limited treatment options. While guidelines recommend treatment with 5-FU or gemcitabine-based chemotherapy for patients with a good performance status (PS), many patients do not receive palliative chemotherapy or discontinue treatment shortly after initiation. Non-treatment is often attributed to frailty, comorbidities, or organ dysfunction; however, patients’ treatment decisions may also reflect the toxicity burden and modest effectiveness of available chemotherapy options. This study aimed to characterize and improve the understanding of patients with mPDAC who do not receive or are intolerant to systemic therapy. Methods: This study used the ConcertAI Patient360 electronic health record dataset with linked claims. Adult patients were included if they were diagnosed with de novo mPDAC between January 2020 and March 2025 and had at least 3 months of follow-up, unless censored due to death. Exploratory analyses were performed to characterize patients who did not receive chemotherapy and to better understand the proportion who may have been eligible for treatment. Among treated patients, treatment discontinuation in the absence of disease progression was evaluated to assess treatment intolerance. Results: Of the 2708 patients meeting eligibility criteria, 953 patients (35%) did not receive systemic anticancer therapy (median age, 72 years). Among those patients not treated, 375 patients (39% of 953) had an ECOG PS of 0-1, and 161 patients (17% of 953) also had no obvious contraindications to systemic therapy or provider-documented reason for treatment ineligibility. Among the 1755 chemotherapy-treated patients (median age, 69 years), 1306 patients (74%) had an ECOG PS of 0-1. Overall, 911 (52%) of these patients discontinued treatment within 90 days of initiation. Furthermore, 603 (median age, 70 years) of the 911 patients discontinued treatment despite no documented evidence of disease progression. Conclusions: In a large real-world population of patients with de novo mPDAC, over one-third did not receive chemotherapy, including patients who may have been eligible for treatment but remained untreated. Among chemotherapy-treated patients, approximately one-third discontinued treatment early in the absence of disease progression, suggesting potential chemotherapy intolerance. These findings further characterize patterns of systemic therapy non-treatment and early discontinuation among patients with mPDAC and potentially highlight a significant unmet need related not only to treatment efficacy but also to treatment tolerability and burden. A comparison of patient characteristics and outcomes between these populations and those who continue treatment is underway.
Elevated genomic risk and treatment gaps in Black patients with HR+ early breast cancer: A MammaPrint-based retrospective analysis.
e12766 Background: Black women with hormone receptor-positive (HR+) early-stage breast cancer (EBC) have a 38% higher mortality rate than White women, even after adjustment for socioeconomic and access-related factors. Genomic differences may contribute. Some gene expression (GE) assays may underestimate risk in Black patients, while MammaPrint has shown greater sensitivity in identifying high-risk disease. Objective: To evaluate MammaPrint risk classification and treatment patterns in an exclusively Black cohort with HR+ EBC and compare results with historic White-majority populations such as the MINDACT trial. Methods: We performed a retrospective review of 116 self-identified Black/African American women aged ≥18 years with Stage I–III HR+ breast cancer who underwent MammaPrint testing between October 2024 and June 2025 at West Cancer Center and the University of Tennessee in Memphis. One Stage IV patient was grouped with Stage III. Tumor features, molecular subtype, and treatment data were collected. Statistical analyses included descriptive statistics and trend testing. This pilot cohort will expand to approximately 1,000 patients. Results: Of 116 patients, 64 (55.2%) were classified as High Risk and 52 (44.8%) as Low Risk; mean age was 62.5 years. A significant trend showed increasing High Risk classification by stage (50.6% Stage I, 66.7% Stage II, 88.3% Stage III/IV; P trend = 0.02). MammaPrint risk strongly correlated with molecular subtype (p < 0.001), with most Low Risk tumors being Luminal A and most High Risk tumors Luminal B. Despite over half the cohort being High Risk, only 42.2% received neoadjuvant and 18.8% adjuvant chemotherapy, raising concerns for potential undertreatment. In contrast, the MINDACT trial reported a High Risk rate of 35.8% in a largely White population. Conclusions: MammaPrint identified a substantially higher genomic risk burden in this exclusively Black cohort compared with historic White-majority populations. Although High Risk tumors were predominantly Luminal B, chemotherapy use remained low, highlighting gaps in the application of genomic risk stratification and the need for more equitable precision oncology.
Trends and disparities in mortality from malignant neoplasms and cardiac arrest in the United States, 1999–2023.
e23365 Background: Malignant neoplasms (MN) significantly heighten mortality risk when they co-occur with cardiac arrest (CA), reflecting tumor burden and cardiovascular compromise. This study aims to analyze and interpret annual trends and disparities in mortality to evaluate public health initiatives. Methods: The mortality data from the CDC WONDER multiple cause of death files for adults aged ≥25 years were used to analyze age-adjusted and crude mortality rates (AAMRs and CMRs) per 100,000 for MN (ICD-10 Codes: C00-C97) and CA (ICD-10 Codes: I46.0; I46.1; 146.9), stratified by year, gender, race/ethnicity, place of death and geography. Joinpoint regression was used to estimate average annual percent change (AAPC) and annual percent change (APC) with 95% confidence intervals (CIs). Statistical significance was defined as p < 0.05. Results: A total of 1,497,522 deaths (females: 700,232; males: 797,290) were reported among malignant neoplasms and cardiac arrest patients, mostly in medical facility inpatient settings. The overall AAMR has decreased from 37.12 in 1999 to 21.17 in 2023 (AAPC: -2.25; 95% CI: -2.55 to -1.94; p < 0.001), with the most significant declines observed between 1999–2004 (APC: -3.49) and 2004–2019 (APC: -2.38). Adults aged ≥65 years experienced the highest CMR (104.23), with an annual decline in mortality by -2.50% (p < 0.001). Men were analyzed to have higher AAMR (34.36 vs 22.69), but a more pronounced decline in mortality than women (AAPC: -2.47 vs -2.06). Racial disparities show that the highest AAMR was observed among non-Hispanic (NH) Blacks (40.43), while the lowest was noted among NH Americans (20.88). Geographic disparities were evident, with the Northeastern region having the highest AAMR (44.69) and the Midwest having the least (12.64). Metropolitan areas showed a higher AAMR (29.26 vs 23.19) and a steeper decline in mortality than non-metropolitan areas (AAPC: -2.80 vs -1.85). At the state level, New York (88.12) and California (55.93) ranked highest, placing in the top 90th percentile during 1999–2020 and 2021–2023, respectively. Conclusions: Despite a significant decline in mortality related to malignant neoplasms and cardiac arrest over the past two decades, disparities persist, especially among older men, NH Blacks, and those living in metropolitan areas and the Northeastern region. Targeted interventions and equitable access to healthcare are needed to reduce mortality and address persistent health inequities among vulnerable populations. Average annual percent change (AAPC) of age-adjusted mortality rates for Malignant Neoplasms and Cardiac-arrest in the United States, 1999 to 2023. Variable Deaths AAPC (95%CI) Overall 1,497,522 -2.25 (-2.55 to -1.94) Male 797,290 -2.47 (-2.77 to -2.16) Female 700,232 -2.06 (-2.34 to -1.79) Non-metropolitan areas 191,983 -1.85 (-2.03 to -1.66) Metropolitan areas 1,126,984 -2.80 (-3.01 to -2.57)
Middle-high altitude residence as a predictor of improved immune checkpoint inhibitor outcomes in advanced NSCLC: A multicenter cohort study.
e20597 Background: Immune checkpoint inhibitors (ICIs) have transformed treatment for advanced non-small cell lung cancer (NSCLC), but clinical effectiveness remains variable. Altitude may modulate host immunity and treatment responses. This study investigated the association between residential altitude and outcomes, and explored potential mechanism. Methods: This is a retrospective cohort study across 11 medical centers in China. Patients with advanced NSCLC receiving ICIs were classified by residential altitude: low-altitude ( < 1000m), middle-altitude (1000-2000m) and high-altitude ( > 2000m). Endpoints included progression-free survival (PFS) and overall survival (OS). Landmark and restricted mean survival time (RMST) analyses were employed due to violation of proportional hazards assumptions. Propensity score matching (PSM) and Cox regression addressed confounding. Tumor immune profiles were characterized by RNA sequencing and multiplex immunohistochemistry. Results: A total of 1793 patients were included: low-altitude (n = 1024), middle-altitude (n = 342), and high-altitude (n = 427). Median PFS was 11.2 months in low-altitude groups, 14.7 months in middle-altitude and 13.4 months in high-altitude. 2-years landmark analyses demonstrated improved PFS in both middle-altitude (HR = 0.78, 95%CI 0.65-0.93, P = 0.0058) and high-altitude (HR = 0.77, 95%CI 0.65-0.91, P = 0.0018) groups versus the low-altitude group, with no difference between the former two. Thus, we pooled these into a single M-H (middle-high) altitude group (n = 769). In PSM cohort, RMST analysis showed sustained PFS benefit with M-H altitude at 1 year (0.79 months, P = 0.0002), 2 years (1.70 months, P = 0.0007), and 3 years (1.88 months, P = 0.0171). Multivariable Cox regression during the first 2 years confirmed lower progression risk with M-H altitude (HR 0.78, 95%CI 0.68-0.89, P = 0.0003). OS benefit was significant at 1-2 years but attenuated by year 3. Further analyses demonstrated PFS and OS benefit with M-H altitude in most subgroups. RNA sequencing (n = 124) revealed higher effector cell and lower suppressor cell immunophenoscores with M-H altitude. Immunohistochemistry (n = 172) demonstrated increased tissue-resident memory CD8 + T cell infiltration associated with improved outcomes. Conclusions: M-H altitude residence is independently associated with improved clinical outcomes in advanced NSCLC patients receiving ICIs. This is supported by enhanced effector immune signatures and tissue-resident memory CD8 + T cell infiltration in tumors from M-H-altitude residents.
Immunologic determinants in procured melanoma tissue as drivers of durable response to tumor-infiltrating lymphocyte therapy.
9511 Background: Predictive biomarkers that identify melanoma tumors capable of generating therapeutically effective tumor-infiltrating lymphocytes (TIL) remain inadequately defined. We conducted an integrated spatial and histopathologic evaluation of resected melanoma specimens to characterize tumor microenvironmental features associated with durable clinical benefit (≥12 months) and improved survival following TIL therapy. Methods: Data were extracted from early-phase clinical trials conducted at Moffitt Cancer Center enrolling patients with advanced melanoma treated with TIL. Tumor specimens from 45 of 50 patients undergoing TIL manufacturing were evaluable based on tissue availability. Histopathology, multiplex immunofluorescence, and NanoString GeoMx spatial transcriptomics were performed on procured tumors. Tertiary lymphoid structures (TLS) were defined as organized aggregates of CD3⁺ T cells and CD20⁺ B cells and classified as immature or mature based on CD21/CD23 expression. Associations with ex vivo TIL expansion, infused product composition, clinical response, progression-free survival (PFS), and overall survival (OS) were assessed. Results: Procurement sites included subcutaneous/soft tissue (78%), lymph node (18%), and lung (4%). Viable tumor content and necrosis were not associated with ex vivo TIL expansion or response. TLS were present in 56% (25/45) of tumors and were strongly associated with clinical response (18/45 responders overall; response rate 56% [14/25] in TLS-positive tumors vs 20% [4/20] in TLS-negative tumors; p=0.014), improved PFS after adjusting for procurement site (HR=0.32; p=0.005) and improved OS (p<0.0001). Evaluation of ex vivo TIL expansion demonstrated that TLS presence did not affect the total number of expanded TIL (p = 0.3) but was significantly associated with a higher proportion of CD8⁺ T cells within the infusion product (83% vs 56%, p=0.027). Spatial transcriptomics of 132 immune-enriched regions of interest demonstrated that responders exhibited marked upregulation of antigen-presentation and interferon-response programs, including MHC I/II genes, STAT1/2, IFI6, and CXCL9 . A patient-level immune activation score derived from the top 25 responder-associated transcripts correlated with improved PFS (p<0.0001). To independently validate the significance of this immune gene set score, we analyzed an external dataset from the Lauss et al., 2017 cohort. Consistent with our findings, the gene set score was significantly higher in TIL responders compared with non-responders (p=0.048). Conclusions: TLS and spatial immune activation signatures in procured melanoma tumors are strongly associated with response and survival following TIL therapy. These findings support the integration of tumor microenvironment biomarkers into patient selection and optimization strategies for TIL therapy.
Sequencing in the post-immunotherapy era: Does second-line tyrosine kinase inhibitor choice impact survival and safety in advanced HCC?
4140 Background: IMbrave150 trial established atezolizumab/bevacizumab as first line (1L) treatment for advanced hepatocellular carcinoma (HCC) in 2020. Current guidelines for second line (2L) therapy in advanced HCC rely on pre-immunotherapy (IO) trials (Lenvatinib, REFLECT trial and Cabozantinib, CELESTIAL trial). We investigated whether Lenvatinib (potent FGFR 1–4 inhibitor) offers superior efficacy over Cabozantinib (MET/AXL inhibitor with minimal FGFR activity) in post-IO setting by targeting the FGF-driven angiogenic escape pathways. Methods: Using TriNetX global network, we identified advanced HCC patients who received 1L atezolizumab/bevacizumab followed by 2L Lenvatinib (n=436) or Cabozantinib (n=115) within 6 months. 1:1 propensity score matching (PSM) balanced demographics, liver function, viral hepatitis, alcohol-related disorders, chronic liver diseases and key comorbidities. Outcomes include 1-year overall survival (OS), hepatic decompensation, cardiovascular (CV) outcomes and 90-day healthcare utilization, GI toxicity and acute renal failure (ARF). Each cohort was analyzed for 1 year competing risk of transition to third line (3L) systemic therapy vs. death vs. hospice. Results: Baseline characteristics were balanced except for lower pre-existing hypertension in Lenvatinib cohort (64% vs 74%; p=0.02). Post matching (n=110/arm), Lenvatinib showed significantly higher 1-year overall survival (OS). Safety analysis revealed significantly higher rates of new onset hepatic decompensation and a trend toward increased acute healthcare utilization with Cabozantinib. Renal, GI, and CV outcomes were comparable between cohorts. Lenvatinib arm had lower competing risk of mortality and higher cumulative incidence of receiving 3L therapy. Conclusions: In the real-world post-IO setting, Lenvatinib conferred significant 1-year survival benefit with superior hepatic safety profile compared to Cabozantinib. Cabozantinib exhibited higher rates of new hepatic decompensation and a trend toward increased healthcare resource utilization. Beyond a favorable pharmacoeconomic profile, results suggest superior sustained clinical benefit while preserving eligibility for 3L therapy. Given sample size constraints, these hypothesis-generating signals warrant validation in larger, multi-institutional cohorts. Key clinical outcomes. Outcome Lenvatinib Cabozantinib HR/ RR (95% CI) p-value Median OS (months) 10.2 8.3 1 year OS 47.1% 31.9% 0.65 (0.45, 0.95) 0.026 Hepatic decompensation 22.1% 37.5% 0.59 (0.34, 1.01) 0.046 CV outcomes 18.2% 16.4% 1.11 (0.62, 1.98) 0.72 90-day outcomes Healthcare utilization 37.3% 50.0% 0.75 (0.55, 1.01) 0.057 ARF 12.7% 13.6% 0.93 (0.47, 1.84) 0.84 GI events 25.5% 23.6% 1.08 (0.68, 1.71) 0.75 1 year Competing risks Death 36.1% 48.7% 3L therapy 30.7% 27.9% Probability of being event-free 32.6% 23.4%
Amivantamab in HPV-unrelated recurrent/metastatic head and neck squamous cell cancer after disease progression on immune checkpoint inhibitor and chemotherapy: Pivotal results from the phase 1b/2 OrigAMI-4 study.
6008 Background: Prognosis is poor for patients with HPV-unrelated recurrent/metastatic (R/M) head and neck squamous cell cancer (HNSCC) after disease progression on immune checkpoint inhibitor (ICI) and chemotherapy, with participants (pts) who received cetuximab showing an objective response rate (ORR) of 24% and median progression-free survival (PFS) of 3.8 months (Fayette Clin Cancer Res 2025). In addition to EGFR, MET expression is also elevated in R/M HNSCC. Therefore, we evaluated amivantamab, an EGFR-MET bispecific antibody with immune cell–directing activity, as monotherapy in HPV-unrelated R/M HNSCC after progression on platinum-based chemotherapy and a PD-(L)1 inhibitor. Methods: Cohort 1 of OrigAMI-4 (NCT06385080) evaluated subcutaneous (SC) amivantamab at a dose of 1600 mg (≥80 kg, 2240 mg) on Cycle 1 Day 1, then 2400 mg (≥80 kg, 3360 mg) on Cycle 1 Day 8 and Day 15, and then every 3 weeks. Pts with R/M HNSCC who had disease progression on a PD-(L)1 inhibitor and platinum-based chemotherapy were enrolled. Prior anti-EGFR therapy was exclusionary. The primary endpoint was ORR per RECIST v1.1. The sample size provided >99% power to reject the null hypothesis (ORR ≤10%) assuming an ORR of 30% with a 2-sided alpha of 5%. Secondary endpoints included duration of response (DoR), PFS, and safety. Results: As of 6 Jan 2026 (median follow-up: 9.0 months), the cohort was fully enrolled with 102 pts having received ≥1 dose of SC amivantamab. The median age was 63 years (range, 30–81), 77% were male, and 67% had an ECOG performance status of 1. All pts had received prior PD-(L)1 inhibitor and platinum-based chemotherapy. The confirmed ORR was 47% (48/102; 95% CI, 37–57), with 4 complete responses, 44 partial responses, and 39 pts with stable disease. A majority (79%) experienced shrinkage of target lesions. Among confirmed responders, the median DoR was 7.2 months (95% CI, 5.8–not estimable [NE]). Responses were rapid, with a median time to initial response of 6.6 weeks (range, 5.6–43.4). Median PFS was 6.8 months (95% CI, 5.2–8.2). Treatment-emergent adverse events (AEs) were mainly EGFR/MET-related, with the most common (>25%) being hypoalbuminemia, rash, dermatitis acneiform, paronychia, stomatitis, and fatigue. Administration-related reactions were seen in 13% of pts (all grade 1–2). In total, 6 (6%) pts discontinued due to treatment-related AEs. Longer follow-up, subgroup, and biomarker analyses will be presented at the meeting. Conclusions: SC amivantamab monotherapy demonstrated an ORR of 47%, with rapid and durable responses in pts with HPV-unrelated, R/M HNSCC after disease progression on an ICI and chemotherapy. The safety profile and tolerability are consistent with prior reports. Clinical trial information: NCT06385080 .
Randomized phase 3 study (MarsLight-11) evaluating IBI363 (TAK-928) versus docetaxel in patients (pts) with squamous non-small cell lung cancer (sqNSCLC) after prior chemotherapy (chemo) and immunotherapy (IO).
TPS8673 Background: In most series, sqNSCLC has worse clinical outcomes compared with non-squamous NSCLC with IO combinations. After chemo and IO failure, docetaxel±ramucirumab remains the standard of care for advanced sqNSCLC, but offers only short-lived disease control (median progression-free survival [PFS] of approximately 3–4 months), and high rates of severe toxicities. Thus, effective post-chemo and IO options for advanced sqNSCLC remain a significant unmet clinical need. IBI363 is a first-in-class, PD-1/IL-2 α-bias bispecific antibody fusion protein designed to block the PD-1/PD-L1 pathway and simultaneously activate the IL-2 pathway. It selectively expands and rejuvenates exhausted tumor-specific T cells by cis-activating IL-2 receptors. The IL-2 arm of IBI363 is engineered to retain its affinity for IL-2Rα while reducing binding to IL-2Rβ and IL-2Rγ thereby minimizing off-target toxicity. This dual mechanism has shown potential to address the unmet clinical needs of pts with IO-resistant and immune-cold tumors. In prior phase 1/2 studies, IBI363 monotherapy at 3 mg/kg every 3 weeks (Q3W) was well-tolerated and showed encouraging, durable efficacy in pts with advanced, IO-treated NSCLC and other solid tumors (2025 ASCO [8509, 2502 and 104]). Here, we present the trial in progress for MarsLight-11 (NCT07217301), a randomized, open-label, multi-regional Phase 3 study evaluating IBI363 versus docetaxel in pts with sqNSCLC after prior chemo and IO. Methods: This study is enrolling eligible pts with unresectable, locally advanced or metastatic sqNSCLC who have progressed on or after platinum-based chemo and anti-PD-1/PD-L1 treatments (defined as radiographic progression per RECIST v1.1 during or within 6 months after discontinuation of IO). Pts with known actionable genomic alterations, active or symptomatic brain metastases are excluded. Pts are randomized 1:1 to IBI363 or docetaxel (control). Stratification factors include the type of IO resistance (primary vs. acquired), the sequence of prior IO and chemo (concurrent vs. sequential), and region (Asia vs. non-Asia). Pts in the experimental arm will receive a priming dose of IBI363 (0.1 mg/kg) seven days prior to the first full dose (3 mg/kg Q3W). The control arm will receive docetaxel (75 mg/m² Q3W). The primary endpoint is overall survival (OS). Secondary endpoints include investigator-assessed PFS, objective response rate, disease control rate, duration of response, and time to response per RECIST v1.1, as well as safety, pharmacokinetics, and immunogenicity. One interim analysis (IA1) and one final analysis are planned for OS. The study plans to enroll approximately 600 pts globally, including sites in China, the United States, Canada, the European Union, the United Kingdom, Japan and South Korea. Clinical trial information: NCT07217301 .
Are lobectomy and neoadjuvant therapy the missing link in improving early-stage small cell lung cancer survival?
8077 Background: Small cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis. This study evaluates national trends in surgical management of early-stage SCLC using the National Cancer Database (NCDB), aiming to identify factors associated with improved outcomes and assess the survival benefit of surgical resection. Methods: Patients diagnosed with clinical stage T1–T3 N0 M0 SCLC between 2004 and 2022 were identified from the NCDB. Exclusions included non-SCLC histologies, advanced or missing staging, non-lobectomy surgeries, and incomplete survival data. Propensity score matching (1:1) was used to balance surgical and non-surgical cohorts based on demographic, clinical, and socioeconomic variables. Kaplan-Meier and Cox regression analyses were used to evaluate overall survival, stratified by T stage. Results: Among 17,762 patients with early-stage SCLC, 3,234 (18.2%) underwent lobectomy with mediastinal lymph node dissection. Surgical rates increased from 5% in 2004, 17% in 2013 to 24% in 2021. Surgery was more common in T1 (26.5%) than T2 (11.4%) or T3 (4.6%) disease. After matching, surgery was associated with improved survival across all T stages, with no significant interaction between T stage and surgical benefit (p=0.43). Older age, male sex, and higher comorbidity scores predicted worse outcomes. Among surgical patients, 2.3% received neoadjuvant therapy and 71.6% received adjuvant treatment. Systemic therapy-both neoadjuvant (HR 0.63) and adjuvant (HR 0.69)-was significantly associated with improved survival. Conclusions: Lobectomy remains underutilized in early-stage SCLC but is linked to significantly improved survival. Albeit small patient's number, neoadjuvant systemic therapy further enhanced survival, supporting broader use of surgery and multimodal treatment in appropriately selected patients Univariable results 1 Multivariable results 2 Characteristic No. deaths Person-months HR (95% CI) p-value HR (95% CI) p-value Charlson score <0.001 <0.001 0 761 77727 1.00 (ref) 1.00 (ref) 1 623 60483 1.06 (0.95,1.18) 1.07 (0.96,1.20) 2 or more 350 27025 1.30 (1.15,1.48) 1.30 (1.13,1.48) Clinical T-stage 0.011 0.014 cT1N0M0 1266 124916 1.00 (ref) 1.00 (ref) cT2N0M0 406 33924 1.18 (1.06,1.32) 1.20 (1.06,1.35) cT3N0M0 62 6393 0.96 (0.75,1.24) 1.00 (0.76,1.31) Residual disease <0.001 <0.001 No residual tumor 1626 158838 1.00 (ref) 1.00 (ref) Residual tumor 92 4699 1.91 (1.55,2.36) 1.91 (1.52,2.40) Neoadjuvant systemic treatment 0.253 0.034 No 1629 154116 1.00 (ref) 1.00 (ref) Yes 30 3495 0.81 (0.56,1.16) 0.63 (0.41,0.97) Adjuvant radiation 0.067 <0.001 No 1209 118925 1.00 (ref) 1.00 (ref) Yes 452 40471 1.11 (0.99,1.23) 1.33 (1.18,1.51) Adjuvant systemic treatment <0.001 <0.001 No 563 44045 1.00 (ref) 1.00 (ref) Yes 1096 113566 0.75 (0.68,0.83) 0.69 (0.62,0.78)
Incidence, survival, and persistent age and sex disparities in uveal melanoma: A SEER population study (2000–2022).
e21538 Background: It is unclear whether population-level incidence and survival for uveal melanoma have changed over time and whether demographic discrepancies persist. We evaluated temporal changes and differences in survival by age, sex, race/ethnicity, and tumor subsite. Methods: Using SEER (2000–2022), we identified primary uveal melanoma of the choroid (C69.3) or ciliary body/iris (C69.4), histology ICD-O-3 8720/3. Age-adjusted incidence (per 100,000; 2000 US standard) was compared between 2000–2004 and 2018–2022. Overall survival (OS) was assessed using Kaplan–Meier estimates of 5-year OS across four eras (2000–2005, 2006–2010, 2011–2015, 2016–2022). Multivariable Cox models evaluated OS by era, age, sex, race/ethnicity, and tumor subsite. Results: Among 5,856 patients (50.1% male), 89.8% had choroidal tumors and 10.2% ciliary body/iris tumors. Incidence rose modestly from 0.24 (95% CI 0.22–0.30) to 0.30 (0.30–0.38) per 100,000 (+0.06; +25%). The relative increase was larger in women (+36.4%) than in men (+13.3%), though the absolute rates were similar. OS improved over time: 5-year OS increased from 72.4% (69.8–75.1) in 2000–2005 to 77.9% (75.4–80.5) in 2016–2022. Recent diagnosis remained independently associated with better survival (HR 0.775, 95% CI 0.669–0.898 vs 2000–2005). Survival declined with age: 5-year OS 89.3% ( < 50) vs 42.3% (≥80); age ≥80 was associated with > 9-fold higher mortality (HR 9.153, 7.771–10.780). Men had worse OS than women (74.6% vs 77.1%; HR 1.179, 1.081–1.286). Ciliary body/iris tumors were associated with poorer survival than choroidal tumors (HR 1.253, 1.090–1.441). Race/ethnicity analyses were limited by small non-White samples. Conclusions: Uveal melanoma incidence increased gradually while survival improved, particularly in recent years. However, marked disparities persist in older patients, men, and those with ciliary body/iris tumors have worse outcomes. Gains in survival have not been evenly distributed. Findings should be interpreted in light of the restricted histologic definition (ICD-O-3 8720/3). Incidence trends (Age-adjusted per 100,000). 2000–2004 2018–2022 Change Overall 0.24 (95% CI 0.22–0.30) 0.30 (0.30–0.38) +25% Male 0.30 0.34 +13.3% Female 0.22 0.30 +36.4%
Spatial neighborhood effects and geographic embeddings in random forest modeling of mammography screening rates.
e13643 Background: Mammography screening rates vary geographically across the United States, yet standard machine learning models often fail to account for spatial dependence, limiting their ability to resolve local screening disparities. This study examined whether incorporating spatial neighborhood effects and geographic embeddings improves random forest (RF) prediction accuracy and reduces residual spatial autocorrelation in tract-level screening estimates. Methods: PLACES 2024 tract-level mammography screening data were linked with socioeconomic and healthcare access indicators, including poverty, educational attainment, race, insurance coverage, median home value, proximity to mammography facilities, and the Social Vulnerability Index. Three RF regression models were trained using 5-fold cross-validation: (1) a base model with socioeconomic and access predictors; (2) a spatial-lag model including lag_mammo, defined as the mean screening rate of adjacent tracts; and (3) a spatial-embedded model adding geographic coordinate terms (longitude, latitude, longitude², latitude², and longitude×latitude). Model performance was evaluated using RMSE, MAE, R², and Moran’s I of residuals. Results: Incorporating spatial information improved performance across all metrics. The spatial-lag model reduced RMSE from 3.20 to 2.13 and increased R² from 0.55 to 0.80, eliminating residual spatial autocorrelation (Moran’s I = −0.01, p = 1.0). Adding coordinate embeddings further increased R² to 0.83. Conclusions: Incorporating spatial neighborhood effects and geographic embeddings substantially improved RF model performance and reduced spatial autocorrelation, supporting their use in identifying under-screened communities. This approach may assist in targeting interventions and informing strategies to reduce geographic disparities in preventive breast cancer care. Comparative predictive accuracy and spatial autocorrelation of three random forest models. Model RMSE MAE R² Moran’s I Base RF 3.20 2.50 0.55 +0.66 (p<0.01) Spatial-Lag RF 2.13 1.65 0.80 −0.01 (p=1.0) Spatial-Embedded RF 1.98 1.54 0.83 −0.046 (p=1.0) Negative Moran’s I values indicate no residual spatial dependence.
Association of cardiovascular outcomes with GnRH agonist and antagonist therapy in non-metastatic prostate cancer.
5123 Background: Androgen deprivation therapy (ADT) is known to increase cardiometabolic risk. Randomized trials suggest GnRH antagonists may reduce major adverse cardiovascular events (MACE) compared with agonists, though studies were limited by short follow-up and low event rates. We evaluated the association between ADT mechanism and cardiovascular (CV) outcomes using large-scale real-world data. Methods: We conducted a retrospective cohort study using TriNetX database. Adult men with non-metastatic prostate cancer initiating ADT within 1 year of diagnosis were categorized by GnRH agonist or antagonist exposure. Cohorts were balanced using propensity score, matching demographics, CV co-morbidities, CV medications, and socioeconomic risk. Analyses were performed in the overall cohort and stratified by baseline CVD status. CV outcomes were assessed in years 1-10 following ADT initiation. The primary endpoint was MACE, defined as myocardial infarction, heart failure exacerbation, stroke or cardiac death. Secondary outcomes included atrial fibrillation/flutter, thromboembolism, mortality, and healthcare utilization. Results: After matching, 2,538 patients were included in both the GnRH antagonist and agonist group, including 785 with prior CVD and 1,460 without. In the overall cohort, GnRH antagonist therapy was associated with lower risk of MACE compared with GnRH agonists (OR 0.80, 95% CI 0.70–0.99; p=0.05) with an absolute risk of 8.0% vs 9.6%. Among patients with established CVD, antagonist use was associated with reduced MACE risk (OR 0.77, 95% CI 0.64–0.93; p<0.01) with an absolute risk of 19.6% vs 25.5%. In patients without prior CVD, antagonist use was associated with markedly lower MACE risk (OR 0.30, 95% CI 0.19–0.52; p<0.01) with an absolute risk of 1.3% vs 4.2%. For secondary outcomes, antagonist therapy was associated with lower risk of arterial thromboembolism and Emergency visits in the overall cohort, with no significant differences in all other outcomes. Among patients with baseline CVD, antagonist use was associated with lower risk of atrial fibrillation with no significant differences in all other outcomes. Among patients without baseline CVD, antagonist therapy was associated with lower risk of atrial fibrillation, healthcare utilization, and incident type 2 diabetes with no significant difference in all other outcomes. Conclusions: GnRH antagonist therapy was associated with lower rates of major adverse cardiovascular events compared with GnRH agonists, regardless of baseline cardiovascular disease status in years 1 through 10 after ADT initiation. Events occurring after the first year are more likely to reflect cumulative treatment-related cardiovascular toxicity, rather than unmasking baseline disease. These findings support further prospective, randomized trials to define the comparative CV safety of different ADT formulations.
Time to treatment initiation and clinical, toxicity, and supportive care outcomes in multiple myeloma: A real-world Epic Cosmos analysis.
e19559 Background: Timely initiation of systemic therapy is critical in multiple myeloma (MM), yet real-world variation in time to treatment initiation (TTI) and its association with clinical outcomes, treatment-related toxicities, and supportive care utilization remain incompletely characterized. Methods: We conducted a retrospective cohort study using the Epic Cosmos database (2015–2025). Adults with MM were identified using ICD-10-CM code C90. TTI was defined as days from MM diagnosis to first exposure to systemic anti-myeloma therapy, including proteasome inhibitors, immunomodulatory drugs, or anti-CD38 monoclonal antibodies. Patients were stratified into TTI < 30 days (n = 90015), 30–60(n = 81190), and > 60 days(119,245). Primary outcomes included mortality, infection (sepsis or pneumonia), AKI within 30 days, DVT/PE, and bone marrow transplant (BMT). Secondary outcomes included hemodialysis initiation, febrile neutropenia, thrombocytopenia, herpes zoster reactivation, and use of bone-protective therapy (zoledronic acid, pamidronate, or denosumab) and antiviral prophylaxis (acyclovir/valacyclovir). Outcomes are presented as unadjusted percentages with 95% confidence intervals. Results: Mortality demonstrated a U-shaped association with TTI, occurring in 22.99%, 21.32%, and 21.32% of patients in the < 30-day, 30–60-day, and > 60-day cohorts, respectively. Infection rates were 16.42%, 17.11%, and 17.30%, while AKI < 30 occurred in 16.01%, 16.38%, and 16.49%. BMT utilization was highest in the 30–60-day cohort (19.14%) compared with < 30 days (18.28%) and > 60 days (18.21%). VTE rates increased modestly with delayed treatment (9.39%, 9.82%, and 10.10%). HD occurred in 3.15%, 3.08%, and 3.07% of patients. Febrile neutropenia occurred in 17.15%, 18.03%, and 17.55%, thrombocytopenia in 13.34%, 13.93%, and 13.86%, and herpes zoster reactivation in 1.21%, 1.29%, and 1.42%. Antiviral prophylaxis use was highest in the 30–60-day cohort (91.25%) compared with < 30 days (88.48%) and > 60 days (88.23%). Bone-protective therapy use was also highest in the 30–60-day cohort (31.68%) versus < 30 days (28.90%) and > 60 days (23.79%). Conclusions: In this large real-world analysis, initiation of systemic therapy within 30–60 days of MM diagnosis was associated with lower mortality, higher transplant utilization, and greater use of guideline-recommended supportive care compared with both earlier and delayed treatment initiation. Patients treated within 30 days appeared to represent a higher-acuity phenotype, while delays beyond 60 days were associated with lower supportive care uptake and higher thrombotic risk. These findings suggest that time to treatment initiation may reflect both disease severity and care delivery quality, and identify a potentially actionable window to optimize treatment pathways and supportive care in multiple myeloma.
Anitocabtagene autoleucel (anito-cel) clinical trial manufacturing experience in patients with relapsed/refractory (RR) or newly diagnosed (ND) multiple myeloma (MM).
2550 Background: Anito-cel is an autologous D-Domain–based anti-BCMA chimeric antigen receptor (CAR) T-cell therapy that demonstrated deep and durable efficacy and manageable safety in a Phase 1 study and a Phase 2 registrational study (iMMagine-1) in 4L+ RRMM (Bishop et al. ASH 2024; Patel et al. ASH 2025). The D-Domain has a fast off-rate and facilitates high transduction efficiency, high CAR expression, decreased risk of tonic signaling, and potential for enhanced manufacturing efficiency and optimal tumor cytotoxicity. Anito-cel is also being investigated in patients with RRMM with 1-3 prior therapies and in patients with NDMM. The anito-cel CAR T-cell therapy manufacturing process has been optimized by leveraging the learnings from the robust development process of another CAR T-cell therapy, axicabtagene ciloleucel (axi-cel). Axi-cel is an autologous anti-CD19 CAR T-cell therapy approved in 2L large B-cell lymphoma based on the ZUMA-7 trial, with a demonstrated high manufacturing success rate (MSR) in both clinical trial and commercial real-world settings (100% and 99%, respectively; Alquist et al. TCT 2024). Here we report initial anito-cel manufacturing experience from 2 MM clinical trials. Methods: Pooled manufacturing outcomes from adults with MM enrolled and leukapheresed in iMMagine-3 or GEM-AnitoFIRST from 09/2024 to 10/2025 were included. First pass (FP)-MSR was defined as anito-cel lots manufactured on first attempt and within specification per total first attempt lots dispositioned plus lots not dispositioned due to termination in the period (excluding those terminated for patient withdrawal). The median turnaround time (mTAT) was defined as the time from leukapheresis to the quality release of final anito-cel product. Results: There was a total of 104 patients who were leukapheresed and whose lots were dispositioned as of October 31, 2025; anito-cel was successfully manufactured for 100% of these patients. The FP-MSR was 99.0% with 1/102 lots rejected on disposition (Table). The global mTAT was 18 days (interquartile range [IQR], 17-20 days) for the 101 lots released. Updated data to be presented. Conclusions: Our results demonstrate rapid and reliable anito-cel manufacturing for MM clinical trials globally, with high manufacturing success rates and consistent turnaround times. These results were consistent with axi-cel manufacturing outcomes and highlight the importance of leveraging axi-cel manufacturing experience in the development of anito-cel. Clinical trial information: NCT06413498 and NCT07045909 . FP-MSR, n/N (%) 101/102 (99.0) Global mTAT, days (IQR) Lots released, n 18 (17-20) 101