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A noncanonical RNA polymerase assembly pathway in Bacillus subtilis: α Dimer associates with either β or β′ before forming the core enzyme

SHR-A2102 in combination with adebrelimab as first-line treatment in patients with locally advanced or metastatic squamous or non-squamous non-small cell lung cancer (NSCLC): Results from a phase 1b/2 study.

8527 Background: SHR-A2102 is a novel antibody-drug conjugate composed of a monoclonal antibody targeting nectin-4, a cleavable linker, and a topoisomerase I inhibitor payload. Here, we report the preliminary efficacy and safety of SHR-A2102 plus adebrelimab (an anti-PD-L1 antibody) as first-line therapy in patients with locally advanced or metastatic squamous or non-squamous NSCLC. Methods: This is a multicenter, open-label phase 1b/2 study (NCT06512051). In the phase 2 part, patients aged 18-70 years with ECOG PS 0-1 and histologically/cytologically confirmed stage IIIB-IV squamous (cohort A) or non-squamous (cohort B) NSCLC who had received no prior systemic therapy were enrolled. All patients received intravenous SHR-A2102 (8 mg/kg, day 1 Q3W) plus adebrelimab (1200 mg, day 1 Q3W) until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR). Results: Between Dec 13, 2024 and Nov 19, 2025, 67 patients were enrolled and received treatment (27 with squamous NSCLC and 40 with non-squamous NSCLC). In cohort A, 92.6% were male, the median age was 64 years (range 42-70), 14 patients had PD-L1 TPS 1-49%, and 13 patients had PD-L1 TPS ≥50%. In cohort B, 60.0% were male, the median age was 62 years (range 42-70), 7 patients had PD-L1 TPS <1%, 20 patients had PD-L1 TPS 1-49%, and 13 patients had PD-L1 TPS ≥50%. Efficacy was evaluated in 26 and 33 patients from cohorts A and B, respectively, while all patients were included in the safety analysis. As of Nov 30, 2025, the median follow-up was 9.1 months (range 2.0-11.1), with 9.9 months (range 3.0-11.0) with squamous NSCLC and 9.0 months (range 2.0-11.1) with non-squamous NSCLC. Antitumor activities are shown in Table 1. In patients with PD-L1 TPS ≥1%, ORR was 80.8% (95% CI 60.6%-93.4%) for squamous NSCLC and 69.2% (95% CI 48.2%-85.7%) for non-squamous NSCLC. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 53.7% (36/67) of patients. The most common Grade ≥3 TRAEs were decreased neutrophil count (32.8%), decreased white blood cell count (14.9%), and anemia (9.0%). Conclusions: These results suggested the combination of SHR-A2102 and adebrelimab as the first-line therapy is a promising treatment strategy in patients with squamous or non-squamous NSCLC, supporting further investigation. Clinical trial information: NCT06512051 . Efficacy summary. Squamous NSCLC (N=26) Non-squamous NSCLC (N=33) Total (N=59) ORR, % (95% CI) 80.8 (60.6-93.4) 69.7 (51.3-84.4) 74.6 (61.6-85.0) DCR, % (95% CI) 96.2 (80.4-99.9) 97.0 (84.2-99.9) 96.6 (88.3-99.6) DoR (months), median (95% CI) NR (4.4-NR) NR (5.7-NR) NR (6.5-NR) 6-month PFS rates, % (95% CI) 64.1 (42.3-79.5) 78.9 (58.9-90.0) 71.8 (57.6-81.9)

Association of pre-diagnosis primary care utilization with metastatic disease, treatment adherence, and mortality in colorectal cancer.

3664 Background: In addition to timely evaluation and screening in patients with colorectal cancer (CRC), routine primary care provider (PCP) engagement may improve CRC survival outcomes through earlier diagnosis and increased treatment adherence. We evaluated the association between pre-diagnostic PCP utilization and metastatic disease at diagnosis, cancer-specific mortality (CSM), and cancer treatment adherence. Methods: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a retrospective cohort study of adults aged 68-75 diagnosed with CRC between 2010-2017. PCP visits in the three years preceding diagnosis were categorized as none (0 visits), occasional (1–2), or annual (3). Multivariable logistic regression models evaluated associations between PCP use and metastatic CRC at diagnosis, as well as treatment adherence. Locally advanced (Stage III) treatment adherence was defined as curative therapy ≤1 year from diagnosis, and metastatic treatment adherence was defined as systemic therapy ≤6 months from diagnosis. A competing risk Cox proportional hazards model evaluated cancer-specific mortality (CSM), with non-cancer death as a competing event. Results: Of 18,604 patients with CRC, 12.9% had no prior PCP visits, 48.6% had occasional visits, and 38.5% had annual visits. Compared to patients with no pre-diagnostic PCP use, occasional and annual PCP visits were respectively associated with 43% and 57% lower odds (p < 0.001) of metastatic disease at diagnosis and 48% and 57% lower odds (p < 0.001) of CSM (Table 1). Among patients with locally advanced CRC, occasional and annual PCP use were associated with 64% and 150% higher odds of receiving curative treatment, respectively (Table 1). Similarly, occasional and annual PCP use in patients with metastatic CRC were associated with 2-fold and 3-fold higher odds, respectively, of receiving systemic treatment (Table 1). Conclusions: Primary care utilization prior to CRC diagnosis is significantly associated with lower odds of metastatic disease, lower risk of CSM, and higher odds of treatment adherence, with the highest effects observed with annual PCP utilization. Increasing PCP engagement is an essential strategy to improving outcomes in patients with CRC. Multivariate estimates for the effect of pre-diagnostic primary care provider (PCP) utilization prior to cancer diagnosis. Metastatic Disease at DiagnosisOR, [95% CI], p-value Cancer-Specific MortalitysHR, [95% CI], p-value Received Treatment (Locally advanced CRC)OR, [95% CI], p-value Received Treatment (Metastatic CRC)OR, [95% CI], p-value 1-2 PCP visits (Occasional) 0.57 [0.51-0.64], p < 0.001 0.52 [0.48-0.56], p < 0.001 2.64 [2.10-3.30], p < 0.001 2.08 [1.70-2.56], p < 0.001 3+ PCP visits(Annual) 0.43 [0.40-0.47], p < 0.001 0.43 [0.40-0.47], p < 0.001 3.50 [2.76-4.24], p < 0.001 2.90 [2.31-3.64], p < 0.001

First-in-human phase I study of CEB-01, a biodegradable SN-38–releasing membrane, to prevent local recurrence after resection of retroperitoneal sarcoma: Updated results.

e23559 Background: Local recurrence is the main cause of mortality in retroperitoneal sarcoma (RPS), and perioperative systemic therapies have shown limited benefit. CEB-01 is a biodegradable PLGA membrane designed for loco-regional delivery of SN-38 to the surgical bed. We report updated safety, pharmacokinetic, and efficacy data from this first-in-human phase I study. Methods: This multicenter, open-label phase I trial followed a 3+3 dose-escalation design with expansion at the recommended phase 2 dose (RP2D). CEB-01 was implanted after tumor resection at SN-38 doses of 9, 18, or 36 mg. Primary objectives were RP2D determination and safety. Secondary objectives included pharmacokinetics and preliminary efficacy. Local recurrence was defined as relapse within the membrane-covered area. Results: Between July 2020 and November 2023, 14 patients were enrolled (median age 63 years; 71% male). Most tumors were liposarcomas (93%), de novo (64%) and R0 resection in 79%. No dose-limiting toxicities were observed. Following safety review, 18 mg was established as RP2D. In that cohort, after a median follow-up of 13.8 months, a local recurrence was observed within the treated area in 1 patient receiving RP2D. No deaths have been reported. Grade ≥3 treatment-related adverse events occurred in one patient (12.5%) at RP2D. PK analysis showed sustained SN-38 release with up to 70-fold lower Cmax, a half-life (~300 hours) compared with SN-38 PK values after intravenous irinotecan, with detectable plasma levels up to 28 days. Conclusions: Updated data confirm that CEB-01 at 18 mg has an acceptable safety profile and promising local control in RPS. Prolonged loco-regional delivery of SN-38 may represent a novel strategy to reduce post-surgical local recurrence. Further clinical investigation Phase 2/3 is warranted. Clinical trial information: NCT04619056 .

Evaluation of a remote electronic assessment of survivors with tailored follow-up recommendations and survivorship messaging (REASSURE) to improve the delivery of follow-up for low-risk breast cancer survivors.

1669 Background: Current follow-up care for the 2 million+ low-risk breast cancer survivors fails to adequately address survivors’ needs and burdens survivors and oncology teams. We evaluated a novel approach to follow-up that comprehensively assesses survivors’ symptoms and concerns and uses that information to tailor follow-up frequency. Methods: We conducted a randomized trial at an academic and community breast clinic. Eligible survivors had a history of stage I breast cancer that was ER or PR +/Her2-, were 6-36 months from diagnosis, and did not receive chemotherapy. Survivors were randomized 1:1 to REASSURE versus usual care and followed for 18-months. REASSURE was developed through stakeholder engagement and comprises three components integrated around follow-up visits: 1) Online patient-reported symptoms and concerns (PRO), 2) Tailored follow-up visit recommendations based on the PRO, and 3) Survivorship messaging. The primary outcome was survivors’ preparedness for survivorship and confidence about follow-up, measured at 18-months by the Preparing for Life as a (New) Survivor (PLANS) scale. Secondary outcomes included number of oncology follow-up visits, proportion of reported symptoms that were discussed, and acceptability of REASSURE. Continuous variables were analyzed using t-tests or Wilcoxon tests. The proportion of symptoms discussed was analyzed using a generalized linear mixed model for binomial data. Results: Of the 104 consented patients, 3 did not complete any study activities and 1 withdrew (n=100). The median age was 63 (range 36-86), most were White (98%), and 19% resided in a rural locale. Preparedness for survivorship and confidence did not differ between REASSURE and usual care (Table). Symptoms or concerns were reported on 50.4% of PRO assessments. In the REASSURE arm, 80% of survivors accepted the recommendation to forgo a visit. Fewer follow-up visits were observed with REASSURE (M=2.1, SD 1.0) than usual care (M=2.6, SD 1.0), p=0.007. There was no difference in likelihood of discussing symptoms. REASSURE was acceptable to survivors, with 78% saying they would recommend REASSURE to others. Conclusions: In this implementation of a novel tailored approach to follow-up for low-risk breast cancer survivors, we did not find improvement in preparedness for survivorship. However, we demonstrated a decrease in number of follow-up visits with strong survivor support for this approach. Further research will focus on implementing REASSURE in more diverse clinical settings. Clinical trial information: NCT05609435 . REASSUREM (SD) or % Usual CareM (SD) or % P value PRIMARY OUTCOMES  Preparedness 29.3 (1.7) 28.9 (2.1) 0.36  Confidence 24.0 (14.4) 18.7 (13.6) 0.08 SECONDARY OUTCOMES  # of follow-up visits 2.1 (1.0) 2.6 (1.0) 0.007  % of symptoms discussed 89.3% 83.0% 0.29  % of survivors who would recommend REASSURE 78% NA

Breast cancer screening is heating up: A novel thermophysics-based AI modality for screening subjects with BIRADS 4 or 5 mammograms.

3064 Background: Although mammography is an effective cancer detection modality, limited specificity at population scale leads to unnecessary biopsies, highlighting a need for adjunctive approaches. Cancer exhibits increased metabolic activity, leading to temperature differentials when compared with benign tissue. In this study, ultra-high sensitivity infrared imaging (IRI) was utilized with a novel thermophysics-based AI neural network to leverage temperature differentials for cancer screening. Methods: This prospective validation pilot study enrolled 14 patients with BI-RADS 4 or 5 breast lesions on diagnostic imaging prior to biopsy. IRI and optical images were acquired using an infrared imaging device at angular intervals, encoding the breast surface. Thermal and optical data were processed using a 3D reconstruction algorithm to generate breast surface thermal-spatial point-clouds, encoding temperature values at corresponding locations. Tumor presence or absence was predicted using an AI physics-informed neural network (PINN) that solves inverse bioheat transfer equations to identify heat sources associated with increased metabolic activity and blood perfusion. The PINN result was then compared to diagnostic mammography and to histologic findings on pathology. Results: 14 patients aged 42-83 years were included in a prespecified salient interim analysis approved by the study committee to assess feasibility. Histologic outcomes ranging from normal breast tissue to benign and premalignant/malignant conditions as outlined in Table 1. The PINN accurately predicted the presence and location of all premalignant/malignant lesions, including all incidences of IDC (n=3), DCIS (n=3), and ADH (n=2). Histologically benign lesions (n=6) were not detected by the PINN as a heat source. The mean size error for the PINN was 1.3 cm compared to size on pathology. Conclusions: Infrared imaging combined with a thermophysics-based AI neural network was able to localize and detect premalignant/malignant breast lesions with 100% sensitivity and specificity. Our findings suggest that IRI adjunctive screening may have the potential to both accurately detect breast cancer and minimize unnecessary biopsies. Comparison of PINN assessment with histological outcome. Number of Patients Breast Tissue Type PINN Assessment PINN Diameter (cm) Histologic Assessment Histologic Diameter (cm) 2 SF + 1.2, 2.2 ADH 2.1,3.0 3 SF + 1.1, 1.4, 1.4 DCIS 2.1, 2.0, 2.8 3 SF + 1.0, 1.2, 1.6 IDC 0.5, 3.0, 5.0 1 SF − Fibrosis 1 SF − Cystic Fluid 1 SF − Fibrocystic 1 SF − Fibroadenoma 1 SF − Duct Ectasia 1 HD − Normal Breast Breast tissue density classifications: scattered fibro-glandular (SF), heterogeneously dense (HD). Histology subtypes: invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS), atypical ductal hyperplasia (ADH). PINN=physics-informed neural network.

Real-world one-year comparative outcomes of quadruplet and triplet induction regimens in older, transplant-ineligible multiple myeloma patients.

7567 Background: Older patients with newly diagnosed multiple myeloma (MM) frequently experience early treatment discontinuation due to toxicity, comorbidities, and frailty. Although randomized trials support anti-CD38-based induction regimens, real-world comparative data evaluating early clinical outcomes in older, transplant-ineligible patients remain limited. Methods: We conducted a retrospective, multi-institutional cohort study using TriNetX, including adults aged ≥70 years with newly diagnosed MM after 2019 who initiated treatment within two months of diagnosis and did not undergo autologous stem cell transplantation. We performed two matched comparative analyses: Dara-RVd versus RVd and Dara-RVd versus Dara-Rd. We first assessed the proportion of patients initiating second-line therapy at 12 and 24 months. Analyses were then restricted to patients who remained on first-line therapy for at least one year to evaluate early clinical outcomes, including all-cause mortality and healthcare utilization (emergency department [ED] visits, ICU admissions, and bacterial infection or sepsis). Matching included demographics, comorbidities, presence of extramedullary plasmacytoma, and baseline laboratory values (LDH, albumin, β2 microglobulin, creatinine, and hemoglobin), BMI and recent hospitalization. Hazard ratio (HR) and risk ratio (RR) with 95% confidence intervals (CI) were reported. Results: Compared with RVd, Dara-RVd showed similar second-line initiation within 12 months (13% vs 14%; p=0.857) and 24 months (14% vs 19%; p=0.086). Among 768 matched patients per group who remained on first-line therapy at one year (mean age 75 years), Dara-RVd was associated with lower 1-year all-cause mortality (12% vs 17%; HR 0.70; 95% CI 0.55–0.90) and reduced healthcare utilization, including ≥1 ED visit (30% vs 36%; RR 0.85; 95% CI 0.73–0.98) and ICU admission (8% vs 12%; RR 0.70; 95% CI 0.52–0.95), while infection rates were similar. Compared with Dara-Rd, Dara-RVd showed comparable second-line initiation within 12 months (13% vs 10%; p=0.126) and 24 months (15% vs 11%; p=0.218). Among 511 matched patients per group who remained on first-line therapy at one year (mean age 76 years), no significant differences were observed in 1-year all-cause mortality or healthcare utilization outcomes. Conclusions: In older, transplant-ineligible patients with newly diagnosed MM who remained on therapy at one year, Dara-RVd was associated with improved early survival and lower healthcare utilization compared with RVd, while outcomes were comparable to Dara-Rd. Despite the retrospective design and potential unmeasured confounding, these findings support daratumumab-based regimens in older patients. Prospective studies incorporating frailty and early treatment discontinuation are needed to better define optimal induction strategies.

Opportunities for breast cancer prevention among pediatric lymphoma survivors treated with chest radiation: Projected gap in breast cancer deaths with real-world uptake rates.

10048 Background: For survivors of pediatric lymphoma previously treated with chest radiotherapy (RT), the Children’s Oncology Group recommends initiation of breast cancer screening with mammography and MRI starting at age 25. The National Comprehensive Cancer Network also recommends risk-reducing medications (e.g. tamoxifen) for breast cancer prevention in high-risk women. While low uptake among survivors has been described, the missed opportunity in terms of avoidable breast cancer deaths remains unknown. Methods: Using a Cancer Intervention and Surveillance Modeling Network model adapted to reflect the elevated breast cancer risk and competing mortality among 5-year lymphoma survivors previously treated with mediastinal RT, we estimated the number of breast cancer deaths by age 65 versus no screening or tamoxifen for a 20-year-old cohort under three scenarios: i) optimal uptake and adherence (100%) to early initiation of recommended screening (mammography with MRI) at age 25 and standard dose tamoxifen for 5 years at age 25; ii) real-world uptake of screening alone based on Childhood Cancer Survivor Study data (18% at age 25, increasing over time to 60% by age 35, with 50% reporting MRI within 1 year of mammogram); iii) real-world screening uptake as described in scenario 2, plus real-world tamoxifen use based on published estimates (16%). We assumed tamoxifen reduced breast cancer risk for a minimum of 20 years based on follow-up data from clinical trials. Breast cancer deaths averted were calculated as the difference in breast cancer deaths between each scenario and a baseline of no screening or tamoxifen. Results: In the absence of screening or tamoxifen, 53.2 breast cancer deaths per 1000 female survivors were projected by age 65. Under optimal uptake, screening averted 28.5 deaths per 1000 women (54%); screening plus tamoxifen increased the number averted to 31.6 deaths per 1000 (59% total reduction). Under real-world uptake, the number of breast cancer deaths averted was only 11.7 per 1000 women with screening alone and 12.6 for screening plus tamoxifen, suggesting only a 19-24% mortality reduction. Conclusions: Low real-world uptake of screening and tamoxifen represents a substantial missed opportunity to prevent breast cancer deaths among survivors of pediatric lymphoma treated with chest RT. Strategies to increase uptake are needed to fully realize the mortality benefits of breast cancer control in this high-risk population. Modeled breast cancer mortality at age 65 under optimal and real-world uptake scenarios. Scenario Breast Cancer Deaths per 1000 Breast Cancer Deaths Averted per 1000 % Breast Cancer Deaths Averted No screening or tamoxifen 53.2 - - Optimal (100%) Mammo/MRI 24.8 28.5 54% Mammo/MRI + tamoxifen 21.7 31.6 59% Real-world Mammo/MRI 41.5 11.7 19% Mammo/MRI + tamoxifen 40.7 12.6 24%

AACR GENIE analysis of 211,526 patients to evaluate hormone receptor alterations across solid tumors: Rationale for tissue-agnostic basket trials.

3133 Background: Steroid Hormone receptors (HR) that include estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) were oncology's first predictive biomarkers, yet HR-directed therapies remain largely confined to breast, prostate, and endometrial cancers. Emerging data suggest broader HR relevance across tumor types. The development of oral SERDs (selective ER degraders) and next-generation AR degraders/antagonists creates new opportunities to target HR alterations across tumor types. We performed pan-cancer genomic profiling to define the landscape of ESR1/AR alterations and resistance co-alterations, providing rationale for biomarker-enriched basket trial designs. Methods: We analyzed the AACR Project GENIE v18 public dataset, comprising 250,018 tumor samples from 211,526 patients across multiple solid tumor types. Genomic alterations in ESR1 and AR were assessed, including mutations, copy-number alterations, and structural variants. Co-alterations with selected genes involved in resistance and cell-cycle regulation (PIK3CA, PTEN, AKT1, TP53, RB1, CDKN2A) were evaluated using pairwise co-occurrence analyses. Results: Across 250,018 solid tumor samples, ESR1 alterations were identified in 2.0% of cases, with highest prevalence in breast (8.4%) and endometrial cancers (4.6%), and lower frequencies in uterine sarcoma (2.7%) and melanoma (3.6%). Most ESR1 alterations were missense mutations localized to the ligand-binding domain, with recurrent hotspots at codons Y537 and D538. AR alterations were present in 2.4% of samples overall, most frequently in prostate cancer (7.6%), and were also detected in endometrial cancer (5.5%), lung cancer (~5%), and melanoma (4.9%). AR alterations consisted predominantly of copy-number amplifications, with additional ligand-binding domain mutations observed. Co-alteration analyses demonstrated frequent co-occurrence of ESR1 with PIK3CA, PTEN, and AKT1, and AR with TP53, RB1, and CDKN2A, whereas ESR1 and KRAS alterations did not significantly co-occur. Conclusions: Recurrent ESR1 and AR alterations occur in 2-5% of diverse solid tumors beyond breast, prostate, and endometrial cancers, with co-enrichment of PI3K-AKT and cell-cycle pathway alterations mirroring resistance patterns in canonical HR-driven malignancies. These findings support systematic evaluation of selective ER and AR degraders in biomarker-selected basket trials, expanding precision oncology beyond anatomically-defined indications.

Adjuvant immunotherapy following upfront surgery for stage II–III triple-negative breast cancer: A National Cancer Database Study.

e12520 Background: In early-stage triple-negative breast cancer (TNBC), immunotherapy (IO) improves outcomes when administered with chemotherapy in the neoadjuvant setting, with standard post-operative continuation. For patients undergoing upfront surgery, the benefit of adjuvant-only IO remains uncertain. IMpassion030 demonstrated no benefit from adding adjuvant atezolizumab after upfront surgery; the benefit of adjuvant-only pembrolizumab remains unclear, with SWOG 1418 pending. We leveraged a large national database to evaluate real-world outcomes. Methods: Using the 2022 National Cancer Database (NCDB), we identified patients with pathologic stage II–III TNBC diagnosed between 2015 and 2020 who underwent upfront surgery. Patients receiving neoadjuvant systemic therapy or preoperative radiation were excluded. Overall survival (OS) was calculated from diagnosis to last contact or death. Survival was compared between adjuvant chemotherapy alone versus chemotherapy + IO (captured as categorical variable in NCDB) using Kaplan–Meier methods and log-rank testing, stratified by pathologic stage. Stage-stratified analyses were univariate. Results: Among n=13,961 included patients, 11,805 had stage II and 1,835 had stage III disease. Of these, 98.5% (13,749) received adjuvant chemotherapy alone and 1.5% (212) received adjuvant chemotherapy + IO. There was no difference in median age (59 vs 59 years; p=0.85); race (White: 70.3% vs 71.6%; Black: 24.3% vs 19.9%; p=0.068); comorbidities (Charlson–Deyo score 0: 80.7% vs 81.6%; p=0.38) between chemotherapy vs. chemotherapy + IO groups. More patients with stage III disease received chemotherapy + IO (stage III: 24.5% vs. 13.4%; stage II: 85.9% vs. 73.6%, p<0.001). Landmark OS at 36, 60, and 96 months for chemotherapy alone versus chemotherapy + IO was 86.0% vs 83.2%, 79.7% vs 74.8%, and 73.3% vs 72.4%, respectively (log-rank p=0.17). There was higher survival rate among those with stage III disease who received chemotherapy vs. chemotherapy + IO, although not statistically significant. Conclusions: In this real-world cohort of patients with stage II–III TNBC treated with upfront surgery and adjuvant chemotherapy, the addition of IO was not associated with improved OS. These findings align with recently reported prospective trials and reinforce ongoing uncertainty regarding the benefit of adjuvant-only IO, underscoring continued prioritization of neoadjuvant approaches. Results from SWOG S1418 will further clarify this question. Overall survival by treatment and pathologic stage. Chemo Chemo + IO Stage II N 11,805 156 Events, n (%) 1,994 (17) 23 (15) Median OS, months (95% CI) NR NR OS 36 months, % 90.0 89.8 OS 60 months, % 83.9 83.4 OS 96 months, % 77.1 80.7 Stage III N 1,835 52 Events, n (%) 781 (43) 24 (46) Median OS, months (95% CI) 91.7 (79.8–NR) 54.7 (45.0–NR) OS 36 months, % 70.9 68.5 OS 60 months, % 58.4 49.2 OS 96 months, % 49.2 44.3 NR, not reached.

Clinical characteristics and risk factors of individuals ineligible for lung cancer screening at a tertiary care center.

10529 Background: Lung cancer screening (LCS) reduces mortality, yet many individuals with lung cancer do not meet the 2021 USPSTF eligibility criteria. We compared clinical characteristics and risk factors in individuals with lung cancer who were ineligible and eligible for LCS. Methods: We conducted a retrospective study of individuals with a new or prior diagnosis of lung cancer at Indiana University Health from April 1, 2025 - December 4, 2025. We recruited individuals during their clinic visits and used electronic medical records and a patient-completed survey to obtain demographic information, smoking history, and lung cancer risk factors at diagnosis (high-risk lung disease/occupation, first-degree family history of lung cancer, autoimmune disease, prior chest-wall radiation). Individuals were stratified using the 2021USPSTF criteria. Continuous and categorical variables were compared with T-tests and χ²/Fisher’s exact tests. Logistic regression models were used for multivariate analysis. Results: 242 individuals were evaluated and 128 (53%) were ineligible for LCS. The median age was 63 among ineligible individuals, 56% were female, 70% were white, and 25% were black (64, 55%, 80%, and 17% respectively among LCS eligible). These individuals were more likely to have adenocarcinoma (80% vs. 56%, p <0.001) and present with stage IV disease compared to those eligible for LCS [51% vs. 26%, adjusted OR 2.13 (95% CI, 1.01 – 4.57), p =0.048]. Of note, 24 individuals (19%) were <50 or >80 years old and 46 (36%) were never-smokers; however, tobacco exposure was common (64% ever-smokers, 21% used other tobacco products, 56% secondhand exposure). Most of these individuals had high-risk lung disease (61%), Table. Multivariate analysis adjusting for smoking revealed no association between LCS eligibility and secondhand exposure or high-risk occupation, p =0.340 and 0.275. Interestingly, 1/3 of individuals in both cohorts had a first-degree relative with lung cancer. Conclusions: Most individuals with lung cancer in our cohort were ineligible for LCS using the 2021 USPSTF criteria and were more likely to present with metastatic disease. Many had significant tobacco exposure and other risk factors similar to those eligible for LCS. Our findings suggest the current LCS criteria exclude a large at-risk population and should be re-evaluated to account for risk factors beyond age and pack-years. Risk Factor Ineligiblen=128 (%) Eligiblen=114 (%) p Ever-smokers (≥ 100 cigarettes) 82 (64.1) 114 (100) <0.001 Use of Other Tobacco Product 27 (21.1) 47 (41.2) <0.001 High-Risk Lung Disease (e.g., COPD) 78 (60.9) 95 (83.3) <0.001 Secondhand Smoking 71 (55.5) 79 (69.3) 0.340* High-Risk Occupation (e.g., firefighting) 47 (36.7) 58 (50.9) 0.275* 1 st Degree Family History 42 (32.8) 40 (35.1) 0.343 Autoimmune Disease 12 (9.4) 10 (8.8) 1.000 Chest Wall Radiation 11 (8.6) 11 (9.6) 0.951 *Adjusted for smoking.

Evaluation of factors affecting diagnostic delay in patients referred to the pediatric oncology clinic of Ankara University: A developing country model.

e22010 Background: Early diagnosis is a major determinant of survival and treatment success in childhood cancers. However, diagnostic delay (DD) remains a significant public health problem, particularly in developing countries, and may lead to diagnosis at advanced disease stages. This study aimed to evaluate patient-, physician-, and healthcare system–related factors affecting DD among patients referred to the Pediatric Oncology Clinic of Ankara University Faculty of Medicine. Methods: This retrospective study included patients aged 0–18 years who were diagnosed with malignancy between 2003 and 2023. A total of 799 patients were analyzed. Data were obtained from patient medical records and discharge summaries, and missing information was completed through phone interviews. DD was categorized as patient-related, physician-related, and total delay. Evaluated factors included patient age and sex, parental education level, type of first healthcare facility visited, number and specialty of physicians consulted prior to diagnosis, presenting symptoms, and malignancy type. Statistical analyses were performed using Mann–Whitney U, Kruskal–Wallis, and chi-square tests, with p<0.05 considered statistically significant. The study was approved by the local ethics committee. Results: Patients aged 0–1 year were diagnosed earlier, whereas adolescents experienced significantly longer DDs (p<0.001). Maternal education level was significantly associated with DD (p=0.007). Mean DD was 20 days in children of university-educated mothers and 85 days in children of illiterate mothers. Paternal education level was not associated with DD. Patients initially presenting to a university hospital had shorter time to diagnosis than those presenting to secondary healthcare facilities (6 vs 15 days, p<0.01). Consultation with 1–3 physicians prior to diagnosis was associated with shorter DD (p<0.05). Bone tumors (17.8%), lymphoma (17.4%), and central nervous system tumors (11.7%) were associated with the longest DD and frequently required more than four physician visits. DD varied according to presenting symptoms. Nonspecific symptoms such as fever and fatigue resulted in delays of approximately 50 days in leukemia and 53 days in central nervous system tumors. In malignant bone tumors, extremity pain and swelling were associated with a DD of 70 days. Longer DD was associated with more advanced disease stage at diagnosis. Conclusions: DD in childhood cancers is a multifactorial process. Maternal education level, type of initial healthcare facility, and number of physicians consulted prior to diagnosis were the most influential factors. Longer DD was associated with advanced disease stage. Improving parental education, awarness and physician recognition of childhood cancers may contribute to earlier diagnosis and improved outcomes.

Patterns, causes, and predictors of inpatient mortality among cancer patients in a tertiary center in south India: A 10-year retrospective analysis.

e24049 Background: Inpatient mortality among cancer patients reflects a complex interaction between advanced disease, treatment toxicity, and health-system factors. However, systematic data describing the timing, causes, and determinants of inpatient oncology deaths from low- and middle-income countries remain limited. We analyzed a 10-year cohort of inpatient cancer deaths to characterize mortality patterns and identify factors associated with place and cause of death. Methods: All adult inpatient oncology deaths between 2016 and 2025 were analyzed. Demographic, disease, treatment, and admission variables were collected. Causes of death were categorized as cancer-related, treatment-related, or other. Early death was defined as death within 48 hours of admission. Variables underwent univariate screening, followed by multivariable logistic regression to identify predictors of ICU death and multinomial regression with likelihood ratio testing to assess contributors to cause of death. Results: Among 426 inpatient deaths, median age was 56.68 years; 64.5% were male and 83.8% had solid tumors. At last admission, 78.0% had advanced-stage disease, 71% were metastatic, and 82.8% had poor performance status (ECOG 3–4). Emergency admissions accounted for 76.2%. Altered sensorium was present in 44.8% and 74.17% had documented comorbidities. Overall, 159 patients (37.3%) died in the ICU and 266 (62.4%) died in ward/room settings. Overall, 350 deaths (82.15%) were cancer-related, 27(6.3%) were treatment-related, and 49 (11.5%) were due to other causes. Nearly one-third (29.6%) died within 48 hours of admission. Univariate screening identified no significant predictors of early death, indicating that early in-hospital mortality was multifactorial with no single identifiable baseline predictor. On multivariable analysis, decreasing age (adjusted OR [aOR] 0.98, 95% CI 0.96–0.997, p = 0.024), and greater number of prior systemic therapy lines (aOR 0.68, 95% CI 0.49–0.93, p = 0.017) were independently associated with ICU death. Conclusions: In this large, decade-long inpatient mortality audit, the majority of deaths were cancer-related and occurred outside the ICU, reflecting appropriate recognition of advanced disease trajectories and end-of-life care needs. Treatment-related mortality was infrequent, underscoring the overall safety of systemic therapy delivery. Nearly one-third of patients died within 48 hours of admission, highlighting the complexity of late-stage hospital presentations. ICU death was independently associated with younger age and greater cumulative exposure to systemic therapy. These findings emphasize the need for earlier goals-of-care discussions, timely integration of palliative care, and structured frameworks to guide escalation decisions, particularly in heavily pretreated patients.

OP-NEU-101: A phase 1/2 open-label, dose finding and expansion study to investigate the safety and effectiveness and determine the optimal dose of N17350 administered intratumorally in participants with advanced solid tumors.

TPS2679 Background: Despite advances in targeted therapies and immunotherapy, many patients with advanced solid tumors have limited treatment options. N17350 is a first-in-class, optimized therapeutic elastase designed for intratumoral administration that selectively induces cancer cell death by activating the neutrophil elastase (ELANE) pathway while preserving immune cell viability. Preclinical studies demonstrated broad antitumor activity across 30 cancer cell lines, 15 in vivo models, and 45 patient-derived tumor samples, as well as induction of antitumor immunity in both immunologically cold and hot tumors (Gujar et al., 2025; doi:10.1016/j.xcrm.2025.102446. Together with preclinical toxicology studies supporting a starting dose within the therapeutic range, these findings support the clinical evaluation of N17350. Methods: This first-in-human, multicenter, open-label Phase 1/2 study (OP-NEU-101) is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of intratumorally administered N17350 in adults with advanced solid tumors. The study consists of a dose-finding and dose-optimization phase (Parts A1 and A2) followed by monotherapy expansion cohorts (Part A3). Dose-finding in participants with superficial (Part A1) and visceral lesions (Part A2) is guided by a Backfill Bayesian Optimal Interval (BF-BOIN) design to determine the maximum tolerated dose, optimal biologic dose, and/or recommended Phase 2 dose (RP2D). Once optimal dose(s) are identified, up to five tumor-specific expansion cohorts (data dependent: SCCHN, NSCLC, TNBC, cuSCC, Melanoma) may be opened to further characterize safety and clinical activity. Key Eligibility Criteria: Eligible participants are adults with advanced or metastatic solid tumors who have progressed on or are intolerant to standard therapies, have ECOG performance status 0–1, adequate organ function, and at least one superficial or visceral lesion suitable for intratumoral injection. Endpoints: The primary endpoints of the dose-finding phase are safety and tolerability, including the incidence of dose-limiting toxicities and treatment-emergent adverse events. Secondary endpoints include PK, immunogenicity, and preliminary antitumor activity assessed per RECIST v1.1 and/or itRECIST. Exploratory endpoints include evaluation of ELANE pathway activation, immune modulation, circulating tumor DNA, and multiomic analyses of tumor tissue and peripheral blood. The study has been initiated and will be enrolling participants at sites in the United States and Australia. Clinical trial information: NCT07339176 .

Cognitive effects of darolutamide vs enzalutamide: Results of ARACOG (AFT-47), a randomized clinical trial from the Alliance for Clinical Trials in Oncology.

5005 Background: Androgen receptor pathway inhibitors (ARPIs) may have distinct central nervous system (CNS) penetration and differential effects on cognition or quality of life (QOL). AFT-47, “ARACOG” is a prospective, randomized open-label phase 2 trial comparing objective and patient-reported cognitive and QOL outcomes between patients with metastatic hormone sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC) or non-metastatic castration-resistant prostate cancer (nmCRPC) treated with darolutamide (DAR) or enzalutamide (ENZ). Methods: Between 8/17/2021 and 3/11/2025, 111 pts were enrolled and randomized 1:1 to treatment with ENZ or DAR. CANTAB, a validated computer-based platform evaluating 5 cognitive domains (PALFAM-memory recall, SWM- spatial working memory, SSP-short-term visual memory, working memory, RVP-rapid visual processing, and OTSMCC- executive function), was performed at baseline, 12, 24, and 48 weeks. Crossover (Xover) was allowed at 12 or 24 weeks for significant pre-specified decline in cognitive testing or patient reported outcome measures (PROMs), or for CNS-associated adverse events, including falls. The primary endpoint was the percent change in the maximally changed cognitive domain (MCCD) from baseline to 24 weeks and was compared between groups with the Wilcoxon rank sum statistic. Patients crossing over prior to 24 weeks were evaluated at the time of Xover and analyzed with their randomized arm. Secondary endpoints included comparison of Xover rates. Results: Among 111 pts, 55 received DAR and 56 received ENZ; median age was 71, 83% White. 95 pts (48 DAR, 47 ENZ) were evaluable for the primary endpoint. Baseline CANTAB was similar between groups. Median cognitive change in MCCD between baseline and 24 weeks was -15.8% and -36.1% for the DAR and ENZ pts, respectively (p = 0.009) (Table). Individual cognitive domains suggest possible learning effect (increased scores) for DAR and are stable or show mild decline for ENZ treated patients at 24 weeks. 32 DAR (58%) and 33 ENZ (59%) participants were eligible for Xover by 24 weeks, and 23 pts crossed over by 24 weeks. All Xover was pts randomized to ENZ (crossed to DAR), with the most common causes being decline in objective (N = 14) or subjective (N = 11) cognitive testing. Conclusions: In this US randomized trial comparing DAR to ENZ, the primary endpoint of differential cognitive effects was met. ENZ showed significantly greater cognitive score decline than DAR at 24 weeks in the MCCD after treatment initiation. Learning effect was seen with DAR but not ENZ. Longer term follow-up of cognitive change and PROM analyses are ongoing. Clinical trial information: NCT04335682 . Percent change in maximally changed cognitive domain by treatment. DAR (N=48) ENZ (N=47) Wilcoxon Rank Sum Test Result CANTAB domain PALFAM SWM Degree of change -15.8 (-38.8, -2.6) -36.1 (-59.3, -16.7) P=0.009

PROTRACT: A randomized phase II trial comparing ctDNA-guided biomarker directed therapy vs patient/clinician’s choice for metastatic castration resistant prostate cancer (mCRPC) progressing after abiraterone plus prednisone (AAP).

5017 Background: A subset of mCRPC patients (pts) will benefit from enzalutamide (ENZA) following disease progression on AAP. Preliminary data suggests that higher plasma ctDNA/total cfDNA fraction (ctDNA%) post-AAP predicts poor response to ENZA but preserved sensitivity to docetaxel (DOC). We hypothesize that ctDNA%-guided selection of enzalutamide or docetaxel in chemotherapy-naïve mCRPC post-abiraterone will improve clinical outcomes versus patient/clinician’s choice of treatment. Methods: A multi-centre, open-label, phase II trial randomized mCRPC pts progressing after AAP 1:1 to biomarker-directed therapy (Arm A: ctDNA% ≥2% receives DOC; ctDNA% <2% receives ENZA) or clinician’s choice of ENZA or DOC (Arm B, ctDNA% blinded). Baseline ctDNA% was assessed at screening using somatic mutations and genome-wide ploidy models. At progression, eligible pts could cross over to the alternative therapy. The primary endpoint was progression-free survival (PFS) defined as the time from treatment initiation to first documented disease progression (clinical, radiological, or PSA) or death from any cause. PFS was estimated using the Kaplan-Meier method and compared between arms using the log-rank tests. Secondary endpoints included PSA50 response (PSA decline ≥50% from baseline) and overall survival (OS). Results: Between October 2020 and June 2025, 56 pts were screened and 42 randomized 1:1 to Arm A (n=17) or Arm B (n=25). The trial was terminated due to slow accrual prior to the planned enrollment of 100 patients. At data cut-off (January 7, 2026), median follow-up was 38.0 months, and 94% (Arm A) and 92% (Arm B) had experienced disease progression or death. Baseline characteristics were balanced. ctDNA% <2% was observed in 35.3% and 32% of pts in Arm A and B, respectively. In Arm A, 11 pts were assigned to and received DOC (ctDNA% ≥2%) and 6 pts to ENZA (ctDNA <2%). In Arm B patient/clinician choice was DOC in 4 patients (3 pts with ctDNA ≥2%) and ENZA in 21 patients (7 pts with ctDNA <2%). PFS, OS and PSA50 all favoured biomarker directed therapy (Arm A) (Table). Conclusions: In this clinical utility study, ctDNA% to guide ENZA or DOC selection in patients previously treated with AAP led to superior PFS and OS compared to patient/clinician-selected therapy. These hypothesis-generating results illustrate the potential for ctDNA% as a predictive biomarker to assist in clinical decision making and support further studies. Clinical trial information: NCT04015622 . Primary & secondary outcomes. Biomarker-Directed (Arm A, n=17) Clinician’s Choice (Arm B, n=25) HR (95% CI) P-Value Progression-Free Survival (PFS), Months, median (95% CI) 5.6 (3.2-8.2) 2.5 (1.5-3.7) 0.4 (0.2-0.8) p = 0.01 PSA50 Response (%) 52.9% 28.0% p = 0.12 Overall Survival (OS), months, median (95% CI) 46.3 (12.2-NR) 15.3 (13.5-20.7) 0.4 (0.2-0.9) p = 0.04

Mental health and malignancy: Real-world associations between early-onset gastrointestinal cancers and mental illness.

11174 Background: Although progress has been made in reducing overall cancer incidence, early-onset cancers have continued their troublesome rise. Similarly, the incidence and/or prevalence of psychiatric disorders has increased, particularly among young adults. Mental illness may influence cancer development, however, real-world evidence linking mental illness to early-onset gastrointestinal cancers is limited. Methods: We sought to conduct a real-world, retrospective cohort study using the TriNetX United States Research Database, a federated network of de-identified electronic health records from over 70 healthcare organizations, to examine this association. Adults aged 18–50 years with at least one of five pre-determined core mental illnesses, including generalized anxiety disorder (GAD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), bipolar disorder, and/or schizophrenia, were compared with same-aged individuals without any of the core mental illnesses. A five-year lookback period was used from January 25th, 2021 to January 25th 2026. Propensity score matching adjusted for demographic and clinical confounders. Incidence of early-onset cancers diagnosed were then assessed during five-year follow-up. Sensitivity analyses required a ≥ 1-year lag between mental illness diagnosis and cancer onset. Results: 2,911,432 patients ages 18-50 were identified as having a core mental illness, whereas 21,439,614 patients ages 18-50 were identified as not having any core mental illness. All-cause mental illness was associated with an increased risk of developing early-onset gastric cancer (RR 1.451, CI 1.189-1.771, p < 0001), pancreatic cancer (RR 1.566, CI 1.328-1.822, p < 0.0001) and colorectal cancer (RR 1.407, CI 1.313-1.506, p < 0.0001). Associations with early-onset esophageal cancer, biliary tract cancer, and small intestine cancer did not meet thresholds for statistical significance. In addition, subgroup analysis was completed for each core mental illness. GAD was associated with an increased risk of developing early-onset pancreatic cancer (RR 1.627, CI 1.220-2.169, p < 0.0001), small intestine cancer (RR 2.435, CI 1.498-3.956, p < 0.0001), and colorectal cancer (RR 1.625, CI 1.441-1.833, p < 0.0001). MDD was only associated with an increased risk of developing early-onset colorectal cancer (RR 1.425, CI 1.213-1.674, p < 0.0001). OCD, bipolar disorder, and schizophrenia had no statistically significant association with the development of the early-onset cancers noted above. Conclusions: In this large, real-world cohort study, all-cause mental illness, GAD, and MDD were associated with an increased risk of several early-onset gastrointestinal cancers. These findings suggest that one’s mental health represents a potentially modifiable risk factor in early-onset gastrointestinal cancers and warrants further investigation.

Sun-protective behaviours amongst indigenous communities: A scoping review.

e21583 Background: Due to longstanding historical and systemic barriers, Indigenous communities experience disproportionate health inequities, including poorer cancer outcomes. Within this broader context, disparities are also evident in dermatologic health, particularly in skin cancer prevention, diagnosis, and outcomes. Among studied Indigenous populations, engagement in sun-protective behaviours is lower, contributing to increased skin cancer risk, including later-stage melanoma diagnoses and higher mortality. However, research examining these behaviours remains limited, particularly with respect to both primary and secondary sun-protective practices. This scoping review seeks to characterize sun-protective behaviours and identify trends among Indigenous populations. Methods: Following PRISMA-ScR guidelines, we searched Medline, Scopus, and Embase, including peer-reviewed studies from January 2010 to December 2025. Screening was done by two reviewers. Observational studies on Indigenous populations and behaviours relating to sun protection were included. All other study designs and Indigenous populations outside of North America were excluded. Results: Five cross-sectional studies were included, conducted on Indigenous populations in the United States (4/5) and Canada (1/5). The sample was comprised of 6,220 participants, with four studies reporting on sex. However, only two studies provided sex-specific distributions to Indigenous participants. All studies (5/5) reported on primary sun-protective behaviours and secondary sun-protective behaviours. Most studies (3/5) reported reduced engagement with sun-protective behaviours compared with non-Indigenous groups, and one study found low engagement without a comparator. Sunscreen-use was consistently reduced, whereas findings for shade-seeking behaviours, long-sleeve shirt and hat-use were mixed. Studies that assessed skin examinations (3/5) found a higher proportion of Indigenous participants reporting no prior skin checks. Barriers to engaging in sun-protective behaviours included economic, structural, and geographic factors. Two studies highlighted economic barriers, including the cost of sunscreen, as a reason for low sunscreen-use. Conclusions: There is a paucity of research examining sun-protective behaviours among Indigenous populations. Observed gaps in patient education and skin cancer screening highlight opportunities to strengthen prevention and early detection efforts in clinical settings. Culturally responsive, community-informed approaches are needed to address structural barriers and support effective sun-protective practices.

Outcomes of gastrointestinal malignancies in HIV: The impact of opportunistic and non-opportunistic infections.

e16350 Background: Gastrointestinal (GI) malignancies are a major source of cancer-related mortality. Human immunodeficiency virus (HIV) patients face an inordinate cancer burden, and in the antiretroviral therapy (ART) era, non-AIDS-defining GI malignancies account for many HIV hospitalizations. Opportunistic infections (OIs) may represent an overlooked driver of adverse inpatient outcomes. While ART has reduced the incidence of OIs such as cytomegalovirus, hospitalized patients with HIV may still develop OIs or non-OIs, defined as “community-acquired” pathogens. The impact of infection phenotype on inpatient outcomes across individual GI cancer sites remains poorly characterized. Methods: We conducted a retrospective cohort study using the National Inpatient Sample (2018–2021) of adults hospitalized with GI malignancies. HIV status, infection phenotype (OI, non-OI, or none), and cancer site were defined using ICD-10. The primary outcome was in-hospital mortality; secondary outcomes included mechanical ventilation (MV), shock, length of stay (LOS), and non-home discharge. Survey-weighted multivariable regression adjusted for demographics, socioeconomic factors, payer, cancer site, and year. Exploratory subgroup analyses among HIV-positive patients evaluated individual OIs. Results: Infection phenotype was the significant driver of mortality with OIs 3.2 times and non-OIs 5.1 times more likely (p < .0001) but not HIV status (p = 0.64). Mortality varied by cancer site, with increased odds across most sites except rectal. Infection phenotype demonstrated site-specific heterogeneity: OIs were associated with increased mortality among colon, rectosigmoid, and rectal cancers (all p < .012), while non-OIs were associated among esophageal, hepatobiliary, pancreatic, rectal, and other digestive cancers (all p < .024). OIs were associated with increased odds of shock and MV, whereas HIV status and non-OIs were associated with lower odds (all p < .0001). Both OIs and non-OIs were associated with increased LOS and non-home discharge (p < .0001). Subgroup analyses of individual OIs were not statistically significant. Conclusions: Among hospitalizations with GI malignancies, infection phenotype, not HIV status, was the primary driver of mortality and critical illness. Both OIs and non-OIs conferred substantial risk, with non-OIs demonstrating equal or greater associations with adverse outcomes, highlighting the importance of these infections. Infection-associated risk varied by GI cancer site, suggesting site-specific vulnerability to infectious complications. This nationally representative analysis provides one of the first comprehensive evaluations of HIV status, infection phenotype, and GI-cancer site locations emphasizing the need for early recognition and targeted management of infectious complications to improve inpatient outcomes in this population.

Pretreatment spatial immune architecture and 1-year clinical benefit to first-line ICB in advanced melanoma.

9539 Background: Predictive biomarkers for immune checkpoint blockade (ICB) in advanced cutaneous melanoma (CM) remain limited. Imaging mass cytometry (IMC) enables spatially resolved profiling of the tumor microenvironment (TME) and can capture immune–tumor architecture beyond cell density. Methods: Patients with advanced CM treated with first-line ICB and available pretreatment FFPE tissue were analyzed using IMC (40-marker panel). The primary endpoint was durable 1-year clinical benefit (1y-CB: metabolic CR/PR or stable metabolic disease ≥12 months by PERCIST on FDG-PET/CT); the secondary endpoint was 1-year progression-free survival (1y-PFS). Cell densities, tumor marker expression, and spatial neighborhood metrics were evaluated. Reproducibility was assessed by re-analyzing an independent published IMC melanoma cohort (PMC8026677). Results: Twenty-nine patients (anti–PD-1 n=27; ipilimumab+nivolumab n=2); 15 achieved 1y-CB. 1y-CB was associated with higher leukocyte infiltration and increased densities of B cells, conventional CD4⁺ T cells (Tconv), CD8⁺ T cells, and plasma cells, whereas higher tumor density was associated with lack of benefit and inferior 1y-PFS (HR 10.57; p<0.001). Higher CD8⁺ and B-cell densities were associated with improved 1y-PFS (HR 0.26, p=0.013; and HR 0.26, p=0.047). Tumor PD-L1 and HLA-DR expression correlated with 1y-CB (p=0.022 and p=0.040). Spatial metrics further stratified outcomes: increased tumor–tumor proximity was associated with poor 1y-CB (p=0.0016), while increased B–Tconv proximity was associated with 1y-CB and longer 1y-PFS (HR 0.20; p=0.037). The strongest spatial association was macrophage proximity to HLA-DR⁺ tumor cells (p≤0.0001). In the external cohort (n=60), responder enrichment for Tconv/CD8⁺ T cells and macrophage proximity to HLA-DR⁺ tumor cells were reproduced. Conclusions: Pretreatment IMC identifies both compositional and spatial TME features associated with durable benefit from first-line ICB in advanced CM. T-cell enrichment and macrophage proximity to HLA-DR⁺ tumor cells emerged as reproducible candidate spatial biomarkers warranting prospective validation. Main predictors of 1y-CB and 1y-PFS. Parameters 1y-CB events/N 1y-CB p-value 1y-PFS HR (95% CI) 1y-PFS p-value B cells ≥9.5 5/15 vs 9/14 0.026 0.26 (0.00–0.99) 0.047 CD8⁺ T cells ≥36 7/20 vs 7/9 0.023 0.26 (0.00–0.76) 0.013 Plasma cells ≥1 3/12 vs 11/17 0.017 0.28 (0.08–1.00) 0.050 Tumor density ≥4194 5/5 vs 9/24 0.006 10.57 (3.08–36.23) <0.001 B–Tconv proximity ≥13.3% 2/10 vs 10/16 0.018 0.20 (0.00–0.91) 0.037 HLA-DR ≥58.4% 1/7 vs 13/22 0.040 0.17 (0.02–1.28) 0.085 PD-L1 ≥3.3% 8/20 vs 6/9 0.022 0.48 (0.16–1.38) 0.171