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Prior CTLA-4 blockade as associated with a hyperactive immunosuppressive signature and limited response to subsequent immunotherapy in melanoma.

2634 Background: Checkpoint blockade achieves durable long term responses in about 30-50% of patients with malignant melanoma (MM). However, a substantial proportion of patients either fail to respond or develop resistance after initial response. As a result, many MM patients undergo multiple sequential immunotherapeutic treatments in an attempt to achieve clinical benefit. However, the effects of repeated rounds of immunotherapy on the immune system remain poorly understood. We herein report that prior anti-CTLA-4 blockade within 12 months of analysis associated with a hyperactive immunosuppressive immune signature involving IL-6, in 24 patients with anti-PD-1 refractory metastatic MM enrolled in a Phase I/II trial. Methods: The patients received continued checkpoint inhibition with an anti-PD-L1 antibody in combination with an immunostimulatory gene therapy based on replication-competent adenovirus targeting the CD40 and 4-1BB pathways (LOKON003, NCT04123470). Using unsupervised clustering, plasma biomarker profiles at baseline and post treatment initiation was evaluated and correlated to clinical parameters. Results: Two plasma protein profiles were identified at baseline among enrolled patients and one of those included immunosuppressive biomarkers. While patients with this hyperactive immunosuppressive signature (n=8) at baseline experienced a median overall survival (mOS) of 4.0 months, patients without this baseline signature (n=15) had a mOS of 28.1 months. The hyperactive immunosuppressive signature was not related to M1 status, sex, age, or number of prior treatments, but prior anti-CTLA-4 treatment within a year of enrollment was more prevalent in patients with this signature. If dividing the patients only based on receiving anti-CTLA-4 therapy within 12 months (n=10) versus later or not at all (n=14), mOS was 5.3 and 30.7 months, respectively. Patients that had received recent anti-CTLA-4 treatment, presented with a plasma protein signature resembling the hyperactive immunosuppressive signature with IL-6 as a central node among the upregulated proteins. Patients who did not receive anti-CTLA-4 blockade during the past 12 months responded to the combination of the immunostimulatory gene therapy and continued checkpoint blockade with upregulation of biomarkers associated with T cell activation and cell killing capacity, which may have supported the better survival outcome in this patient group. Conclusions: The findings highlight the need for further clinical evaluation of the consequences of repeated immunotherapeutic treatments, IL-6 inhibition in this population, and consideration for a wash-out period from further immunotherapy to allow for immune system recovery post anti-CTLA-4 treatment. Clinical trial information: NCT04123470 .

DART (NCI/SWOG S1609): Comprehensive results from dual checkpoint inhibition with CTLA-4 and PD-1 blockade in rare cancers.

2502 Background: Rare tumors are underrepresented in clinical trials, though they collectively comprise an estimated 22% of all cancer cases. The NCI/SWOG S1609 trial evaluated efficacy signals across 53 rare cancer cohorts treated with dual CTLA-4 and PD-1 inhibition. Methods: A prospective, open-label, multicenter phase 2 trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks) was conducted from 1/13/2017 to 3/15/2023. A statistical framework was established to evaluate each cohort in a two-stage design. The primary end point was objective response rate (ORR); progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR, ORR + stable disease >6 months), i-outcomes, and toxicity were secondary and exploratory endpoints. Results: 798 patients were enrolled and 727 eligible patients received treatment. 1,083 national (USA) sites opened the trial. Median (range) patient age was 60 (18-88) years; 344 (47%) patients were male. 24 of 53 cohorts (45%) demonstrated clinical activity, defined as ≥2 patients with confirmed response. Median (range) ORR was 12% (0-75%); CBR, 27% (0-75%). Median (range) 2-year PFS was 10% (0-75%); 3-year OS was 23% (0-100%). 6-month PFS was moderately correlated with 1- and 3-year OS (R 2 =0.61 and 0.54, respectively). Patients who attained an iOR versus OR had similar OS. 82 patients (11%) had iPFS ≥2 years. Treatment-related adverse events (AEs) of any cause and immune-mediated occurred in 603 (82.9%) and 465 (64.0%) patients. AEs led to treatment discontinuation in 102 patients (14.0%). Most common AEs were fever (38.1%), diarrhea (21.2%), and rash/pruritis (19.3%). 13 patients (1.8%) experienced treatment-related grade 5 AEs. Patients alive at 6 months who discontinued treatment due to immune-related AE had longer OS than those who discontinued for other reasons (p = 0.021). Conclusions: Patients with multiple rare cancer types derived meaningful response to ipilimumab plus nivolumab. Characterization of biologically defined subsets is underway to optimize therapeutic selection. Clinical trial information: NCT02834013 . Response among all cohorts and cohorts with iRECIST iClinical benefit rate (iORR+iSD>6 mos) ≥50%. Cohort N iConfirmed response iClinical benefit iCR iPR 6-month iPFS 2-year iPFS 1-year OS 3-year OS Median iPFS (months) All 727 13% 29% 3% 10% 30% 12% 48% 24% 2.2 Gestational trophoblastic disease 4 75% 75% 25% 50% 75% 75% 100% 100% Not Reached Basal cell carcinoma 17 35% 71% 0 35% 76% 24% 76% 53% 12.1 Chordoma 10 0 70% 0 0 80% 30% 80% 30% 13.1 Bronchoalveolar carcinoma lung 8 25% 62% 0 25% 62% 33% 88% 44% 8.3 Desmoid tumors 16 19% 62% 0 19% 73% 40% 100% 80% 19.3 Carcinomas of pituitary, thyroid, parathyroid, adrenal cortex 19 21% 53% 0 21% 58% 26% 74% 42% 9.4 Fibromyxoma, low grade mucinous adenocarcinoma 10 0 50% 0 0 50% 0 60% 30% 5.7 Malignant giant cell tumors 6 0 50% 0 0 50% 33% 83% 50% 3.4

Vitamin D insufficiency and risk of taxane-induced peripheral neuropathy: Results from SWOG S1714.

12012 Background: Taxane-induced peripheral neuropathy (TIPN) affects up to 70% of patients treated with taxanes and can lead to functional impairment, reduced quality of life, and treatment disruption. There are no proven TIPN preventive strategies. Vitamin D insufficiency is a modifiable factor that has been linked to increased TIPN risk in paclitaxel-treated patients with breast cancer. We analyzed the association between baseline vitamin D levels and TIPN among patients receiving taxane-based treatments in a large, multicenter, prospective cohort study (SWOG S1714). Methods: In a prespecified analysis, baseline vitamin D levels were quantified from plasma samples using liquid chromatography-tandem mass spectrometry. Vitamin D insufficiency was defined as total 25-hydroxyvitamin D ≤20 ng/mL. The primary endpoint was development of TIPN, defined as an increase of ³8 points from baseline in the sensory subscale of the EORTC QLQ-CIPN20 (0-100 scale, with higher score indicating worse symptoms) by week 24. The secondary endpoint was the greatest worsening from baseline in the sensory subscale CIPN20 score. Multivariable Cox proportional hazards model was used to evaluate time to initial development of TIPN and linear regression was used for the secondary endpoint, both adjusting for age, cancer stage, race/ethnicity, comorbidities, taxane type, and planned treatment duration. Statistical significance was set at α = 0.05. Results: Among 1278 evaluable patients, 610 had available serum samples for vitamin D analysis (mean age 54.8 years [standard deviation 11.9]; 98% female; 85% White; 90% breast cancer; 59% paclitaxel-treated). Of these, 134 (22%) were vitamin D insufficient at baseline, and 383 (63%) developed TIPN during 24 weeks of follow-up. At baseline, CIPN20 sensory score did not differ by vitamin D status (p = 0.70). Baseline vitamin D insufficiency was significantly associated with higher risk of TIPN (adjusted hazard ratio 1.35; 95% confidence interval [CI] 1.06-1.72; p = 0.013). Patients with vitamin D insufficiency had more severe worsening of neuropathy (greatest worsening in CIPN20 sensory score: mean 23.4 vs. 18.5 points; adjusted mean difference 4.7 points; 95% CI 1.0-8.4; p = 0.013). Conclusions: Baseline vitamin D insufficiency was associated with significantly increased risk and severity of TIPN in this prospective cohort of patients receiving taxane-based therapy across multiple cancer types. These findings highlight vitamin D status as a potentially modifiable biomarker for TIPN risk and support clinical trials of vitamin D supplementation as a TIPN prevention strategy.

Efficacy of fruquintinib (F) plus sintilimab (S) versus axitinib (A) or everolimus (E) by scores of IMDC risk factors and PD-L1 expression at baseline in previously treated advanced renal cell carcinoma (RCC): A subgroup analysis of the FRUSICA-2 study.

4531 Background: FRUSICA-2 (NCT05522231), a randomized, open-label, controlled phase 2/3 study, demonstrated a significant efficacy of F plus S vs A or E in previously treated advanced RCC (BIRC-assessed mPFS 22.21 vs 6.90 mo; HR 0.373, p<0.0001; ORR 60.5% vs 24.3%, OR 4.622, p<0.0001; D Ye, et al; 2025 ESMO). Given the IMDC classification as the most common prognostic model and PD-L1 expression has demonstrated prognostic value across various cancer types, we conducted this exploratory subgroup analysis to evaluate clinical outcomes by baseline scores of IMDC risk factors and PD-L1 expression. Methods: Patients (pts) with histologically confirmed advanced RCC previously treated with VEGFR-TKI were randomized 1:1 to receive either F (5 mg QD, 2 weeks on/1 week off) plus S (200 mg iv, every 3 weeks), or investigator's choice of A (5 mg twice daily) or E (10 mg once daily). Efficacy was analyzed by IMDC risk factor scores (0, 1, 2, and ≥3) and PD-L1 combined positive score (CPS≥1, <1, or unknown). Data cutoff was February 17, 2025. Results: Among 234 patients in the phase 3 part, IMDC risk scores and PD-L1 CPS distributions are detailed in table. With a median follow-up of 16.56 mo, BIRC-assessed mPFS for F+S vs A/E across IMDC subgroups were: score 0, not estimable(NE) vs 8.31 mo (stratified HR 0.270, p=0.0009); score 1, 24.87 vs 8.25 mo (HR 0.289, p<0.0001); score 2, 13.8 vs 6.9 mo (HR 0.436, p=0.0164); and score ≥3, 9.69 vs 4.21 mo (HR 0.591, p=0.3267). Across PD-L1 expression subgroups, BIRC-assessed mPFS for F+S vs A/E were: CPS ≥1, 22.21 vs 3.22 mo (stratified HR 0.232, p=0.0004); CPS <1, NE vs 8.28 mo (HR 0.350, p<0.0001). An additional 82 patients had unknown PD-L1 CPS status (F+S: n=40; A/E: n=42) and were not included in PD-L1 subgroup analysis. ORR analyses consistently favored F+S over A/E across all subgroups defined by IMDC risk factors and PD-L1 expression, with detailed results presented in table. Conclusions: In the exploratory analyses, these findings suggest that the efficacy benefit of F+S vs A/E is maintained across different IMDC risk scores and PD-L1 CPS in previously treated advanced RCC patients, supporting its broad application. Clinical trial information: NCT05522231 . Efficacy results by IMDC risk scores and PD-L1 expression. F+S v A/E IMDC score 0(33 v 32) IMDC score 1(43 v 41) IMDC score 2(30 v 31) IMDC score ≥3(13 v 11) PD-L1 CPS≥1(23 v 20) PD-L1 CPS<1(56 v 53) mPFS mo NE v 8.31 24.87 v 8.25 13.80 v 6.90 9.69 v 4.21 22.21 v 3.22 NE v 8.28 HR (95%CI) 0.27 (0.12, 0.62) 0.29 (0.15, 0.55) 0.44 (0.22, 0.88) 0.59 (0.20, 1.72) 0.23 (0.10, 0.56) 0.35 (0.20, 0.61) Unstratified Log-rank p 0.0009 < 0.0001 0.0164 0.3267 0.0004 < 0.0001 ORR, % 63.6 v 25.0 62.8 v 26.8 60.0 v 19.4 46.2 v 27.3 78.3 v 10.0 64.3 v 35.8 Odds Ratio (95%CI) 5.25(1.61, 17.71) 4.60(1.66, 12.98) 6.25(1.75, 23.80) 2.29(0.32, 19.10) 32.40(4.67, 338.60) 3.22(1.37, 7.61)

Chemotherapy over surgery: The dominant prognosticator in synchronous pancreatic cancer with liver metastases—A multi-center propensity score–matched analysis.

e16403 Background: Patients with pancreatic ductal adenocarcinoma (PDAC) liver metastases have a poor prognosis, and the best treatment remains uncertain. While systemic chemotherapy is standard, the benefit of liver metastasis resection in oligometastatic patients lacks high-level evidence, with many studies affected by bias and mixed results. This study evaluates the effect of synchronous liver metastasis resection on overall survival, adjusted for confounders through multicentre, propensity score-matched analysis, and identifies independent prognostic factors. Methods: This retrospective multicenter study in seven Chinese centers enrolled patients with pancreatic cancer and liver metastases from January 2017 to July 2025. Patients were divided into complete liver lesion management and partial/untreated groups based on intervention extent. Propensity score matching used covariates like sex, tumor location, and metastasis burden, with oligometastasis defined as < 3 lesions without extrahepatic spread. The primary endpoint was overall survival. Kaplan- Meier and Cox regression analysis compared groups and identified prognostic factors. Results: After matching, 48 patients (24 in each group) formed a balanced cohort. No significant baseline differences were found. Median survival was 19 months in the complete management group and 25 months in the partial/untreated group, with no significant difference (HR = 1.07. 07, P = 0. 853). Univariate analysis showed preoperative neoadjuvant chemotherapy, higher BMI, and lower ALT levels were associated with better prognosis. Multivariate analysis confirmed preoperative neoadjuvant chemotherapy and higher BMI as independent favorable factors. Subgroup analysis indicated complete metastasis management did not improve survival among those responding to neoadjuvant chemotherapy. Conclusions: This study found that aggressive liver metastasis resection does not significantly prolong survival. Systemic therapy, especially neoadjuvant chemotherapy, and nutritional status (BMI) are stronger prognostic factors. The results suggest focus should be on systemic and health management rather than aggressive surgery, providing high- level evidence supporting' chemotherapy over surgery" in this setting.

Patient experiences with UGN-102 for recurrent low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC): Insights for shared decision making.

4602 Background: Recurrent LG-IR-NMIBC can be managed using various approaches, including repeat transurethral resection of bladder tumor (TURBT) and non-surgical intravesical therapies. One option is UGN-102, a reverse thermal hydrogel containing 75mg mitomycin. Given LG-IR-NMIBC tends to recur, understanding patients’ experiences/preferences across management strategies is essential to support clinical shared decision making. Methods: The ENVISION study (NCT05243550) assessed patient-reported outcomes via EORTC-QLQ-NMIBC24. Patients with biopsy-confirmed LG-IR-NMIBC and ≥1 previous NMIBC episode at baseline had 6 once-weekly intravesical instillations of UGN-102 in an outpatient setting. 32 US-based patients had semi-structured prospective phone interviews that compared experiences of prior TURBT (at enrollment) vs UGN-102 at 3 months. Results: 232 patients were included; 94.8% received all 6 doses of UGN-102. Mean change from baseline (CfB) scores at 3- and 12-months post-treatment did not reach minimal clinically important difference (MCID) thresholds for any of the EORTC-QLQ-NMIBC24 domains (Table). Patients perceived more interference with routines/responsibilities with TURBT vs UGN-102, similar urinary symptoms, expressed concern regarding more bleeding with TURBT, and would recommend UGN-102 as a less invasive, painful, and time-consuming procedure than TURBT. A small number of patients preferred surgery as a 1-day procedure vs 6 weekly intravesical instillations. Conclusions: UGN-102 maintained stable quality-of-life scores across NMIBC24 domains and was generally preferred by patients over surgical resections. These important insights support shared decision making, enabling clinicians to discuss trade-offs between procedural convenience and treatment invasiveness in recurrent LG-IR-NMIBC management. Clinical trial information: NCT05243550 . EORTC-QLQ-NMIBC24 domain MCID Baseline, mean (SD) n 3-month CfB, mean (SD) n 12-month CfB, mean (SD) n Urinary symptoms 6.34 13.7 (14.50) 231 0.8 (13.30) 217 −0.6 (10.71) 154 Malaise 4.37 4.0 (8.79) 231 0.2 (10.57) 217 1.2 (9.55) 154 Intravesical treatment issues 9.38 12.8 (18.74) 231 −0.8 (20.14) 217 0.2 (20.34) 154 Future worries 11.08 35.6 (22.49) 231 −4.1 (21.71) 217 −7.1 (22.84) 154 Bloating and flatulence 7.59 9.2 (15.35) 231 1.1 (16.24) 217 0.8 (15.52) 154 Risk of contaminating partner 13.66 10.9 (23.74) 141 −1.6 (17.45) 106 −7.5 (20.78) 67 Female sexual problems 12.87 9.6 (22.04) 45 −2.1 (18.81) 32 −3.5 (15.29) 19 Male sexual problems 16.29 21.9 (32.77) 144 1.2 (23.71) 134 0 (26.89) 94 Sexual intimacy 8.69 8.0 (17.27) 142 1.3 (22.35) 103 2.9 (20.55) 68 Sexual function 10.61 79.4 (25.01) 231 4.0 (15.25) 218 4.1 (16.97) 154 Sexual enjoyment 11.64 60.5 (33.11) 140 8.0 (25.23) 104 10.4 (29.71) 67 SD, standard deviation. A positive CfB indicates worsening across all scales/items.

Real-world survival outcomes and prognostic factors with adjuvant pembrolizumab for renal cell carcinoma.

e16555 Background: The KEYNOTE-564 trial established adjuvant pembrolizumab as a standard of care for high-risk renal cell carcinoma (RCC) post-nephrectomy. We sought to validate these findings in a real-world setting and identify clinical prognostic factors within a large, multi-institutional cohort. Methods: We conducted a retrospective cohort study in Epic COSMOS, identifying the largest-to-date RCC cohort undergoing nephrectomy who received post-nephrectomy adjuvant pembrolizumab. The study period spanned from the FDA approval date (Nov 17, 2021) to Dec 20, 2025, ensuring at least one month of follow-up prior to the query date. Overall survival (OS) was estimated using the Kaplan–Meier method. Univariate Cox proportional hazards models with false discovery rate (FDR) correction were used to evaluate factors associated with OS and systemic therapy–free survival (STFS) (time to post-adjuvant systemic therapy initiation, used as a proxy for metastatic disease). Results: Among 2,656 patients, the median age was 64 years, 67.8% were male, and 75 deaths occurred during follow-up. The real-world OS rates at 12, 24, 36, and 48 months were 98.2%, 96%, 94%, and 93.5%, respectively, and were comparable to the OS reported in KEYNOTE-564. Worse OS was significantly associated with increasing age (HR: 1.05 [1.03-1.07], FDR < 0.01) and the Charlson comorbidity index (HR: 1.19 [1.11-1.28], FDR < 0.01). Gender and BMI had no impact on OS. Regarding laboratory biomarkers, protective effects on OS were observed for Hemoglobin (HR: 0.73 [0.64-0.83], FDR < 0.01), RBC count (HR: 0.40 [0.27-0.58], FDR < 0.01), MCHC (HR: 0.77 [0.68-0.87], FDR < 0.01), lymphocyte-to-monocyte ratio (HR: 0.74 [0.61-0.90], FDR = 0.01), Albumin (HR: 0.31 [0.18-0.53], FDR < 0.01), and Total Bilirubin (HR: 0.24 [0.07-0.80], FDR = 0.04). Conversely, worse OS was associated with high eosinophil-to-lymphocyte ratio (HR: 4.84 [2.14-10.91], FDR < 0.01), Monocytes (HR: 3.20 [1.34-7.59], FDR = 0.02), WBC (HR: 1.11 [1.03-1.95], FDR = 0.02), and RDW (HR: 1.11 [1.02-1.21], FDR = 0.03). Initiation of subsequent systemic therapy occurred in 232 (8.7%) patients and was associated with significantly worse OS (HR: 3.96 [2.48–6.34]; p < 0.001). For STFS, shorter time to systemic therapy was significantly associated with higher baseline RDW (HR: 1.12 [1.07-1.17], FDR < 0.01), whereas longer STFS was significantly associated with higher hemoglobin (HR: 0.86 [0.79-0.93], FDR < 0.01), and MCHC (HR: 0.87 [0.79-0.94], FDR = 0.01). Conclusions: The real-world OS after adjuvant pembrolizumab following nephrectomy for RCC was comparable to the trial. Comorbidity burden and baseline laboratory variables were associated with outcomes and may support real-world risk stratification.

Cell-based second-generation immunotherapy BC1 in metastatic breast cancer.

e13083 Background: BC1 (BC-OTS-001; BriaCell Inc) is an allogeneic cancer cell line derived from invasive ductal carcinoma, engineered to secrete GM-CSF; part of the personalized off-the-shelf platform technology currently under development, which builds on the clinical and scientific observations from Bria-IMT (Bria-ABC trial). Intradermal administration of BC1 targets dendritic cell uptake and lymph node trafficking for T-cell priming against tumor antigens. Methods: Descriptive analysis of a single-site Phase 1/2a and expanded access program in metastatic, locally recurrent unresectable, or refractory MBC (HER2+, HR+, TNBC), ECOG ≤2 and brain metastases allowed. Primary endpoint: safety/tolerability dose optimization. Secondary and exploratory endpoints: tumor response, PFS, OS, HLA match, delayed-type hypersensitivity (DTH), time to subsequent therapy, and PFS2. Phase 1/Part 1: intradermal monotherapy dose escalation of 20, 40, or 60 x10 6 cells q2wk x3 at 4 injection sites (upper back and thighs). Escalation proceeds if ≤1 of 3 patients experiences a dose limiting toxicity (DLT) (≥ grade 3 possibly related AE within 4 wks); Phase 1/Part 2: combination with tislelizumab (BeOne Medicines Ltd.) ± adjuncts. Phase 2 expansion: up to 9 subjects at optimal regimen. Expanded access program (EAP) allowed protocol-similar treatment. Adverse events per CTCAE v5.0. Subjects followed for PFS2 and survival q3mo up to 2 years. Results: As of abstract submission, there are 5 Phase 1/2a and 3 EAP participants. Using evaluable subjects with available data; median age 64; 43% HER2-/HR+, 43% TNBC, 14% HER2+; median prior lines 4; 43% DTH+, 29% DTH-, and 29% not yet reported. 4 patients received BC1 monotherapy @20 x10 6 cells (one Phase 1 pt @20M received 17 cycles/12 mo with CR of lung lesion, stable bony lesions and no new lesions reported); one @40M ×4 cycles; 1@60M ×1 cycle; another @60M ×3 cycles. Phase 1 Part 2: one patient received BC1 @20M + tislelizumab with cyclophosphamide 300 mg/m² day −2/−3 and peginterferon 18 μg day 0 q3wk. EAP exposure: @20M ×4 cycles (N = 2), one patient unknown. TEAEs overall and ≥ grade 3 both reported at 29%; there were no DLTs. Median follow up 3 mo. Conclusions: Dose escalation from 20M to 60M and combination with CPI showed tolerable intradermal BC1 and potential clinical benefit in refractory MBC. One patient received 17 cycles with 12 mo of disease control. Expansion cohorts will assess HLA match, DTH, dose optimization, and combination activity. Based on very early preliminary data, BC1 is a potential new option for late stage cancer patients with minimal toxicity and potential home administration as a single agent. The current optimal induction schedule for further evaluation is: BC1 @20M q2wk ×3 + CPI C1D1, then BC1 + CPI q3wk without adjuncts until progression/toxicity. Clinical trial information: NCT06471673 .

Expert perspectives in the management of myelofibrosis (MF): A survey of 20 US-based specialists.

e18590 Background: Management of MF has faced a wide variety of clinical challenges. Allogeneic stem cell transplantation (allo-SCT), the only potentially curative therapy, carries substantial treatment burden, limiting its use in many patients with MF. For management without curative intent, conventional strategies often provide modest benefit and are often limited by cytopenias. The introduction of newer JAK inhibitors (JAKi) has broadened options and improved symptom burden and splenomegaly in patients with anemia or thrombocytopenia. With four FDA-approved JAKi now available, this survey examined how MF specialists approach prognostication, monitoring, and treatment to understand how advancements are shaping expert practice patterns amid increasingly complex decision-making. Methods: A cohort of 20 MF specialists from diverse US centers of excellence were invited via email to complete a 34-item survey in September 2025. Data were aggregated and analyzed to inform the development of a CME activity. Respondents were compensated for participating. Results: Most respondents (60%) reported routinely combining molecular (e.g., MIPSS70+ 2.0) and dynamic clinical scoring systems (e.g., DIPSS+) to guide prognosis. Regarding disease monitoring, experts favor a targeted approach: 50% repeat next-generation sequencing (NGS) selectively based on clinical scenario (e.g., transplant candidates) while 40% perform NGS only at disease progression or therapy change. Allo-SCT remains limited, with the majority (60%) pursuing transplant in fewer than 20% of their patients with MF. For INT-1 risk disease, symptom burden emerged as the predominant trigger for treatment initiation (55%), followed by progressive splenomegaly (30%). In the absence of cytopenias, ruxolitinib was overwhelmingly favored (95%) in a patient with INT-2 MF; however, treatment selection was highly cytopenia-dependent: in patients with symptomatic anemia, 85% selected up-front momelotinib. For thrombocytopenic patients with disease progression, 85% switched to pacritinib over other JAKi options. Upon JAKi progression with new-onset cytopenias (Hgb = 7.6 g/dL; platelets = 55,000/µL), 55% switched to momelotinib and 25% to pacritinib. Worsening cytopenias were the leading cause of JAKi discontinuation (70%). Regarding supportive care, ESAs (100%) and luspatercept (85%) were most frequently combined with JAKis to manage anemia, while danazol was used by 40% of respondents. Constitutional symptoms drove therapy switches in ~50% of cases, with 40% reporting that symptoms frequently influenced clinical decisions even in the absence of splenic progression. Conclusions: These findings demonstrate convergence among MF experts in integrated risk stratification and targeted JAKi selection, while underscoring that cytopenias and symptom burden remain key drivers of individualized treatment decisions in current practice.

Scaling prior authorization for philanthropic funding with artificial intelligence (AI): Five-year outcomes from Indian Cancer Society Cancer Cure Fund (ICS-CCF) NavyaAI implementation.

1610 Background: Indian Cancer Society - Cancer Cure Fund (ICS-CCF) is one of the largest charitable program for directly reimbursable treatment expenses to needy cancer patients. The prior authorization process at ICS-CCF requires the Due Diligence Team (DDT) and the Governing Advisory Council (GAC) to review every application for compliance with standardized treatment guidelines, expected cure rates, and approved costs. To augment and enhance this process, ICS-CCF evaluated and implemented the use of Artificial Intelligence (AI) to support application review and recommendations over a five-year study period. This study is a five year report on operational outcomes to reduce dependence on expert oncologists in the prior authorization setting using AI for care delivery. Methods: The NavyaAI platform is a clinically validated AI model that matches clinical data from beneficiary applications (input) with available clinical evidence and National Cancer Grid (NCG) guidelines, adapted to ICS-CCF approval criteria (output). Applications in which the AI output matched the input were classified as “recommended” and forwarded directly to the GAC for approval. All remaining cases were referred to the DDT, comprising a minimum of two expert oncologists, who reviewed the applications and forwarded recommendations to the GAC as appropriate. Concordance between NavyaAI and GAC decisions was assessed. The time spent by the DDT reviewing referred applications was recorded. DDT reviews were conducted weekly, and GAC reviews were conducted bi-monthly. Results: From April 2020 to November 2025, a total of 12001 (malignant solid tumors 63.77% (7653/12001) and hemato-lymphoid malignancies 36.23% (4348/12001) applications were reviewed by NavyaAI. Of these, 82.58% (9,910/12001) were recommended, 1.71% (205/12001) were rejected, and 15.72% (1,886/12001) were referred to the DDT. Concordance between NavyaAI and GAC decisions was 99.57% (9,867/9,910) for authorizations and 92.68% (190/205) for rejections. The DDT spent an average of 3 minutes reviewing each application referred by NavyaAI. On average, NavyaAI forwarded 35 applications directly to the GAC per week, saving a minimum of 210 minutes of oncologist review time weekly. Conclusions: NavyaAI can independently review and assess the majority (~84%) of beneficiary applications for recommendation or rejection with high concordance to expert decision-making. Further implementation of AI-assisted authorization models is warranted to scale their long-term impact on quality, efficiency, and scalability of philanthropic funding decisions within governmental and non-governmental healthcare schemes.

Association of Klotho protein with the risk of late complications in cancer survivors.

e24128 Background: Chemotherapy (CT) may cause late toxicities and accelerate aging. Klotho (Kl) is a protein involved in tissue homeostasis, and its deficit has been related to early aging and comorbidities. Our objective was to explore the correlation between plasma levels of KI and the risk to develop late toxicities and comorbidities after CT. Methods: Pilot retrospective study of patients included in the CARDIOTOX registry (Eur Heart J 2020;14:1720-9) (1,324 pts). All patients had received CT for a malignant condition. Plasma levels of a-Kl were measured by ELISA and correlated with: 1) comorbidities, assessed using the Charlson Comorbidity Index (CCI) and the CIRS-G score; 2) hospitalizations (H); and 3) visits to the emergency ward (EW) (unrelated to cancer or its treatment). Results: 185 patients were included (age 57 [25-88], 90% women, 78% with breast cancer. Median follow-up was 124 months (95% IC:116-131), CCI deteriorated in 56 patients (30%) and CIRS-G in 97 (52%). Patients with Kl ≥ 580 pg/mL at baseline had a lower risk of increased comorbidities, as assessed by the CCI (HR: 0.184; 95% CI:0.10-0.33; P<0.001) or the CIRS-G score (HR:0.324; 95% IC: 0.21-0.48; P<0.001). The number of H and EW visits for non-oncologic reasons per year was 0.05 (0-0.6) and 0.22 (0-1.9), respectively. Patients with Kl ≥ 580 pg/mL at baseline had a significantly lower risk of H for non-oncologic reasons (HR:0.277; 95% IC:0.143-0,538). No relationship was detected between KL and EW visits. KI measurements obtained at 6 and 24 months after the initiation of CT did not improve the biomarker’s predictive capacity. Conclusions: This exploratory study suggests that normal Kl levels protect against the development or worsening of comorbidities and late complications in cancer survivors. These results should be validated in the entire cohort of patients included in the CARDIOTOX registry. Variables correlated with increased comorbidity (CCI) in the Cox regression analysis. Variable b SE P Exp(B) (95%IC) Klotho ≥580 -1,404 ,405 ,001 0,246 (0.111-0.543) Age ,055 ,025 ,027 1,056 (1.006-1.108) Radiotherapy 3,161 ,997 ,002 23,605 (3.354-166.590)

Ablation plus immunotherapy in advanced NSCLC patients who develop oligo-residual disease after anti–PD-1/L1 therapy: Updated results from the BOOSTER trial.

8563 Background: Local consolidative therapy (LCT) has been demonstrated to augment the survival benefits of immunotherapy in non-small cell lung cancer (NSCLC) patients with oligo-residual disease (ORD) in the phase2 BOOSTER Trial (ChiCTR2000032479) as previously reported (2024 WCLC OA05.03; Signal Transduction and Targeted Therapy 2025). Here we report updated data with longer follow-up. Methods: This randomized, phase 2 trial enrolled patients with advanced NSCLC who developed oligo-residual disease after anti-PD-1/L1 therapy, defined as partial response or stable disease as the best response with residual tumors confined to a maximum of three organs and five lesions. Participants were randomly assigned (2:1) to receive ablation (thermal ablation or cryoablation) plus immunotherapy or immunotherapy maintenance alone. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), safety, patterns of disease progression and immunogenic changes after ablation. Results: Among 65 patients enrolled, the full analysis set finally included 42 patients in ablation plus immunotherapy group and 20 patients in immunotherapy maintenance group. In this updated data cutoff (December 2025) compared to the prior data cutoff (March 2024), median duration of follow-up has increased from 17.8 months to 28.9 months. Patients receiving ablation were associated with significantly longer PFS than those without ablation (median 28.1 vs. 12.8 months, p < 0.001, HR = 0.310, 95%CI 0.169–0.596). The median OS was not reached in either group. The 48-months OS rate were 79.0% (95% CI, 59.5–90.0) in ablation group and 67.6% (95% CI, 41.3–84.1) in the without ablation group. Updated subgroup analysis further suggested a trend of superior efficacy of cryoablation (n=13) compared with thermal ablation (n=29), with a median PFS of 37.6 versus 22.4 months, respectively (p=0.028). The safety profile of ablation combining with immunotherapy was similar to previously reported, and most of the adverse events were well managed. Conclusions: With extended follow up, the updated data suggested that the addition of local consolidative ablation confers durable clinical benefit in patients with advanced NSCLC who develop ORD after anti-PD-1/L1 therapy. Cryoablation was associated with potentially superior survival outcomes compared with thermal ablation. Clinical trial information: ChiCTR2000032479.

ProTACT: A first-in-human, phase 1 dose escalation and expansion study evaluating the safety, tolerability, and anti-tumor activity of [ ²²⁵ Ac]Ac-FL-020, a PSMA-targeted radioconjugate, in patients with mCRPC.

TPS5141 Background: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is an emerging treatment modality for metastatic castration-resistant prostate cancer (mCRPC). However, many agents targeting PSMA have resulted in quality of life-limiting toxicities, such as xerostomia, due to expression of PSMA in salivary glands and other organs. [ 225 Ac]Ac-FL-020 is a next-generation, PSMA alpha radioconjugate developed using the proprietary UniRDC linker-chelator technology designed to optimize biodistribution. It is intended for the treatment of patients with mCRPC and aims to enhance tumor uptake while sparing radiosensitive organs, such as salivary glands, thus potentially leading to an improved therapeutic window. Methods: ProTACT (FL-020-001) is a first-in-human, open-label, multicenter Phase 1 study investigating the safety, tolerability, and preliminary anti-tumor activity of [ 225 Ac]Ac-FL-020 in patients with advanced PSMA-positive mCRPC. This study consists of 2 parts: dose escalation (Part 1) and dose expansion (Part 2). Patients eligible for enrollment must be aged ≥18 years and have: histologically confirmed mCRPC, evidence of disease progression, ≥1 PSMA-positive lesion (uptake higher than liver) on PSMA positron emission tomography/computed tomography imaging, an Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function. Prior treatment with androgen receptor signaling inhibitors or CYP17 inhibitors and ≥1 taxane-based chemotherapy is required, unless declined by the patient. Prior therapy with Lu-177 is allowed. Patients with extensive PSMA-negative disease are excluded. [ 225 Ac]Ac-FL-020 will be administered intravenously at the assigned dose every 6 weeks for up to 6 cycles. Throughout the study, 10 eligible patients will receive 185 ± 20 MBq of [ 111 In]In-FL-020 for dosimetry evaluation ≥8 days prior to their first dose of [ 225 Ac]Ac-FL-020. Part 1 will apply a Bayesian logistic regression model with overdose control to guide dose escalation decisions. Dose cohorts of 1–3 patients (for Cohorts 1 and 2) and 3–6 patients (for Cohorts 3 and beyond) will evaluate ascending dose levels from 1–10 MBq to determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D). Once the RP2D is established, 18 additional patients will be enrolled in Part 2 to further assess safety and explore early signals of efficacy. Primary endpoints include incidence of dose-limiting toxicities and type, frequency, and severity of adverse events/serious adverse events. Secondary endpoints include overall response rate, disease control rate, radiological progression-free survival, and pharmacokinetic parameters (eg, maximum plasma concentration). The study is active in Australia, the United States, Turkey, and China. Clinical trial information: NCT06492122 .

Dynamic disease trajectories, not treatment timing, as a driver of outcomes in intrahepatic cholangiocarcinoma: A machine learning analysis.

e16018 Background: Intrahepatic cholangiocarcinoma (iCCA) exhibits marked heterogeneity in outcomes that is incompletely explained by stage or treatment timing. Although treatment delay is frequently cited as a modifiable risk factor, its prognostic significance in real-world practice remains unclear. We applied machine learning (ML) to model iCCA as a dynamic disease process and to evaluate whether longitudinal disease trajectories better explain outcomes than treatment timing alone. Methods: We conducted a population-based retrospective analysis of adults diagnosed with iCCA using the Surveillance, Epidemiology, and End Results (SEER) database (2000–2022). Time from diagnosis to first cancer-directed therapy was categorized as ≤30 days, 31–60 days, or > 60 days. Associations between treatment delay, disease characteristics, and overall survival (OS) were assessed using multivariable logistic and Cox regression models. To capture real-world disease evolution, each patient’s clinical course was encoded as an ordered longitudinal sequence of diagnosis, treatment states (surgery, chemotherapy, radiation), and outcome. Unsupervised ML was used to identify latent disease-course trajectories. A supervised ML model using variables available at diagnosis was developed to predict membership in high-risk trajectories. Results: The cohort included 18,312 patients with iCCA. Treatment initiation beyond 30 days occurred in more than half of patients and was more common in localized than advanced disease. In adjusted survival analyses, shorter time to treatment was paradoxically associated with worse OS, consistent with confounding by disease severity rather than a protective effect of delay. Unsupervised ML identified four distinct and reproducible disease trajectories with markedly different outcomes. Median OS ranged from approximately 2 months in early-failure trajectories to approximately 15 months in favorable multimodality trajectories. Trajectory membership was not fully explained by stage or treatment timing. A supervised ML model predicted high-risk trajectory membership with good discrimination (AUC 0.82). Key predictors included tumor grade, age, tumor burden, and incomplete staging, whereas treatment timing had minimal influence. Conclusions: In iCCA, treatment delay reflects underlying disease biology and care prioritization rather than independently determining survival. ML-based trajectory modeling reveals clinically meaningful disease courses that better explain outcome heterogeneity than treatment timing or stage alone and enables early identification of patients at highest risk for unfavorable real-world outcomes.

Association of GLP-1 receptor agonist therapy with BCG response in high-risk non–muscle invasive bladder cancer.

4620 Background: Observational studies suggest glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with reduced cancer incidence and improved survival in patients with established malignancies. Cohort data in lung cancer also suggest improved outcomes with immune checkpoint inhibitor therapy among patients receiving GLP-1RAs, raising the possibility of enhanced anti-tumor immunity. Intravesical Bacillus Calmette–Guérin (BCG) remains the mainstay treatment for high-risk (HR) non-muscle invasive bladder cancer (NMIBC). We hypothesized that GLP-1RA exposure during BCG therapy is associated with more favorable clinical outcomes in HR-NMIBC. Methods: Patients with HR- NMIBC treated between November 1 st 2015 to November 1 st 2025 were evaluated retrospectively using the TriNetX US Research Network. Patients were stratified by GLP-1RA exposure before BCG initiation (with or without overlap during BCG) versus no exposure. Cohorts were propensity score–matched for demographics and comorbidities, and outcomes were evaluated using multivariable logistic regression. The primary outcome was mortality; secondary outcomes included recurrence, progression to muscle-invasive bladder cancer (MIBC), cystectomy, and distant metastasis. Results: A total of 12,423 patients were evaluated, of which 791 (7%) received GLP-1RAs, while 11,630 (93%) did not. After propensity score matching, 787 patients were analyzed in each group. The average age in both cohorts was 73 years. Majority of patients were white (85%), male (80%), and non-Hispanic (85%). The distribution of GLP-1RAs use included semaglutide (67%), dulaglutide (37%), tirzepatide (21%), liraglutide (17%), exenatide (8%), and lixisenatide (1%). Patients who received GLP-1RAs demonstrated a significant reduction in 10-year mortality (RR 0.65; 95% CI 0.45 – 0.93, p = 0.017) and a lower risk of developing MIBC (RR 0.43; 95% CI 0.26 – 0.89; p = 0.018). No significant changes were noted in the risk of disease recurrence, radical cystectomy or distant metastasis (Table 1). Conclusions: In this real-world, retrospective, multi-cohort analysis we found that patients who received GLP-1RAs prior to BCG treatment are at a decreased risk of all-cause mortality, and less likely to develop progression to MIBC. This study underscores the need for further evaluation of GLP-1RAs in patients with NMIBC treated with BCG. Outcomes comparing HR-NMIBC patients exposed to GLP-1RA prior to BCG therapy versus those without exposure. Outcome Risk Ratio (95% CI) p- value Mortality 0.65 (0.45 – 0.93) 0.017 MIBC progression 0.43 (0.26 – 0.89) 0.018 NMIBC recurrence 0.98 (0.89 – 1.09) 0.84 Radical cystectomy 0.94 (0.72 – 1.22) 0.65 Distant metastasis 0.83 (0.62 – 1.11) 0.19

Clinical validation of a comprehensive genomic profiling–based approach for homologous recombination deficiency assessment.

e15087 Background: Homologous recombination deficiency (HRD) is a clinically actionable genomic biomarker in ovarian cancer and other solid tumors, guiding therapeutic selection and translational research. HRD testing is traditionally performed using dedicated assays; however, comprehensive genomic profiling (CGP) platforms offer the opportunity to integrate HRD assessment within routine molecular testing workflows. We evaluated the concordance and diagnostic performance of a CGP-based HRD prediction approach using clinically and genomically characterized tumor cohorts. Methods: A total of 122 ovarian cancer samples (111 tissue biopsy + 11 liquid biopsy samples) and 74 pan-cancer samples (10 Breast cancer, 57 Prostate cancer, and 7 pancreatic cancer) were retrospectively analyzed using OncoIndx comprehensive gene panel sequenced on NextSeq 550 Dx platform. HRD scores were determined from genome-wide patterns of loss of heterozygosity (LOH), large-scale transitions (LST), and telomeric allelic imbalance (TAI). In the external ovarian cancer cohort, HRD status was benchmarked against Myriad myChoice HRD scores, while BRCA1/2 stratification was used as a reference standard in the internal cohort. Diagnostic performance was assessed using sensitivity, specificity, predictive values, and overall accuracy. Concordance between tissue and liquid biopsy HRD status was evaluated in paired samples. Results: In the ovarian cancer cohort, CGP-based HRD predictions demonstrated strong concordance with myChoice classifications, achieving approximately 95% sensitivity and overall diagnostic accuracy exceeding 90%. In the BRCA-stratified cohort, HRD-high predictions showed high alignment with reference classifications, with sensitivity and specificity near 90% and diagnostic accuracy above 90%. Performance remained consistent across combined datasets, supporting stable and reproducible HRD prediction. In liquid biopsy ovarian cancer samples, HRD classification achieved 93% overall accuracy, with 88% specificity, 67% sensitivity. In paired pan-cancer tissue-liquid biopsy samples, HRD status demonstrated 73% concordance. Conclusions: This CGP-based HRD prediction approach enables simultaneous detection of actionable mutations and HRD status from a single assay and demonstrates high concordance with established HRD reference standards across ovarian and pan-cancer cohorts, supporting streamlined clinical testing and expanded access to HRD-informed therapeutic decision-making in both tissue and liquid biopsy settings.

Population-specific heterogeneity in ontogeny of the broadly-conserved blood transcriptional program during the first week of life

Real-world effectiveness of CDK4/6 inhibitor re-treatment in HR+/HER2- metastatic breast cancer.

e13039 Background: The postMONARCH trial showed modest progression-free survival (PFS) improvement with abemaciclib after progression on ribociclib/palbociclib among patients with HR+/HER2- mBC. Real-world evidence is limited by single-center data and lack of appropriate comparators. This study assessed real-world effectiveness of abemaciclib compared to endocrine therapy (ET) monotherapy to complement evidence from the postMONARCH trial. Methods: This retrospective cohort study used the US-based, electronic health record-derived deidentified Flatiron Health Research Database to analyze patients with HR+/HER2- mBC who received second-line or later treatment with either abemaciclib±ET or ET monotherapy (2020-2025) following documented progression on first-line palbociclib-/ribociclib-based therapy. In the treatment cohort, abemaciclib was allowed to be sequential (without intervening ET) or non-sequential (with intervening ET monotherapy). In the comparison group, multiple consecutive ET monotherapy lines were allowed. Descriptive statistics were used to compare baseline characteristics and treatment patterns. PFS and overall survival (OS) from second-line initiation were analyzed using time-varying multivariable Cox models. Interaction and stratified analyses were conducted to assess potential effect modification by baseline ECOG status. Results: Among 411 patients (177 abemaciclib, 234 ET monotherapy), 97% received abemaciclib as second-line therapy. Baseline characteristics were generally comparable, with similar first-line CDK4/6i use and ECOG distribution (~80% ECOG 0-1). The abemaciclib group was younger (median age 63 vs. 68 years). Abemaciclib was associated with longer median PFS (7.9 vs. 3.7 months) and OS (31.0 vs. 9.3 months) than ET monotherapy (both log-rank p < 0.001). In adjusted time-varying Cox models, abemaciclib reduced risk of progression (aHR 0.49, 95% CI: 0.39-0.62) and death (aHR 0.37, 95% CI: 0.28-0.49). Stratified analysis by ECOG showed consistent relative treatment effect of abemaciclib vs. ET monotherapy within ECOG strata (PFS: aHR 0.51 in ECOG 0-1 vs. 0.58 in ECOG 2-4; OS: 0.37 vs. 0.34, respectively). Survival benefit of abemaciclib was observed among patients with poor ECOG performance status. Interaction analysis found no evidence that ECOG modified the association between abemaciclib and OS (p = 0.482). Conclusions: Abemaciclib-based CDK4/6i rechallenge was associated with improved survival compared with ET monotherapy following progression on prior palbociclib/ribociclib. Abemaciclib maintained a relative survival benefit compared with ET monotherapy among patients with poor performance status. These findings support the potential utility of abemaciclib-based CDK4/6i rechallenge, including among patients with reduced performance status who are typically excluded from clinical trials (e.g., postMONARCH).

Prognostic utility of baseline hypoalbuminemia vs. peripheral immune biomarkers in a real-world immunotherapy cohort.

e23413 Background: Peripheral immune biomarkers absolute lymphocyte count (ALC), Neutrophil-to-Lymphocyte ratio (NLR) are established prognosticators in clinical trials of Immune checkpoint inhibitors (ICIs) in treatment of solid organ malignancies. However, their utility remains ill-defined in unselected community cohorts in which the populations often characterized by advanced age and multiple comorbidities. We hypothesized that host physiologic reserve (measured by serum albumin), which acts as a surrogate marker for metabolic fitness, can serve as an important predictor of Overall Survival (OS) than peripheral immune counts in a real world setting, predicting survival in the real world setting. Methods: We performed a retrospective study of 185 adult cancer patients with metastatic solid tumors treated with standard-of-care ICIs Immune Checkpoint Inhibitors (Excluding concurrent chemotherapy) at a single center from January 2017 to December 2025. Patients were stratified by baseline immune status (High: ALC < 1,000/µL or NLR > 5) and baseline metabolic status (Hypoalbuminemia: Albumin < 3.5 g/dL). The primary endpoint was Overall Survival (OS). Multivariate Cox models were utilized to identify the independent prognostic value of host frailty versus baseline immune status. Results: The cohort had a median age of 73 years, significantly older than typical trial populations. Baseline immune biomarkers failed to yield a prognostic signal in this setting. Kaplan-Meier analysis showed superimposable survival curves for High vs. Low Immune Risk groups (p = 0.97), confirming that baseline peripheral lymphocyte counts are not predictive of the survival outcome. In contrast, baseline hypoalbuminemia emerged as a powerful, independent predictor of mortality. Patients with low albumin had a 3-fold increased risk of death (HR 2.99; 95% CI 1.07–8.33; p = 0.036) , whereas standard demographic factors failed to reach statistical significance. Kaplan-Meier curves demonstrated early and sustained separation, highlighting the consistently inferior survival outcomes associated with baseline hypoalbuminemia. Conclusions: In this real-world cohort (median age 73), host physiologic reserve emerged as the dominant determinant of survival over peripheral immune biomarkers. This study demonstrates that serum albumin, an established marker of physiologic reserve, far outperforms ALC and NLR as a survival predictor in older patients. These findings suggest that metabolic optimization should be prioritized over isolated immune counts for prognostication in the general oncology population.

A multi-institutional, randomized, phase III trial comparing anatomical segmentectomy and lobectomy for clinical stage IA3 pure-solid non–small-cell lung cancer: West Japan Oncology Group study WJOG16923L (STEP UP trial).

TPS8123 Background: Recent pivotal clinical trials, conducted by the Japan Clinical Oncology Group and West Japan Oncology Group (JCOG0802/WJOG4607L) or Cancer and Leukemia Group B (CALGB140503), have demonstrated the efficacy of anatomical segmentectomy for small-sized early-stage NSCLC measuring ≤ 2 cm. Segmentectomy is gaining attention as an alternative procedure to lobectomy for early-stage NSCLC. However, for tumors larger than 2 cm, particularly those with a pure-solid appearance which indicates higher malignant potential, the efficacy of segmentectomy remains controversial. Therefore, we initiated this randomized phase III trial (WJOG16923L: STEP UP) to confirm the non-inferiority of anatomical segmentectomy to lobectomy for patients with pure-solid NSCLC measuring > 2 cm and ≤ 3 cm. Methods: This multi-institutional, open-label, randomized phase III study is designed to confirm the non-inferiority of anatomical segmentectomy to lobectomy in terms of overall survival (OS) in patients with clinical stage IA3 pure-solid peripheral NSCLC (tumor’s center located in the outer third of the lung field, tumor measuring > 2 cm and ≤ 3 cm, and consolidation-to-tumor ratio = 1). Patients are randomized 1:1 to undergo either lobectomy or anatomical segmentectomy using a minimization method by balancing the arms with the institution, age (≥ 70 or < 70), sex (male or female), location (right upper, right lower, left upper, or left lower lobes), and histological type (adenocarcinoma or non-adenocarcinoma). The primary endpoint is OS in all randomized patients. Secondary endpoints include relapse-free survival, postoperative respiratory function (at 6 months and 1 year after surgery), proportions of patients with respiratory failure and cerebrovascular disease, cumulative incidence of death from other diseases, cumulative incidence of local recurrence, proportion of patients who undergo segmentectomy, number of resected segments, operative time, blood loss, and adverse events. We plan to enroll 520 patients from 64 institutions over a period of 5 years. Enrollment began in January 2024. As of November 2025, 319 patients have been enrolled. This trial is registered with the UMIN Clinical Trials Registry (UMIN000052064). Clinical trial information: UMIN000052064.