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Impact of outpatient CAR T-cell therapy administration on healthcare utilization in patients with hematologic malignancies.

1503 Background: CAR T-cell therapy has revolutionized treatment outcomes in hematological malignancies, but has traditionally required inpatient post-infusion monitoring, which is associated with significant cost and time toxicity. Outpatient CAR T infusion and monitoring has been the standard approach at Mayo Clinic site in Rochester, MN, with demonstrated feasibility and safety (Bansal et al., ASCO 2023). We present data comparing healthcare utilization between CAR T recipients who underwent outpatient remote monitoring and those with traditional inpatient monitoring. Methods: Electronic medical records were retrospectively analyzed for 293 patients who received CAR T-cell therapy for a hematological malignancy at any of the 3 Mayo Clinic sites (MN, AZ, FL) between 2020 and 2024 . Healthcare utilization was compared between patients who received outpatient CAR T with remote patient monitoring in Rochester, MN (N = 125) and those who received inpatient CAR T in the Arizona (n = 90) and Florida (n = 78) sites. Per protocol, patients in the inpatient group underwent mandatory inpatient monitoring for 7 days, with extension per provider discretion. Data was analyzed through Chi-Square and Wilcoxon tests. P values < 0.05 were considered statistically significant. Results: There was no significant difference in baseline sex, age, ethnicity, LDH, platelets, or neutrophils among the 293 patients. Diagnoses included lymphoma (n = 175), multiple myeloma (n = 106), and B-ALL (n = 12). The most common CAR T-cell products used were axicabtagene ciloleucel (n = 138) idecabtagene vicleucel (n = 56), and ciltacabtagene autoleucel (n = 50). Median hospital days were lower in the outpatient group vs the inpatient group at 30 days (4.4 vs 13.3, P < 0.001) and 90 days (4.6 vs 13.6, P < 0.001). ICU admission occurred in 1 outpatient patient ( < 1%) vs 18 inpatient patients (11%) in the first 30 days (P < 0.001). In the first 30 days, 22% of patients in the outpatient group did not require hospitalization, while 56%, 15%, and 6% required 1, 2, and 3 hospitalizations, respectively. Similarly, only 11 (8.8%) patients in the outpatient group had ≥1 ED visit in the first 30 days compared with 32 (20%) pts in the inpatient group (P = 0.009). At 30 days, there was no difference in patient portal use, with 58% of patients using the portal at least once and a median of 1 message in both groups. Within the first 30 days, 53% and 2% of patients in the outpatient group required 1 and 2 outpatient visits, respectively, vs 29% and 2% in the inpatient group (P < 0.001). There was no difference in 30-day mortality (1.6% outpatient vs 2.4% in inpatient) between the 2 groups (P = 1.00) Conclusions: Outpatient CAR T-cell therapy monitoring was associated with significantly fewer hospital days without increased ED visits, ICU stays, portal use, or 30-day mortality. This demonstrates lower healthcare utilization for outpatient CAR-T therapy.

Racial disparities in maternal outcomes among pregnant patients with cancer: A National Inpatient Sample analysis.

e23244 Background: Pregnancy-associated cancer affects approximately 1 in 1,000 pregnancies. We conducted a national analysis to characterize outcomes and disparities among pregnant patients with cancer. Methods: Using the National Inpatient Sample (2019-2022), we identified pregnancy-related hospitalizations (ICD-10: O00-O9A, Z33-Z34) among reproductive-age women (15-54 years) with concurrent cancer diagnoses (C00-C96). Primary outcomes were in-hospital maternal mortality and severe maternal morbidity (SMM), defined using CDC criteria. Multivariable logistic regression estimated adjusted odds ratios (aOR) for racial/ethnic disparities, controlling for age, insurance, hospital type, cancer type, and metastatic status. Results: Among 15.2 million pregnancy hospitalizations, 13,305 (0.09%; 8.7 per 10,000) involved a cancer diagnosis. The most common malignancies were leukemia (20.2%), breast cancer (16.6%), and lymphoma (13.2%). Overall maternal mortality was 7.5 per 1,000, and SMM occurred in 24.8%. Significant racial disparities emerged: Black women experienced 2.5-fold higher crude mortality (14.1 vs 5.6 per 1,000) and 41% higher SMM rates (32.6% vs 23.1%) compared to White women. After full adjustment, Black race had mortality of (aOR 1.88, 95% CI 1.14-3.11, p = 0.013) and SMM (aOR 1.63, 95% CI 1.46-1.83, p < 0.0001). Specific SMM indicators demonstrated profound disparities: Black women had 4.2-fold higher rates of mechanical ventilation, 3.3-fold higher acute kidney injury, 2.8-fold higher DIC, and 2.7-fold higher VTE compared to White women. Metastatic disease (aOR 5.80, 95% CI 3.42-9.85) and leukemia (aOR 2.42, 95% CI 1.31-4.48) were additional independent mortality predictors. Conclusions: Black pregnant patients with cancer face nearly twice the mortality risk of White patients, with disparities persisting after adjustment for clinical and socioeconomic factors. These findings support the need for targeted interventions, enhanced multidisciplinary care coordination, and equity-focused quality improvement initiatives for pregnant patients with cancer, with particular attention to Black maternal health. Racial disparities in maternal outcomes among pregnant patients with cancer. Outcome Overall White Black Hispanic Asian/PI aOR (Black vs White) 95% CI P-value Key Finding Cohort (N) 13,305 7,165 (53.9%) 2,130 (16.0%) 2,435 (18.3%) 590 (4.4%) — — — Rate: 8.7/10,000 pregnancies MATERNAL MORTALITY Per 1,000 admissions 7.5 5.6 14.1 6.2 8.5 1.88 1.14-3.11 0.013 Black 2.5× higher mortality SEVERE MATERNAL MORBIDITY SMM Rate (%) 24.8 23.1 32.6 23.2 26.3 1.63 1.46-1.83 <0.0001 Black 63% higher SMM SMM INDICATORS (Black vs White) Mechanical Ventilation (%) — 1.4 5.9 — — 4.2× — — Most striking disparity AKI / Blood Transfusion (%) — 2.2 / 4.1 7.0 / 9.2 — — 3.3× / 2.2× — — Significant organ dysfunction Mean LOS (days) 5.0 4.4 6.9 5.2 4.8 — — — Black 57% longer LOS

Overall survival benefit of doublet versus triplet BRAF inhibitor–based therapy: Insights from the BEETS study (JACCRO CC-18).

3540 Background: Cetuximab plus encorafenib, with or without binimetinib, is established as one of the standard treatment options for BRAF V600E-mutated metastatic colorectal cancer (mCRC) in the second- or later-line setting. Although the triplet therapy (encorafenib/cetuximab/binimetinib; T) is approved in Japan and commonly used for patients with poor prognostic features based on guideline recommendations, objective biomarkers to guide optimal patient selection remain lacking. Given the BREAKWATER trial support for first-line doublet therapy (encorafenib/cetuximab; D) with chemotherapy, the clinical role of MEK inhibitor–containing regimens may become more limited; nevertheless, the development of biomarkers capable of identifying patients who are likely to benefit from MEK inhibition remains an important unmet need. We therefore performed a prospective translational analysis within the BEETS study to identify biomarkers that guide treatment selection between T and D. Methods: BEETS (JACCRO CC-18: UMIN000045530) was a multicenter, prospective biomarker study of second/third-line encorafenib-based D or T regimen. We prospectively collected paired pre- and post-treatment blood samples, and analyzed pretreatment tumor-educated platelet RNA by RNA sequencing (TEP-seq). To address baseline imbalances, propensity score matching (PSM) was performed using ECOG PS, number of metastatic organs (≥3), C-reactive protein (>1 mg/dL), and prior primary tumor resection. Interaction between gene expression (z-score) and treatment arm was evaluated using Cox proportional hazards models. Candidate biomarkers were prioritized based on |log2(HR)| ≥ 0.5 and P < 0.05. Results: Of 203 enrolled patients, 189 were evaluable for TEP-seq. After PSM, 81 patients per arm were analyzed. In the matched cohort, median overall survival (OS) was longer for D than T (17.4 months [m] vs. 10.2 m, HR 1.80; 95% CI:1.24–2.61). Interaction screening identified 44 genes for which higher expression was associated with better outcomes on D but worse outcomes on T, and six genes showing the opposite pattern. Among these candidates, RAD51C expression emerged as a representative marker; when dichotomized at the arm-specific median, higher expression favored T but indicated worse outcomes with D ( RAD51C Low vs. High; T 7.8m vs. 10.6m, HR 0.79, 95%CI 0.49–1.28; D 28.2m vs. 12.9m, HR 2.02, 95%CI 1.16–3.53). Pathway-level exploration suggested a possible association between elevated RAD51C expression and increased MAPK-related signaling activity, potentially explaining the requirement for more intensive MEK inhibition in these patients. Conclusions: While OS was superior with D regimen in this matched cohort, RAD51C expression was identified as a candidate biomarker for identifying patients who may derive preferential benefit from MEK inhibition. Clinical trial information: UMIN000045530.

Effect of higher initial dose and accelerated titration of ropeginterferon alfa-2b on early hematologic and molecular responses in polycythemia vera: A meta-analysis.

e18592 Background: Ropeginterferon alfa-2b (ropeginterferon) is a mono-pegylated interferon-alpha that received FDA approval in 2021 as the first interferon for adults with polycythemia vera (PV). Dosing and titration schedule of ropeginterferon have varied across previous PV studies. Emerging evidence from clinical studies and real-world experience suggests that a higher initial dose and accelerated titration (HIDAT; starting at 250 µg and escalating from 250 to 350 to 500 µg within 4 weeks) may shorten time to hematologic and molecular responses compared with low initial dose and response-based titration (starting at 50-100 µg, increased by 50 µg every 2 weeks). However, whether the HIDAT regimen provides a meaningful advantage in efficacy and safety remains uncertain. Methods: We conducted a systemic review and meta-analysis in accordance with PRISMA guidelines. A total of 13,769 records were screened using key terms related to PV and ropeginterferon from MEDLINE, Embase, Web of Science, and ClinicalTrials.gov. We identified 18 studies, including randomized controlled trials, single-arm studies, and cohort studies, in which ropeginterferon was administered to adults (≥18 years) with PV. We compared HIDAT (starting dose ≥250 µg) versus low-dose regimens (<250 µg) by pooling single arms of ropeginterferon treatment. Analyses were performed using the meta package in R (version 7.0.0). Outcomes included complete hematologic response (CHR), molecular response (MR; European LeukemiaNet criteria, partial and complete combined), adverse events (AEs), and discontinuation rates in both dosing strategies. Results: HIDAT was associated with higher CHR rates at 3 months (33.5% vs 12.2%, P = 0.029), 6 months (49.6% vs 30.0%, P = 0.016), and 12 months (59.7% vs 31.6%, P = 0.0004), with no difference at 24 months (50.7% vs 54.5%, P = 0.76). Similarly, HIDAT produced significantly higher MR rates beginning at 6 months (38.4% vs 22.7%, P = 0.024), persisting at 12 months (52.7% vs 33.7%, P = 0.013). From a safety perspective, there was a higher incidence of grade ≥3 AEs at 12 months with HIDAT (12.7% vs 3.8%), albeit not statistically significant ( P = 0.157); these higher-grade AEs were primarily laboratory abnormalities (eg, hematologic cytopenias and transient elevation in liver enzymes) and were generally reversible with dose modification and temporary interruption. Discontinuation rates were comparable at 6 months (0% vs 1.1%, P = 0.997), 12 months (2.5% vs 2.6%, P = 0.942), and 24 months (1.6% vs 7.3%, P = 0.146). Conclusions: HIDAT may accelerate achievement of CHR and MR compared with conventional low-dose titration, without compromising overall safety. These findings support future studies to further evaluate the effectiveness and safety of the HIDAT regimen over the traditional low-dose regimen.

Real-world outcomes of microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) biliary tract cancers (BTC).

4128 Background: Immune checkpoint inhibitors have revolutionized the treatment of microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) cancers. MSI-H/dMMR represents a rare molecular subset (1%) within biliary tract cancers (BTC). The role of immunotherapy alone remains unknown. We investigated clinical features, treatment outcomes, and genomic characteristics of MSI-H/dMMR BTCs in two real world cohorts. Methods: Multicenter retrospective study of BTC patients with MSI-H/dMMR status by immunohistochemistry (IHC) and/or PCR. Patients were from two independent cohorts: MD Anderson Cancer Center (MDACC) and the RETUD registry of the Spanish Cooperative Group for Digestive Tumor Therapy (TTD) group. Results: 46 patients with MSI-H BTC were included in this study; with 21 from MDACC and 25 patients from TTD Cohort. Median age 46 years (95% CI38-80), (35 (76.1%) had intrahepatic cholangiocarcinoma 8 (17.4%) had extrahepatic cholangiocarcinoma and 3 (6.5%) had gallbladder cancer. Patient characteristics are summarized in Table 1. The median OS was 24.4 months (95% CI: 19.9, 40.6). The median follow-up time was 50.2 months (95% CI: 36.2, NA). Thirty-one (68.9%) patients received immunotherapy as part of their treatment course, and 14 (31.1%) did not. For first-line therapy (n=40), the median progression-free survival (PFS) for chemotherapy was 3.19 months (95% CI: 2.56-6.6) and for immunotherapy alone was not reached (95% CI: 8.25-NR, p=0.0006), while among those receiving second-line therapy (n=21), the median PFS for chemotherapy was 4.04 months (95% CI: 2.73-NR) and for immunotherapy alone was 9.69 months (95% CI: 4.43-NR, p=0.044). The median OS was 24.7 months (95% CI: 19.91, NA) in patients with IO, and 19.1 months (95% CI: 13.83, NA) without IO (log rank test p value = 0.085). Conclusions: MSI-H/dMMR BTC patients may derive limited benefit with frontline chemotherapy. Immune checkpoint inhibition may drive durable disease control, supporting early dMMR/MSI-H testing to optimize treatment. Summary of patient characteristics. Covariate N (%) Gender F 18(39.1%) M 28(60.9%) Race Asian 2(4.3%) Black 1(2.2%) White/Caucasian 43(93.5%) Grade G2:Moderately differentiated 8(42.1%) G3:Poorly differentiated 11(57.9%) Stage >II 33(71.7%) I-II 13(28.3%) Mismatch Repair Gene Loss MLH1 5(12.2%) MLH1,MSH6 3(7.3%) MLH1,PMS2 20(48.8%) MLH1,PMS2,MSH6 1(2.4%) MSH2,MSH6 7(17.1%) MSH6 1(2.4%) PMS2 4(9.8%) Resectable at Diagnosis No 27(58.7%) Yes 19(41.3%)

Sociodemographic disparities in cervical cancer incidence, mortality, and disability-adjusted life years in Europe, 1990-2023.

e17520 Background: Cervical cancer remains a public health concern in Europe despite effective prevention strategies, including HPV vaccination and organized screening. Although mortality has declined in many countries, progress has been uneven, with persistent regional disparities. We assessed long-term regional trends in cervical cancer incidence, mortality, and disability-adjusted life years (DALYs) across Europe. Methods: We conducted a GBD estimates-based analysis of cervical cancer incidence, mortality, and DALYs among females in Europe from 1990 to 2023 using publicly available data. Estimates were stratified by Western, Central, and Eastern Europe and expressed as age-standardized rates per 100,000 population. Temporal trends were evaluated using Joinpoint regression to estimate annual percent change (APC). Average annual percent change (AAPC) and 95% confidence intervals (CIs) were calculated as weighted averages across the study period. Results: From 1990 to 2023, cervical cancer incidence declined across Europe, with marked regional variation. Incidence decreased most in Western Europe (AAPC: −1.42%; 95% CI: −1.59 to −1.24) and Central Europe (AAPC: −1.27%; 95% CI: −1.35 to −1.19), driven by sustained declines after 2007 in Central Europe (APC: −2.41%; 95% CI: −2.48 to −2.35) and during 2001–2023 in Western Europe (APC: −1.89%; 95% CI: −2.03 to −1.75), following modest increases or stabilization during the 1990s. Eastern Europe showed an early rise (1990–1993; APC: 1.48%; 95% CI: −0.21 to 3.21) followed by prolonged declines after 2003, resulting in a small and non-significant overall change (AAPC: −0.09%; 95% CI: −0.42 to 0.24). In contrast, mortality and DALY rates declined across all subregions, with the largest reductions observed in Western Europe (mortality AAPC: −1.63%; 95% CI: −1.71 to −1.56; DALYs AAPC: −1.74%; 95% CI: −1.81 to −1.66), followed by Eastern Europe (mortality AAPC: −0.55%; 95% CI: −0.82 to −0.28; DALYs AAPC: −0.88%; 95% CI: −1.15 to −0.61) and Central Europe (mortality AAPC: −0.39%; 95% CI: −0.49 to −0.29; DALYs AAPC: −0.70%; 95% CI: −0.79 to −0.60). Trends were non-linear, with early increases in Eastern Europe (1990–1993; mortality APC: 1.65%; 95% CI: 1.05 to 2.25; DALYs APC: 4.60%; 95% CI: 4.07 to 5.14), followed by the steepest declines after 2011 and more gradual reductions in Central and Western Europe. Females experienced greater reductions in mortality, incidence, and DALYs, while trends for both sexes followed similar regional patterns. Conclusions: Despite substantial declines in cervical cancer mortality and DALY burden across Europe, incidence trends remain uneven, with the highest burden persisting in Central and Eastern Europe, underscoring the need for equitable strengthening of HPV vaccination and screening to accelerate cervical cancer elimination.

Progressive locally advanced or metastatic radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) patients treated with donafenib: A real-world study.

e18018 Background: Donafenib was approved for the treatment of RAI-R DTC patients by National Medical Products Administration (NMPA) in 2022, The main objectives of this study were to assess real-world clinical effectiveness and safety in RAI-R DTC patients treated with donafenib at Fudan University Shanghai Cancer Center. Methods: An observational patient chart review was conducted. The study cohort comprised RAI-R DTC patients who were treated with donafenib monotherapy (200 mg, bid, up to 24 months), between January 1, 2023 and December 31, 2025. Data were collected from patient electronic health records by the prescribing physicians and were de-identified before filling in an electronic case report form. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS) and disease control rate (DCR). Time to event endpoints were assessed using Kaplan-Meier methods. Results: Of the 22 patients reviewed, 63.6% were female and the median age of the patients was 61.5 years at donafenib initiation; 90.9% of patients had an ECOG PS of 1, 81.8% of patients were in stage IVB (other 4 patients were in stageⅡbecause of age under 50) , 40.9% of patients had follicular DTC and 90.9% of patients had lung metastases. The median follow-up time was 16.9 months (95%CI:12.7-21.1), the ORR and the DCR by RECIST 1.1 were 22.7% (5/22) and 86.4% (19/22), respectively. The median PFS and median OS were not reached, 1-year PFS rate was 85.6% (95% CI: 70.5-1）and 1-year survival rate was 100%. Median serum Tg dropped from baseline rapidly in the first 3 weeks; early in cycle two, biochemical response was observed in 84.6% of patients. ≥ Grade 3 treatment-related adverse events (TRAEs) were observed in 22.7% of patients, the most frequent TRAE of all grades was hand foot skin reaction (15/22, 68.2%). No treatment-related deaths were observed . Conclusions: The current study enriched the efficacy and safety data of donafenib in the treatment of RAI-R DTC patients in real-world clinical practice in china, which enrolled more patients with ECOG PS ≥ 1 and follicular DTC compared with the phase III DIRECTION study. In addition, the efficacy and safety results are consistent with DIRECTION study.

Concomitant radiotherapy, tremelimumab, and durvalumab for advanced NSCLC patients progressing on first-line immunotherapy: A phase 2 study (CORAL-Lung).

8583 Background: The optimal treatment for advanced NSCLC that developed resistance to immune checkpoint inhibitors (CPIs) remains undefined. We hypothesized that combining anti-PD-L1, anti-CTLA-4 (at an effective dose) and radiotherapy could be effective against CPI-resistant tumors. Methods: This open-label, single-arm, phase 2a trial evaluated two CPIs plus radiotherapy in patients with advanced/metastatic NSCLC who progressed on/after 1L CPI given alone or in combination with chemotherapy. Co-Primary endpoints were safety and response rate (RR; by RECIST 1.1). Secondary endpoints were to evaluate progression free survival (PFS) and overall survival (OS). The study included a safety run-in cohort and a Simon two-step design expansion. RR ≥ 20% in non-irradiated lesions was required to advance from the initial efficacy to expansion cohort. Patients with prior anti-CTLA-4 treatment were excluded. At least one measurable non-irradiated lesion was required. Treatment included tremelimumab at a fixed dose of 300 mg at D1 and 12 weeks later and 1500 mg Durvalumab q4w (starting from D1). This dosing was based on PK and pharmacodyamic data from study D4190C00006, suggesting tremelimumab of dose greater than 1 mg/kg with a higher peak exposure may be associated with a higher pharmacodynamic effect. On D21, patients began radiotherapy: 11 fractions of 3 Gy (total of 33 Gy), selected based on our real-world database analysis (Onn et al, Cancers 2021, 13(11), 2800). The study was sponsored by Sheba MC and funded by AstraZeneca Pharmaceuticals. NIH trials registry identifier: NCT05000710. Results: Ten patients were enrolled, median age was 71 (range 51-82); 50% males; all stage IV; 50% adenocarcinoma; 50% with PD-L1 < 1%; 80% past/current smokers; none had actionable driver mutations. Previous treatment lines were 1/2 in 80%/20% respectively; all patients received prior pembrolizumab and platinum-based doublet. Median (range) durvalumab and tremelimumab cycles administered were 2 (1-7), 1(1-3). Median radiotherapy dose was 33 Gy, in 78% targeting lung lesions. Nine patients were included in the safety run-in, three experienced treatment-related toxicities leading to treatment discontinuation (all grade 3 diarrhea), remaining below the predefined 40% threshold and permitting continuation. All other treatment-related toxicities were grade 2 or lower. The initial efficacy cohort (n = 10) RR was 10%, leading to the study closure. Median PFS was 2.2 months, median OS was 13.9 months. The study was terminated on Dec 31, 2024. Conclusions: In unselected patients with advanced CPI-resistant NSCLC, the combination of anti-PD-L1, anti-CTLA4 at a high dose and radiotherapy did not demonstrate a meaningful response rate. Toxicity of a high dose of anti-CTLA-4 is not negligible. Better patient selection might lead to higher efficacy and lower toxicity. Clinical trial information: NCT05000710 .

Non-random patterns of multiple primary malignancies in the era of cancer survival.

10584 Background: Improved cancer therapies have increased survival, placing survivors at risk for subsequent primary cancers, yet the epidemiology of multiple primary cancers (MPC) is poorly defined. Methods: Using the VA Cancer Registry (2003–2023), we quantified MPC frequency, classified cancers by SEER ICD-O-3 codes and histology, and analyzed incidence and expected versus observed occurrence. Results: Among 822,564 veterans with cancer, 11.1% (n=91,279) developed ≥2 primary cancers. The frequencies of patients with 2, 3, 4, or ≥5 MPC were 81715 (9.9%), 8655 (1.1%), 800 (0.1%), and 109 (0.01%), with similar relative risks across successive cancers. Interestingly, the median age at first cancer was similar across groups (67.3 years for 1 cancer; 66.6, 65.8, and 65 years for 2, 3 and 4 cancers). In contrast, intervals between successive cancers progressively shortened (2.7 years – 2 cancers; 2.5 and 1.8 years – 3 cancers; 2.2, 1.9, and 1.4 years – 4 cancers), suggesting prior cancer influences the risk of subsequent cancer. The 7 most common first and subsequent cancers were prostate, bladder, lung, colon, melanoma, kidney, and oral cavity cancers. We identified three etiologic patterns underlying MPC. First, exposure-related cancers, clustered as expected, lung cancer was the most common 2 nd and 3 rd cancer after bladder (n=1850 and 231) and oral cavity (n=1581 and 148) cancers, suggesting a relationship to smoking. Second, genetically predisposed cancers did not cluster, likely reflecting the older population. Third, therapy-related cancers increased, with acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) standard rates rising from 0.02/0.003 (1 st ) to 39.01/3.19 (AML) and 5.04/0.03 (ALL) as 2 nd and 3 rd primary cancers. Interestingly, the frequency of prostate cancer and chronic lymphocytic leukemia (CLL) declined with increasing cancer order, consistent with earlier detection through established screening practices, and in contrast, lung cancer and multiple myeloma (MM) frequency increased as subsequent cancers, suggesting more complex etiologies, including aging-related risk. Conclusions: In this large VA registry analysis, over 11% of cancer survivors developed MPC with consistent patterns of occurrence, shortening inter-cancer intervals, and non-random clustering by exposure-, therapy-, and disease-specific factors. These findings underscore the need for risk-adapted surveillance and long-term survivorship strategies that account for shared etiologies and treatment-related risks rather than assuming stochastic occurrence. Frequency of a cancer as MPC. 1 st primary 2 nd primary 3 rd primary 4 th primary Pts with 2 cancers Prostate 29.4% 14.1% CLL 2.3% 1.1% Lung 7.8% 20% MM 1.1% 1.7% Pts with 3 cancers Prostate 28.1% 15.6% 9.3% CLL 2.8% 2.2% 1% Lung 5.4% 11.7% 20.6% MM 0.8% 1.5% 2% Pts with 4 cancers Prostate 26% 14.8% 12.1% 7.3% CLL 2.4% 1.8% 1.9% 1.4% Lung 5.4% 8.4% 13.9% 22.9% MM 1% 1.1% 1.8% 2.1%

Results of peripheral blood immune analysis in patients receiving immune checkpoint inhibitor therapy and correlation with immune-related adverse events.

e19568 Background: Immune-related adverse events (irAEs) result from T-lymphocyte activation induced by immune checkpoint inhibitor (ICI) therapy. Although T cells are central to irAE pathogenesis, a contributory role for B cells is suggested by the mechanistic overlap between irAEs and autoimmune diseases. Monoclonal gammopathy of undetermined significance (MGUS), has also been increasingly associated with autoimmune conditions. We investigated the occurrence of MGUS in cancer patients who developed irAEs following ICI therapy. Methods: We conducted a retrospective, single-center observational study of patients treated with ICIs who developed irAEs, evaluating for the presence of MGUS. Peripheral blood samples were analyzed by serum protein electrophoresis and immunofixation to detect monoclonal gammopathy. MGUS status was correlated with tumor type, ICI regimen, and the presence and severity of irAEs. Results: Twenty-four patients that developed toxicity following ICI were identified, including those treated with pembrolizumab (n = 8), nivolumab (n = 6), cemiplimab (n = 3), or combination ipilimumab/nivolumab (n = 7). Tumor types included cutaneous melanoma (n = 16), head and neck cancer (n = 2), cutaneous squamous cell carcinoma (n = 2), and one case each of spindle cell carcinoma, cutaneous T-cell lymphoma, Merkel cell carcinoma, and basal cell carcinoma. MGUS was detected in 12 patients (Group A) (50%): IgM (n = 7), IgG (n = 4), and IgA (n = 1), with kappa light-chain restriction in 9 and lambda in 3 patients. The remaining 12 patients (Group B) had no detectable MGUS. Median age was 78 and 76 between Groups A and B, respectively. Our results show a Male:Female ratio of 8:4 and 7:5 respectively between Groups A and B. Grade III-IV irAEs occurred in 11/12 patients with MGUS compared with 2/12 patients without MGUS. Severe cutaneous toxicity predominated among patients with MGUS, with grade III–IV skin rash observed in 6 of 7 patients with skin involvement. Additional irAEs included grade III diarrhea/gastritis (n = 1) and severe fatigue (n = 1). Among patients with IgM MGUS, two developed cryoglobulinemia and one developed antiphospholipid antibody syndrome with vasculitis, resulting in significant morbidity. In patients without MGUS, severe irAEs were limited to skin rash (n = 1) and colitis (n = 1). Conclusions: MGUS was frequently detected in cancer patients who developed severe irAEs following ICI therapy and was strongly associated with grade III–IV toxicity. IgM MGUS and kappa light-chain restriction were predominant and were associated with immune-complex–mediated complications. These findings suggest that clonal B-cell activity may contribute to irAE severity in a subset of patients. Larger studies are warranted to validate these observations, help elucidate this mechanism and help detect tissue biomarkers of B cell activity.

Real-world patterns of PD-L1 expression, biomarker testing, and immunotherapy utilization across lung and other solid tumors in an Asian cohort.

e23380 Background: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is an established enrichment biomarker guiding immune checkpoint inhibitor (ICI) therapy across multiple solid tumors, as reflected in NCCN and ESMO guidelines. While clinical trials have defined tumor-specific PD-L1 thresholds, limited real-world data are available on PD-L1 expression patterns, concurrent biomarker testing, and alignment with ICI use in Asian oncology practice. We evaluated PD-L1 testing and treatment patterns across lung and other solid tumors in a real-world Asian cohort. Methods: We retrospectively analyzed 339 predominantly Indian solid tumor cases, tested for PD-L1 IHC between 2019 and 2025. Tumor types included lung, gastric, head and neck, liver, breast, and others. PD-L1 expression was assessed using the SP263 assay and categorized by tumor proportion score (TPS) for lung and combined positive score (CPS) for non-lung tumors. Available clinical data included demographics, disease status, histology and subsequent therapy. Patterns of concurrent diagnostic and predictive biomarker testing were also reviewed by tumor type. Our analyses focused on PD-L1 testing patterns by tumor type and intensity, PD-L1 positivity by disease status, and concordance between PD-L1 expression and use of ICIs. Results: Lung cancer accounted for 35% of cases, followed by gastric (12.7%), head and neck (10%), liver (6.8%), breast including TNBC (5.6%), with other cancers comprising less than 5% each. Median age was 60 years. Males comprised 56.6% of the overall cohort and 61.7% of lung cancer cases. PD-L1 positivity (TPS ≥1%) in lung cancer was 52.1%, including 10.1% with TPS ≥50%. PD-L1 positivity across other tumors was highest in head and neck (88.2%), gastric (73.8%), breast (65%), and liver cancers (25%). Treatment data were available for 74 PD-L1–tested NSCLC cases; among PD-L1–positive patients, 20% received PD-1 inhibitor–based therapy, as also one PD-L1 negative case, mostly in combination with chemotherapy. Among other PD-L1–positive tumors, ICI utilization was highest in head and neck (42%), followed by gastric (27%), breast including TNBC (14%) and absent in liver cancers. Conclusions: In this real-world Indian cohort, PD-L1 testing is integrated into multi-biomarker diagnostic pathways across several solid tumors, with substantial variability in expression by tumor type and disease status. Importantly, PD-L1 positivity did not consistently translate into immunotherapy use, underscoring real-world barriers to treatment access and implementation. These findings highlight the clinical relevance of Asian PD-L1 epidemiology and the diagnostic importance of harmonized biomarker testing strategies to optimize patient identification and treatment selection in routine oncology practice.

An AI-enabled framework for pre-visit decision support using patient similarity analysis in melanoma.

e21533 Background: Clinical decision-making in melanoma is challenged by heterogeneous disease biology, evolving treatment paradigms, and fragmented longitudinal data. Although EMRs contain real-world information, clinicians often lack tools that organize these data around clinically meaningful milestones to support pre-visit decision-making. We developed CODE-M, an AI–enabled framework designed to identify clinically similar patients (“patients like mine”) and surface outcome-relevant insights using real-world data. Methods: CODE-M was developed using data derived from EMRs at a large academic cancer center. Patient data were normalized and aligned to a clinically defined ordinal timeline spanning diagnosis, adjuvant therapy, recurrence, progression, systemic treatment, and outcomes. Similarity modeling incorporated demographics, disease stage, treatment history, longitudinal outcomes, and available molecular and genomic attributes, represented as contextual features within the timeline. AI-based similarity modeling generated retrospective cohorts reflecting shared clinical features of an index patient and supported iterative cohort generation for competing progression-free and overall survival analyses using automated Kaplan–Meier, Cox proportional hazards, and feature association models. A clinician-facing pre-visit summary presents cohort characteristics, outcomes, and relevant clinical trial options prior to patient encounters. Results: The framework reliably aligned heterogeneous longitudinal EMR data to a shared clinical timeline and generated reproducible, clinically coherent patient cohorts reflecting shared disease stage, treatment exposure, and melanoma care patterns. Iterative cohort generation enabled comparative analyses across competing cohorts, resulting in predictable shifts in observed progression-free and overall survival distributions. Pre-visit summaries and analytic outputs were reviewed by clinicians and demonstrated interpretability and relevance for visit preparation. The platform also identified clinical trials based on eligibility criteria, trial availability, and patient geographic proximity, integrating trial matching into the clinical decision workflow. Conclusions: An AI-enabled, ordinal timeline–based approach can structure real-world melanoma data to support pre-visit clinical context through patient similarity analysis and comparative outcome visualization. CODE-M summarizes observed outcomes among clinically similar patients and is intended to support contextual understanding of prior care experiences rather than generate treatment recommendations or patient-specific predictions. This framework supports clinical insight, hypothesis generation, and shared decision-making using longitudinal EMR-derived data, with applicability across oncology disease types.

A multi-institutional epidemiologic and oncologic profile of gastrointestinal stromal tumors in the Lebanese population.

e23508 Background: Gastrointestinal stromal tumor (GIST) is a rare type of soft tissue sarcoma that most commonly arises from the gastric mesenchymal cells. This study represents the first GIST registry in Lebanon. The aim of this study is to describe the Lebanese cohort of GIST cases and their management standards in resource-limited setting. Methods: This study is a multi-institutional retrospective study of GIST cases diagnosed at the American University of Beirut Medical Center and Hammoud Hospital University Medical Center between 1996 and 2017. Study objectives included epidemiologic and clinical profiling of patients with GIST, tumor characteristics, approach to diagnosis, evaluation of medical and surgical interventions, and oncological outcomes. Results: The database includes 106 GIST cases with a median age of 63.5 years (24-90) and male predominance of 56.6%. Median tumor size is 6 cm (0.3-21) with the most common presenting symptoms being abdominal pain and anemia. Endoscopy is the most commonly used diagnostic modality (49%) with confirmatory biopsy done in 42% of the cases. The most common tumor location is gastric (56.7%) followed by the small intestine (32.7%) and colon (7.7%). Noteworthy, the most common tumor size in female is between 5-10cm (40%) versus 2-5cm in males (32%). The most common histologic cell type is spindle cell (65.7%) followed by epithelioid and mixed. CD 117 and CD 34 are positive in 91% and 78% of the cases, respectively. Metastasis on presentation is present in 16% of the cases. Only 14.7% of the cases received neoadjuvant therapy in the form of chemo- or targeted therapy while 31% received adjuvant therapy in either form. For the 25% of cases that received adjuvant imatinib or sunitinib, the median tumor size is 8.8cm (4-20cm). Most patients (91%) underwent surgery, either by laparotomy (66%) or laparoscopy (34%). Of those, 97.7% had negative surgical margins. Recurrence occurred in 18.7% of cases with regional and distant recurrence occurring equally (35%) versus local recurrence (30%). Survival analysis shows an overall survival of 87% over a follow up period of 14 years. The 3- and 5-year disease-free survival is 80% and 76%, respectively. Conclusions: Findings from this collaborative study adds to the international epidemiology on GIST. It also shows that GIST features as well as medical and surgical practices in this Lebanese cohort conform with those reported from other populations. GIST histopathological features. Gastrointestinal Stromal Tumor Count Percentage Site of Primary Tumor Gastric 59 56.7 Small Intestine 34 32.7 Colon 8 7.7 Extra-gastrointestinal 3 2.9 Cell Type Spindle 44 65.7 Epithelioid 10 14.9 Mixed 11 16.4 Others 2 3 Cell Biomarkers CD117 85 90.4 CD34 71 78 Metastasis at Presentation Yes 17 16 No 89 84

Exploring the larvicidal and repellent potentials of silver nanoparticles greenly synthesized using three Congolese plant extracts against Anopheles gambiae along with molecular docking analysis

Simultaneously Engineering the Amorphous Phase and Branch Morphology of High‐Entropy Alloy Nanomaterials for Enhanced Ethylene Glycol Oxidation

ABSTRACT High entropy alloy (HEA) nanomaterials have emerged as an intriguing class of catalysts for diverse catalytic applications, yet engineering their morphology and/or crystal phase remains challenging. Herein, we successfully achieve the simultaneous engineering of both the amorphous phase and branch morphology of PdCuNiCoFe HEA nanomaterials. Excitingly, the synthetic protocol is effectively extended to synthesizing a library of amorphous Pd‐based nanobranches, including binary, ternary, and quaternary alloys. When employed as catalysts for ethylene glycol oxidation reaction (EGOR), the amorphous PdCuNiCoFe HEA achieves superior activity and selectivity of glycolic acid approaching 98.6%, and enables a remarkable overpotential drop of 774 mV at 100 mA cm ‒2 in EGOR‐assisted water electrolysis. Mechanistic investigation demonstrates the excellence of amorphous PdCuNiCoFe HEA in suppressing C−C cleavage, facilitating * OH/ * EG adsorption, and lowering the free energy requirement for glycolic acid production. This study offers a promising means to rationally engineer the morphology and phase of HEAs for enhanced electrocatalysis.

Pan-cancer multi-omic integration for identification of clinically aggressive and potentially actionable molecular modules in breast, endometrial, and ovarian cancers.

e12610 Background: Pan-cancer analysis enable the detection of molecular alterations that are individually infrequent within single tumor types but become detectable across harmonized multi-tumor datasets. Beyond tumor-type aggregation, an unmet need is to understand how coordinated multi-omic programs differ between clinically aggressive and non-aggressive phenotypes. We conducted a multi-omic integrative study across breast, endometrial, and ovarian cancers (Pan-GYN) to identify molecular programs associated with clinical aggressiveness and to prioritize candidate biomarkers and potentially actionable targets. Methods: Approximately 3,800 publicly available tumor profiles with paired somatic mutations, somatic copy number alterations, and gene expression data were integrated across breast, endometrial, and ovarian cancers. Samples were prefiltered using stringent quality control criteria. Patients were classified into aggressive and non-aggressive phenotypes based on recurrence, metastasis, or death versus absence of these events.Multi-omic integration and module discovery were performed using the ModulOmics algorithm. Molecular modules were calculated within each clinical class across all three tumor types, enabling identification of coordinated molecular programs associated with clinical phenotype. A noise-aware framework was applied, and two complementary strategies were implemented: (A) a descriptive strategy for group-level enrichment and (B) an observational and predictive strategy based on individualized oncogenic risk scores for patient-specific prioritization. Results: Joint pan-cancer module discovery identified 143 molecular modules in the aggressive phenotype. Based on clinical association, 42 modules comprising 28 genes were prioritized as associated with aggressive disease. These included well-established oncogenes and tumor suppressors, as well as underreported candidates. Prioritized modules were enriched for oncogenic processes relevant to tumor progression and clinical outcomes. Importantly, prioritized modules were significantly associated with clinical outcomes, and individualized oncogenic risk scores improved discrimination of aggressive phenotypes. Actionability analyses mapped prioritized genes and modules to drug–gene interaction networks, supporting the identification of candidate pharmacologic modulators and potential therapeutic targets. Conclusions: This pan-cancer, multi-omic framework captures differences between aggressive and non-aggressive phenotypes across breast, endometrial, and ovarian cancers, supporting systems-level approaches to identify convergent oncogenic programs linked to clinical aggressiveness, prioritize biomarkers, and inform network-based therapeutic and drug repositioning strategies.

Precision oncology in practice: Real-world multicenter experience with larotrectinib in pediatric extracranial NTRK fusion–positive tumors.

10036 Background: Gene fusions involving NTRK1/2/3 represent actionable oncogenic drivers across a spectrum of rare pediatric solid tumors. Larotrectinib, a highly selective TRK inhibitor, has demonstrated robust efficacy and a favorable safety profile in clinical trials. However, real-world data from middle-income countries remain limited. We report a national multicenter real-world experience evaluating outcomes of pediatric patients with NTRK fusion–positive tumors treated with larotrectinib in Türkiye. Methods: This retrospective, descriptive multicenter study included pediatric patients (0–18 years) with histologically confirmed solid tumors harboring NTRK gene fusions, treated with larotrectinib for ≥1 month between August 2023 and April 2025. Clinical data were collected from 15 tertiary pediatric oncology centers. Treatment response was assessed using RECIST v1.1 or tumor-specific pediatric criteria. Adverse events were graded per CTCAE v5.0. Survival outcomes were analyzed descriptively. Results: Twenty-two patients were included; median age at diagnosis was 3 months (range, 1 day–182 months), and 59% were female. Infantile fibrosarcoma (IFS) was the most common diagnosis (n=16, 72.7%), followed by rhabdomyosarcoma (RMS), epithelioid sarcoma (ES), desmoplastic small round cell tumor (DSRCT). Six patients (27.3%) had metastatic disease at diagnosis. Larotrectinib was initiated due to disease progression or inadequate response to prior therapy in 86% of patients, treatment-related toxicity in 9%, and as maintenance therapy in one patient. After a median follow-up of 24 months, 10 patients achieved complete response, 6 had partial response or stable disease, and 4 experienced progression; 3 patients later relapsed. One patient died due to progressive disease. The 24-month overall survival rate was 95.5%, and 82% of patients remained event-free. No treatment-limiting adverse events were observed. Conclusions: In this national real-world cohort, larotrectinib demonstrated high efficacy, durable disease control, and an excellent safety profile in pediatric patients with NTRK fusion–positive solid tumors, particularly IFS. These findings support early integration of molecular diagnostics and TRK inhibition into routine pediatric oncology practice and provide valuable real-world evidence from a middle-income country setting. *Larotrectinib was provided through the early access to medicines program for humanitarian purposes and the data reflects real world data and does not reflect phase research data. The pharmaceutical company did not provide any kind of support in the planning/reporting/publication of the study.

Endometrial cancer mortality among postmenopausal women in the United States, 1999-2023.

e17621 Background: Endometrial cancer occurs predominantly in postmenopausal women, driven by hormonal imbalance and metabolic comorbidities associated with aging. Despite favorable prognosis with early detection, it remains a notable cause of mortality, underscoring the importance of examining disease patterns and trends in this population. Methods: Mortality data from the CDC WONDER multiple cause of death database were used to examine endometrial cancer–related deaths among postmenopausal women aged ≥45 years. Deaths were identified using ICD-10 code C54.1. Crude and age-adjusted mortality rates (CMRs and AAMRs) per 100,000 population were calculated and stratified by year, age group, race/ethnicity, and geographic region. Temporal trends were assessed using Joinpoint regression to estimate annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals. Results: A total of 125,096 deaths related to endometrial cancer were reported among postmenopausal women. Most deaths occurred among individuals aged 65–85+ years (91,818) and at the decedent's home (38.8%). The AAMRs increased significantly from 6.88 (95% CI: 6.65–7.11) in 1999 to 12.03 (95% CI: 11.78–12.29) in 2023, with an average annual percent change (AAPC) of 2.18 (95% CI: 1.36–3.02; p < 0.000001) .Trend analysis showed an initial decline from 1999 to 2014 (APC = −0.56%), followed by a sharp increase until 2017 (APC = 13.19%), with a continued significant rise through 2023 (APC = 3.94%). The highest mortality rates were observed among non-Hispanic Black/African American individuals, followed by non-Hispanic White and Hispanic/Latino populations. Geographic disparities were evident, with the Northeast experiencing the highest burden, while the West was the least affected. Non-metropolitan regions consistently exhibited higher AAMRs than metropolitan areas (7.63 vs. 7.06).From 1999 to 2023, Columbia ranked in the 90th percentile for mortality rates among U.S. states. Conclusions: Endometrial cancer remains a major health burden among postmenopausal women, with the highest mortality observed in older postmenopausal women. Deaths and age-adjusted mortality rates (AAMRs) per 100,000 for trends related to cancer among postmenopausal women from 1999 to 2023. Variable Deaths AAMR (95%CI) 1999 AAMR (95% CI)2023 Female 125,096 6.88(6.6 to 7.11) 12.03 (11.78 to 12.29) NH Whites 92,898 6.27 (6.03 to 6.5) 9.98 (9.73 to 10.24) NH Blacks 20,786 9.83 (8.95 to 10.72) 17.96(17.08 to 18.83) Northeast 27,363 6.89 (6.41 to 7.37) 10.84 (10.32 to 11.37) West 24,178 5.77 (5.31 to 6.22) 9.66 (9.21 to 10.12) Metro 82,548 (2020) 6.81 (6.57 to 7.01) (2020) 10.98 (10.72 to 11.24) Non-metro 17,334 7.19 (6.64 to 7.74) 11.51 (10.88 to 12.14)

Beyond cardio-renal outcomes with GLP-1RA and SGLT2i in anthracycline-treated diabetic women with breast cancer: A propensity score–matched analysis from Global Federated Health Research Network.

e23079 Background: Anthracyclines remain central to breast cancer therapy but are associated with cardiotoxicity and downstream morbidity. In women with diabetes mellitus, GLP-1 receptor agonists (GLP-1RA) and sodium–glucose cotransporter-2 inhibitors (SGLT2i) may influence outcomes beyond cardio-renal endpoints. We evaluated clinically relevant events (cytopenias, infections, venous thromboembolism, polyneuropathy, mood disorders) in addition to cardio-renal outcomes in anthracycline-treated women with breast cancer and diabetes. Methods: Using the TriNetX Global Collaborative Network, we identified women ≥18 years with breast cancer, diabetes mellitus, and anthracycline exposure. Three 1:1 propensity-matched comparisons were performed: (1) SGLT2i without GLP-1RA vs neither exposure (n = 934/arm), (2) GLP-1RA without SGLT2i vs neither exposure (n = 982/arm), and (3) GLP-1RA vs SGLT2i (n = 703/arm). Matching included demographics, cardiometabolic comorbidities, antihyperglycemic medications, and cancer therapies along with radiation therapy. Outcomes were assessed through 3 years post-index using time-to-event analyses; HRs with 95% CIs are reported. Results: Versus neither exposure, SGLT2i was associated with lower hazard of severe cytopenias (Hb < 8 g/dL, neutropenia and platelets < 50,000/µL), sepsis (0.615, 0.478 - 0.792), neutropenic fever (0.419, 0.283 - 0.622), VTE (DVT: 0.673, 0.468 - 0.967; PE: 0.603, 0.414 - 0.878), polyneuropathy (0.822, 0.687 - 0.984) and mood disorders (0.743, 0.608 - 0.907). GLP-1RA exposure versus neither exposure was associated with lower cytopenias, sepsis (0.553, 0.423 - 0.724), neutropenic fever (0.419, 0.283 - 0.622), and VTE outcomes (DVT: 0.654, 0.468 - 0.914; PE: 0.449, 0.307 - 0.655). In head-to-head analyses, GLP-1RA demonstrated lower hazard of heart failure (0.505, 0.389 - 0.656), cardiomyopathy (0.396, 0.273 - 0.574), AKI (0.704, 0.531 - 0.934), hospital visits (0.862, 0.752 - 0.989), and mortality (0.663, 0.486 - 0.905), while most cytopenia/infection and VTE outcomes were similar with either therapy. Polyneuropathy and mood disorder diagnoses were higher with GLP-1RA versus SGLT2i (1.272, 1.052 - 1.539; 1.241, 1.008 - 1.528). CKD and stroke were not significantly different with either therapy. Conclusions: In this propensity-matched real-world cohort of anthracycline-treated women with breast cancer and diabetes, both GLP-1RA and SGLT2i were associated with improved survival and fewer cytopenias, infections, and VTE versus no exposure. Compared with SGLT2i, GLP-1RA showed more favorable cardio-renal and survival outcomes, whereas SGLT2i was associated with fewer polyneuropathy and mood disorder diagnoses. Prospective validation is needed.

Final analysis of the efficacy and safety of oral S-1 for locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma: A multicenter retrospective study.

9586 Background: Anti–PD-1 antibodies are the standard systemic therapy for advanced cutaneous squamous cell carcinoma (cSCC). Recent clinical trials have reported objective response rates (ORRs) of 44–58.3% in locally advanced (LA) disease and 35.2–45.2% in recurrent or metastatic (R/M) disease, with grade ≥3 adverse events occurring in 31.1–34.5% of patients. S-1, an oral fluoropyrimidine, has been suggested as an alternative option with potential advantages, including favorable clinical response, lower toxicity, feasibility of outpatient initiation, and substantially lower cost; however, evidence remains limited to small case series. We therefore conducted a large multicenter retrospective study to evaluate the real-world efficacy and safety of S-1 in patients with advanced cSCC. Methods: This multicenter retrospective study included patients with LA or R/M cSCC who received oral S-1 between 2007 and 2024. S-1 was administered for 28 consecutive days, followed by 14 days off (one cycle). The primary endpoint was ORR assessed according to RECIST criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Exploratory subgroup analyses were performed based on concomitant radiotherapy use and primary tumor site. Results: A total of 150 patients were analyzed (LA, n = 44; R/M, n = 106). The median age was 76 years (interquartile range, 67–83), and ECOG performance status was 0–1 in 127 patients (85%). Fifty-four patients (36%) had received prior systemic treatment. Among the R/M cohort, 59 patients had nodal metastasis and 47 had distant metastasis. The median follow-up was 13.4 months (LA, 15.0 months; R/M, 12.7 months). ORR was 55% (95% confidence interval [CI], 39–70) in the LA cohort and 40% (95% CI, 30–50) in the R/M cohort. The 12-month PFS and OS rates were 80% and 92% (95% CI, 63–90 and 76–97) in the LA cohort, and 41% and 62% (95% CI, 30–50 and 51–71) in the R/M cohort. Grade ≥3 adverse events occurred in 14% of patients, most commonly anemia (n = 4), thrombocytopenia (n = 3), neutropenia (n = 3), decreased appetite (n = 3), and oral mucositis (n = 3); no grade 5 events were observed. In exploratory analyses, patients receiving concomitant radiotherapy demonstrated higher ORR and PFS compared with those without radiotherapy, while OS was comparable between the groups. Tumors originating in the head and neck region were associated with superior ORR, PFS, and OS compared with other primary sites. Conclusions: Oral S-1 demonstrated antitumor activity comparable to that reported for anti–PD-1 antibodies, albeit without direct comparison, with a lower incidence of severe adverse events, suggesting its potential role in selected patients with advanced cSCC.