e15738 Background: The overall incidence of colorectal cancer (CRC) in the United States is declining, however, the incidence of early onset CRC (EOCRC, < age 50) has increased in the past decade. Hereditary cancer syndromes only explain a small proportion of EOCRC cases and ongoing research is investigating the epidemiologic characteristics of EOCRC compared to classical onset ( > age 50) CRC. The University of California San Diego has observed an increase in the number of EOCRC cases in the perinatal period (1 year before and after delivery) across the last 8 years, warranting further investigation into its unique molecular and genetic characteristics during pregnancy and its influence on patient treatment. Methods: We conducted a single-institution retrospective cohort study of EOCRC patients diagnosed in the perinatal period and age-matched controls. Endpoints include patient demographics, systemic therapy plans, molecular and genetic characteristics, and survival outcomes. Patient identification for inclusion and data collection is ongoing. Results: A total of 35 EOCRC patients were identified between 1/1/2018 and 3/1/2025; 9 (25.7%) were diagnosed during or within a year of pregnancy. The average age at diagnosis was 35.6 years old for cases and 37.3 years old for controls (p = 0.26). Since April 2021, across a 54-month period, a total of 4 patients were deceased, with an average survival of 22.8 months for cases vs 24.56 months for control (ns). One case (11.1%) presented with metastatic disease compared to 4 controls (15.4%). Of the 9 EOCRC perinatal patients, 7 received systemic therapy; 2 (22%) received treatment prior to delivery (both receiving a 5-Fluorouracil backbone), in one case (11%) systemic treatment was delayed until after delivery, and in 4 cases (44%) diagnosis was made after delivery (average 8.9 months after). Germline testing was done in 32 (91.4%) of patients. Two cases (22%) had germline mutations, in MLH1 and MSH2. Three controls (11%) had germline mutations, including BRCA1, APC, and MUTYH. The most identified somatic gene mutations were APC with 29 total mutations, 66% vs 46% patients contained at least 1 mutation in APC (10 mutations total in the perinatal group vs. 19 in controls), followed by KRAS with 17 total, 44% vs 50% (4 vs 13), TP53 with 15 total, 33% vs 46% (3 vs 12), SMAD4 with 6 total, 11% vs 19% (1 vs 5), ARID1A with 6 total, 44% vs 8% (4 vs 2), PIK3CA with 5 total, 22% vs 12% (2 vs 3), and PTEN with 3 total, 0% vs 12% (0 vs 3). Conclusions: The overwhelming majority of EOCRC patients undergo germline hereditary cancer screening. Nearly half of our perinatal cohort were diagnosed with CRC after delivery, indicating that there may be a delay in recognizing symptoms of CRC during pregnancy. In this small EOCRC cohort, some tumor mutations among perinatal cases appear over-represented (ARID1A) while others were under-represented (KRAS and TP53). Further data collection and reanalysis are ongoing.

Abstract Pancreatic cancer (PC) remains one of the deadliest malignancies, with minimal improvement in survival over recent decades. Fundamental questions persist regarding how genomic alterations influence PC biology and therapeutic response. Using a large multi-modal real-world genomic database, we sought to characterize the mutational and transcriptional landscape of PC and identify patterns that may inform future precision medicine approaches. Whole-exome sequencing (WES) data from tumor tissue samples were analyzed for patients with PC included in Natera’s proprietary Real-World Database. Sequencing was performed as part of the tumor-informed, personalized Signatera™ circulating tumor DNA assay designed between May 2019-Nov 2024. After excluding cases of low tumor mutational burden and variant allele frequency, a total of 3,664 patients were included in the analysis. Variant calling was performed using Mutect2 and VarScan2. For prevalence analysis, only non-synonymous somatic SNVs and INDELs were included. Germline variant analysis was performed for 128 cancer predisposition genes in both tumor and normal samples; ClinVar pathogenic/likely pathogenic (P/LP) germline variants were retained. RNA sequencing data, from AlteraTM tumor genomic profiling test (Natera, Inc.), were available for 658 patients, of whom 391 had matched WES data. Among the 3,664 patients with PC, the male/female ratio was [50%/50%], and the stage distribution was: I (14.6%%), II (24.4%), III (24.8%), IV (28.2%), and unknown (7.9%). Genetic ancestry composition included European (74.5%), African (10.9%), Latino/Admixed American (7.9%), East Asian (5.0%), and South Asian (1.5%) populations. The most frequently somatically mutated genes were KRAS (78%), TP53 (62%), CDKN2A (18%), SMAD4 (18%), and ARID1A (8%). The most common individual somatic variants were KRASG12D (32%), KRASG12V (25%), KRASG12R (13%), TP53R175H (5%), and KRASQ61H (4%). No statistically significant ancestry-based differences were observed in either gene or variant-level frequencies. P/LP germline variants were detected in 210 patients, comprising 149 unique variants across 34 genes, most commonly ATM, BRCA2, MUTYH, BRCA1, and PALB2. Among RNA-Seq profiled tumors, expression analysis identified patients with basal and classical molecular subtypes associated with distinct genomic features and clinical outcomes. This real-world study represents one of the most extensive characterizations of PC to date, integrating WES, germline, and RNA-Seq data from over 3,500 patients. The findings confirm the predominance of canonical driver alterations (KRAS, TP53, CDKN2A, SMAD4) and highlight germline and transcriptomic diversity across the disease spectrum. Ongoing analyses are assessing transcriptional variation across KRAS and other genomic features and will link these profiles with survival outcomes to determine clinical relevance. Citation Format: Avinash Ramu, Vasily Aushev, J. Bryce Ortiz, Alyssa Antonopoulos, Maria Diab, Philip A. Philip, David Kwon, Soma Subramaniam, Adham Jurdi, Gregory P. Botta. Large-scale genomic analysis of pancreatic cancer in a real-world patient population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5345.

4013 Background: Pancreatic ductal adenocarcinoma (PDAC) is driven predominantly by oncogenic KRAS signaling, yet prior attempts to target the MAPK pathway have been limited by toxicity and emergence of resistance. Atebimetinib is a next-generation, deep cyclic inhibitor (DCI) of MEK designed to achieve pulsatile pathway inhibition with improved tolerability. We report a Phase 2a cohort evaluating atebimetinib in combination with modified gemcitabine/nab-paclitaxel (mGnP) in the first-line treatment of advanced or metastatic PDAC (NCT05585320). Methods: In this multicenter, open-label, nonrandomized Phase 2a study, patients with previously untreated advanced or metastatic PDAC were eligible for participation and were treated with orally administered atebimetinib daily in combination with mGnP (modification: every other week dosing). The primary endpoint was objective response rate (ORR) per investigator assessment using RECIST 1.1 criteria in response-evaluable patients. The cohort was powered (~80%, one sided alpha 0.05) using an optimal Simon’s 2-stage design. Results: Fifty-five patients were enrolled and treated with 320 mg atebimetinib daily + mGnP. ECOG performance status was 0-1 (100%); median age was 68 years (range 42-85 years), 62% were ≥65 years, and 55% were male. No grade 5 treatment-related adverse events (AE) were observed. No AE related to atebimetinib were higher than grade 3. Grade 3 AE related to atebimetinib occurred in 29% of participants, with the most frequent being rash (5%), ALT increased (5%), and AST increased (5%). Among the 50 response-evaluable patients, best overall response (BOR) achieved were 21 PR, 21 SD, 7 PD, 1 NE. The ORR was 42%, and DCR was 84%. With a median follow-up of 10.4 months (data cutoff Jan 7, 2026), 6- and 9-month OS rates were 88% and 79%, respectively; median PFS was 8.3 months and median OS was not reached. Conclusions: Atebimetinib in combination with mGnP demonstrated favorable safety and promising efficacy compared to historic standard-of-care (SoC) GnP. 1 A phase 3 registrational trial is planned to start in mid-2026 for evaluation of atebimetinib + mGnP versus SoC GnP. 1. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med . 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369 (PMID: 24131140). Clinical trial information: NCT05585320 .

415 Background: Gastric adenocarcinoma remains a leading cause of cancer-related deaths worldwide. Surgery with curative intent, combined with perioperative chemotherapy, is the standard treatment; however, recurrence rates remain high, highlighting the need for additional strategies. Recent clinical trials suggest survival benefits with the addition of immunotherapy in both metastatic and resectable disease. Whether these findings translate to broader, real-world populations is unclear. We conducted a retrospective cohort study using the National Cancer Database to examine immunotherapy utilization over time and the impact of combined chemoimmunotherapy on survival in gastric adenocarcinoma. Methods: We identified patients with stage II–IV gastric adenocarcinoma treated between 2004 and 2022 who received chemotherapy, immunotherapy, and/or surgery. Immunotherapy use over time was analyzed separately for stage II/III and stage IV disease. Treatment groups were defined as follows: stage II/III—surgery plus chemotherapy vs. surgery plus chemoimmunotherapy; stage IV—chemotherapy alone vs. chemoimmunotherapy. Demographic, clinical, and pathologic variables were compared using chi-square and t tests. Survival was analyzed using Kaplan–Meier methods. Results: From 2004 to 2022, 66,117 patients with gastric adenocarcinoma (stage II/III: 45.2% (n=29,889), stage IV: 54.8% (n=36,228) were identified. Among stage II/III patients, treatment included surgery plus chemotherapy (28,475; 95.4%), and surgery plus chemoimmunotherapy (1,414; 4.7%). Among stage IV patients, treatment included chemotherapy (29,646; 81.8%) chemoimmunotherapy (6,582; 18.2%). Immunotherapy use increased substantially, from less than 1% of patients in 2012 to 19.2% of stage II/III and 39.9% of stage IV patients in 2022. For stage II/III patients, there were no significant differences in median positive lymph nodes or margin status across treatment groups. Survival analysis demonstrated significant improvements with chemoimmunotherapy. Median survival for stage II/III: surgery plus chemotherapy, 42.8 months (95% CI: 41.6–43.9); surgery plus chemoimmunotherapy, 55.6 months (95% CI: 45.4–78.8); p < 0.001. Median survival for stage IV: chemotherapy, 9.23 months (95% CI: 9.10–9.33), 13.83 months (95% CI: 13.44–14.29); p < 0.001. Conclusions: Stage II–IV gastric adenocarcinoma patients treated with chemoimmunotherapy experience significantly longer survival compared with chemotherapy alone. Further studies are warranted to refine patient selection and optimize treatment intensity and duration for maximum therapeutic benefit.

Abstract Metastatic pancreatic cancer (PC) has a dismal 5-year survival of only 2% due to limited chemotherapy efficacy, poor drug penetration, and an immunosuppressive TIME. Dense desmoplasia, inactive anti T-cells, and highly enriched immunosuppressive Tregs hinder immunotherapy responses. IL-2, a dual-function cytokine that promotes T-cell growth at high concentrations while also inducing immunosuppression at lower concentrations. High dose (HD) IL-2 is a highly an active immunotherapy that enhances cytotoxic T-cell activity while attenuating suppressive Tregs with cures in melanoma and renal cell carcinoma. Unfortunately, HD IL-2 has significant systemic toxicities that induce capillary leak syndrome (CLS), severe hypotension, and renal failure. The CendR-peptide (iRGD) binds to av/B3 integrins specifically at the tumor and induces a NRP-1 dependent transcytotic uptake of co-administered drug and is currently being evaluated in Phase 2 metastatic PC clinical trials. We hypothesized that iRGD could direct systemically low dose (LD) IL-2 into mouse PC and concentrate it locally within the tumor as HD IL-2. As such, we immunomodulate the TIME of PC to activate CD8 cytotoxic T-cells, reduce tumor growth and increases survival while reducing systemic toxicity associated with HD IL-2.Orthotopic KPC PC were developed in C57BL6 WT mice. Tumor-bearing mice were treated i.v. with iRGD and titrated concentrations of IL-2 (3/week). Tumors were analyzed for CD8+ T-cell proliferation, activation, and cytotoxicity. CD8 T cell depletion confirmed necessity of cytotoxic T cells. Lung tissue was evaluated for IL-2 induced CLS. Patient-derived PDAC slice cultures were treated ex vivo for translational relevance. iRGD + LD IL-2 significantly reduced tumor weight and increased survival compared with monotherapy or HD IL-2. The median survival in treated mice was significantly increased. iRGD combination treatment avoided cachexia, CLS, and systemic inflammation, with no elevation in IL-6 or TNF-a. iRGD combined with LD IL-2 did not reduce Treg numbers or increase CD8 T-cell infiltration/proliferation, but enhanced resident cytotoxic T-cell activity as demonstrated by increased p-STAT5, Granzyme B, and cl-Caspase 3. CD8+ T-cell depletion abrogated these effects, confirming CD8+ T cell dependence. In patient-derived PDAC slice cultures, iRGD+IL-2 increased Granzyme B, supporting translational relevance. Importantly, the peptide combination therapy avoids the severe side effects of CLS and cachexia commonly associated with HD IL-2. This combination significantly improves anti-tumor responses and prolongs survival in preclinical models of mouse and human PC, highlighting a robust, safe, and sustained anti-tumor immune response. iRGD combined with LD IL-2 has appropriate pre-clinical anti-cancer and safety signals to warrant early Phase 1 clinical trials in PC. Citation Format: In Hwan Park, Shawn Abeynaike, Ashley Martinez, Jonathan Cho, Daisuke Nishizaki, Gregory P. Botta. Peptide-delivered low dose IL-2 reprograms pancreatic cancer immunity to improve survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7790.

11177 Background: Early detection of recurrence after curative-intent treatment is a critical priority, traditional imaging often detects relapse when disease burden is high, potentially limiting treatment efficacy. ctDNA has emerged as an established prognostic biomarker for molecular residual disease (MRD) detection and early relapse. We performed a real-world meta-analysis on published datasets that utilized personalized, tumor-informed ctDNA testing to assess its performance across tumor types and clinical management approaches. Methods: Real-world studies published from December 2022 to December 2025 using the personalized, tumor-informed Signatera ctDNA assay (Natera, Inc.) were included. Eligibility required ctDNA assessment in the MRD (2–16 weeks post-surgery (histology dependent)/pre adjuvant therapy (ACT)) and/or surveillance (post-ACT/end of the MRD window if no ACT was given) settings, with outcomes stratified by ctDNA status and hazard ratios (HR) reported from univariable or time-dependent Cox regression analysis. Exclusions included: clinical trials, biobanks, metastatic disease treated with palliative intent, case reports, reviews, editorials, or commentaries. Clinical outcomes were harmonized into a composite event-free survival (EFS) endpoint (time to recurrence, progression, or death). Pooled HRs and 95% CIs were estimated using random and fixed effects models and heterogeneity between studies was assessed using the I 2 and Cochran’s Q test. Median lead time from ctDNA-positivity to radiographic or clinical recurrence was summarized when available. Results: We identified 18 eligible publications comprising 3,004 unique patients across 15 solid tumor types. During the MRD window, ctDNA positivity was associated with a significantly increased risk of an EFS event compared with ctDNA negativity (pooled HR: 8.15; 95% CI: 6.12–10.85, I 2 = 0.00%, P = 0.844, n = 13). During the surveillance window, inclusive of post-definitive treatment, ctDNA positivity conferred an even greater EFS risk (pooled HR: 18.30; 95% CI: 14.17–23.65, I 2 = 0%, P = 0.911 for heterogeneity, n = 16). Across studies, ctDNA detection during surveillance preceded radiographic or clinical recurrence by a median of 3.20 months (95% CI: 2.50-4.10, P < 0.0001, n = 10), although this varied substantially by study/tumor type (I 2 = 80.9%). Conclusions: In this pan-cancer real-world meta-analysis, ctDNA positivity assessed using a tumor-informed assay was highly prognostic following curative-intent therapy at all timepoints evaluated with low heterogeneity between studies. These findings support the broad clinical utility of tumor-informed ctDNA testing for post-treatment risk stratification and longitudinal disease monitoring across solid tumors.

The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex and its SMARC subunits regulate gene expression. Altered SMARC is rare yet may enhance immunotherapy response. In this retrospective analysis of metastatic SMARC-altered solid tumors in the University of California San Diego (UCSD) medical record (6,831 patients), 53 patients with diverse SMARC-altered malignancies were evaluable. Outcomes were compared between patients receiving immune checkpoint inhibitors (ICIs; n = 28, median second line) and those never treated with ICIs who received first-line, non-immune systemic therapy (n = 25). ICI-treated patients had a higher objective response rate (ORR, 48% vs. 16%) and longer median progression-free survival (PFS, 10.6 vs. 5.8 months) and overall survival (OS, 21.8 vs. 10.7 months) (p < 0.05). ICI treatment independently predicted longer OS (hazard ratio [HR] = 0.37, 95% confidence interval [CI]: 0.18-0.74, p = 0.005) and a higher ORR (OR = 4.88, 95% CI: 1.32-18.0, p = 0.02). SMARC-altered metastatic tumors derive superior ORR, PFS, and OS from ICI versus non-ICI therapies, despite ICIs being administered as later-line therapy. Prospective trials in SMARC-altered cancers are warranted.

TPS2673 Background: The main challenge for developing CAR T therapies for solid tumors is the lack of targets that distinguish tumor from normal cells, resulting in on-target, off-tumor toxicity. Tmod logic-gated CAR T therapy addresses this challenge by incorporating 2 CARs on the same T cell: an activator targeting a marker on both tumor and normal cells, and a blocker targeting HLA-A*02 that inhibits CAR T activity against normal cells while allowing activation against tumor cells (with HLA-A*02 LOH), improving tumor selectivity and decreasing toxicity. Early safety results from 3 ongoing phase 1/2 clinical trials of logic-gated, Tmod CAR T therapy (EVEREST-1, EVEREST-2, and DENALI-1) have demonstrated manageable safety and tolerability in patients with advanced solid tumors (Grierson et al, SITC , 2024; Ward et al, SITC 2025; Specht et al, SABCS , 2025). Early efficacy results include the first ever reported complete response in a patient with non-small cell lung cancer following treatment with a CAR T-cell therapy (A2B694). A2B543 is an autologous Tmod CAR T therapy that contains the same Tmod construct as A2B694 with an added membrane-tethered IL-12 (memIL12) booster. Specifically, A2B543 is comprised of autologous Tmod cells transduced with 2 lentiviral vectors: one expressing both the HLA-A*02-targeted blocker and the mesothelin-targeted CAR activator; and a second expressing the memIL12 booster. Interleukin 12 (IL-12) is a potent, pro-inflammatory cytokine that plays a crucial role in inducing antitumor immune responses; however, systemic IL-12 can be prohibitively toxic (Jia et al, Front Immunol , 2022). In A2B543, expression of the memIL12 cassette is under the control of an NFAT promoter and is induced during antigen engagement or T cell activation. This inducible memIL12 is designed to reduce the toxicity associated with systemic IL-12 while enhancing the long-term potency and persistence of Tmod (Zhang et al, J Immunother Cancer , 2025). Methods: EVEREST-2 (NCT06051695) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B543 in adults with recurrent/metastatic mesothelin-expressing cancers with tumor-associated HLA-A*02 LOH, including mesothelioma, colorectal, non-small cell lung, pancreatic, or ovarian cancer. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH via next-generation sequencing and cryopreserves leukapheresis product. Upon progression, A2B543 is manufactured and then administered after lymphodepletion. The phase 1 primary objective is to evaluate the safety and tolerability of A2B543 and identify a recommended phase 2 dose (RP2D). The phase 2 primary objective is to assess overall response rate. Clinical trial information: NCT06051695 .

Background: Circulating tumor (ct)DNA is a prognostic biomarker in gastrointestinal malignancies. In rectal cancer, its utility to inform perioperative management and predict recurrence, particularly in patients undergoing non-operative management (NOM), remains unclear. Studies are needed to clarify how post-neoadjuvant therapy (NAT) and post-surgical ctDNA status correlate with clinical outcomes in localized rectal cancer. Methods: We retrospectively analyzed ctDNA data from 220 patients with rectal cancer using a personalized tumor-informed assay (Signatera™, Natera, Inc., Austin, TX, USA). Of these, 148 (67.3%) underwent NAT followed by surgery, and 72 (32.7%) underwent NAT followed by NOM. We assessed associations between post-NAT ctDNA status and survival outcomes. In the surgical cohort, we examined associations between post-operative ctDNA status and clinical response, pathological response, survival outcomes, and NAR scores. Results: In the surgical cohort, ctDNA positivity at the post-operative MRD timepoint was a strong predictor of recurrence, with an 88.3% relapse rate compared to 11.5% in ctDNA-negative patients (p < 0.001). Among the 64 NOM patients with post-NAT ctDNA, 21.9% (14/64) were ctDNA-positive, of whom 100% (14/14) relapsed (92.9% local-only), 13 relapsed by the time of data cut-off, and one relapsed 8 months after the cut-off. Only 10% (5/50) of the ctDNA-negative NOM patients experienced local recurrence (p < 0.0001). ctDNA positivity post-NAT was associated with inferior DFS (p = 0.003). Conclusion: ctDNA was a strong predictor of recurrence in rectal cancer, including in NOM settings. In NOM patients, ctDNA detected local recurrences, highlighting its potential to guide post-NAT surveillance and treatment.

Total neoadjuvant therapy (TNT) is the standard curative-intent treatment for locally advanced rectal cancer (LARC), where patients receive all of their chemotherapy and radiation therapy before surgery. However, monitoring treatment response during TNT can be challenging since radiographic changes are often delayed. Methylation changes in colorectal cancer (CRC) and other cancers are relatively consistent and can be monitored in real time using cell-free DNA (cfDNA), making them a promising strategy for cancer detection and treatment monitoring. This study aims to determine if methylation changes in cfDNA can be used to monitor treatment response in LARC undergoing TNT. Plasma of CRC patients stage I-IV and healthy controls were obtained to establish the methylation classifier. Patients with stage II or III rectal cancer undergoing TNT were recruited. Blood samples were collected at baseline and about 6 weeks after the start of treatment. Tumor and normal CRC genomic DNA were analyzed using the Agilent Avida Methyl 3400 DMR panel to generate a methylation index score. Cancer treatment response was assessed by the investigator based on computed tomography and/or magnetic resonance imaging. We confirmed low background methylation signals in cfDNA and peripheral blood mononuclear cells of healthy controls. Subsequently, we analyzed methylation signals from plasma of CRC patients with stage I (n=20), II (n=12), and IV (n=5) disease. The sensitivity of the assay was 60%, 75%, and 100% for stages I, II, and IV, respectively, while the specificity was 87.5%. Among LARC patients undergoing treatment with TNT, we observed a decrease in methylation index scores compared to baseline in all three patients who experienced a treatment response and an increase in all three patients who experienced disease progression. Notably, the methylation index scores did not correlate with carcinoembryonic antigen values. Our preliminary results show the feasibility of monitoring rectal cancer treatment response during TNT using a tumor-independent cfDNA methylation analysis. Methylation analysis is a promising technology that may aid in quantifying treatment response to systemic therapy and/or radiation. Kim Nguyen-Ta, Grace Zhao, Heng Wang, Teressa Celma, Lisa Kim, Jeff Pawelek, Bram Herman, Annie Wu, Yun Bao, Gregory Botta, Aaron Miller, Hitendra Patel, Shengrong Lin, Peter Vu. Tumor-independent cfDNA methylation analysis for cancer monitoring during total neoadjuvant treatment in rectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5900.

e14519 Background: The purpose of this study is to determine the safety of autologous TAC T cell administration to subjects with claudin 18.2+ advanced solid tumors. Claudin18.2 (CLDN18.2) is a tight junction protein found in gastric epithelial cells. It can become abnormally expressed in gastric cancer and other solid tumors, rendering it a candidate for targeted therapy. The T cell antigen coupler (TAC) technology modifies T cells ex vivo , allowing cytotoxicity of tumor cells by co-opting the natural T cell receptor. TAC T cells demonstrate a safer profile than chimeric antigen receptor T cells. TAC01-CLDN18.2 is an autologous T-cell product comprising T cells expressing CLDN18.2 TAC. Methods: In this first-in-human study (NCT05862324), subjects undergo leukapheresis (bridging anticancer therapy during cell manufacturing is allowed). Prior to TAC01-CLDN18.2 infusion, subjects undergo lymphodepletion chemotherapy. In Phase I, TAC01-CLDN18.2 is being administered at increasing doses (3 cohorts) in adult subjects with ≥2 lines of prior therapy (1 for subjects with pancreatic ductal adenocarcinoma (PDAC)) using the classic 3+3 dose escalation study design. CLDN18.2 expression levels are determined centrally using a validated clinical trial assay. Dose-limiting toxicities (DLTs) are assessed for up to 28 days after the infusion. A second dose may be administered according to preidentified clinical and safety criteria. In Phase II, dose expansion groups will evaluate the efficacy, safety, and pharmacokinetics of the optimal TAC01-CLDN18.2 dose, with the option of redosing. Indications will include gastric and esophageal adenocarcinoma (group A), PDAC (group B) and ovarian and non-small cell lung cancer (group C) in subjects with < 4 lines of prior therapy. Results: The first two dose cohorts of Phase I have been completed, and the third cohort has been deemed safe by the Data and Safety Monitoring Committee, with no reported dose-limiting toxicities (DLT). One subject experienced two Grade 3 treatment-related adverse events (TRAEs): gastritis and gastric hemorrhage (both resolving within 4 days). Three subjects experienced CRS (one Grade 2 and two Grade 1). One subject in cohort 2 experienced a grade 1 neurotoxicity, which resolved the same day without intervention. Eight subjects reported a total of 18 serious adverse events, with 5 related to TAC01-CLDN18.2. A 67% disease control rate was observed at first tumor assessment (Day 29). Two subjects with high CLDN18.2 expression had partial responses. One of them was enrolled in cohort 1 with heavily pre-treated PDAC (3 prior lines) and has an ongoing, confirmed partial response. This subject received a second dose and is still on treatment (10 months). Conclusions: Treatment with TAC01-CLDN18.2 is safe and shows promising clinical activity in a heavily pre-treated cancer population. Treatment of cohort 3 is ongoing. Clinical trial information: NCT05862324 .

PURPOSE:Circulating tumor DNA (ctDNA) is an emerging tool in the evaluation of GI cancers. Challenges remain in defining its utility and role as a primary end point in therapeutic trials. The National Cancer Institute (NCI) ctDNA GI working group was created to evaluate current data and provide guidance on the inclusion of ctDNA in GI cancer trials. METHODS:The NCI GI steering committee assigned four task force members to serve as co-chairs for the working group. Co-chairs identified experts within each GI disease group to form a panel that convened to review data and provide recommendations. The group focused on ctDNA's role as a potential surrogate for assessing prognosis and guiding treatment decisions that may enhance GI cancer trials. A manuscript was drafted, circulated, revised, and voted on by the panel. The final draft was reviewed by the Cancer Therapy Evaluation Program. RESULTS:Further data are required to support ctDNA as a primary end point for late-phase therapeutic trials, particularly in studies that could change the standard-of-care. However, the group supports ctDNA as a primary efficacy end point for phase II studies and as a noninvasive evaluation strategy for new drug development. Incorporation of ctDNA as a biomarker in trial design must consider the specific context of disease biology of the GI cancer subtypes. ctDNA should be incorporated as an exploratory end point across a variety of disease settings and indications. Several practical considerations were identified to optimize the incorporation of ctDNA in future trial design. CONCLUSION:Prospective trials are required to clarify the role of ctDNA as a valid surrogate end point for progression-free or overall survival in GI cancers.

Treatment of hematologic malignancies with patient-derived anti-CD19 chimeric antigen receptor (CAR) T-cells has demonstrated long-term remissions for patients with otherwise treatment-refractory advanced leukemia and lymphoma. Conversely, CAR T-cell treatment of solid tumors, including advanced gastric cancer (GC), has proven more challenging due to on-target off-tumor toxicities, poor tumor T-cell infiltration, inefficient CAR T-cell expansion, immunosuppressive tumor microenvironments, and demanding preconditioning regimens. We report the exceptional results of autologous Claudin18.2-targeted CAR T cells (CT041) in a patient with metastatic GC, who had progressed on four lines of combined systemic chemotherapy and immunotherapy. After two CT041 infusions, the patient had target lesion complete response and sustained an 8-month overall partial response with only minimal ascites. Moreover, tumor-informed circulating tumor DNA (ctDNA) reductions coincided with rapid CAR T-cell expansion and radiologic response. No severe toxicities occurred, and the patient’s quality of life significantly improved. This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy.Clinical Insight: Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.

212 Background: ctDNA is a highly prognostic biomarker for pts with GI malignancies. However, its utility in perioperative treatment decision-making is not established. We evaluated the association of post-NAT and post-surgical ctDNA status with outcomes in rectal cancer pts. Methods: We analyzed 1,656 longitudinal plasma samples from 257 rectal cancer pts (clinical stages I: 7%; II: 23%; III: 65%; IV: 5%). A personalized, tumor-informed assay (Signatera, Natera, Inc.) was used for ctDNA detection and quantification. In this cohort, 169 (66%) pts received NAT followed by surgery, 26 (10%) received surgery alone, and 62 (24%) had nonoperative management (NOM) after NAT. NAT included total neoadjuvant therapy (N=183), chemoradiation (N=33), and chemotherapy (N=15). Post-NAT time point (tp) was taken after completion of NAT and before surgery (surgery cohort) or between 2-16 weeks post completion of NAT (NOM cohort). Event-free survival (EFS) was defined as the interval from end of NAT to the date of clinical progression (NOM cohort). Disease-free survival (DFS) was defined as the interval from surgery to radiological recurrence. Results: The median follow-up was 619 (0-2,535) days. Pre-treatment ctDNA results were available for 50/257 pts; 94% (47/50) of whom were ctDNA+. Post-NAT tp was available for 87 pts, of whom 29.9% (26/87) were ctDNA+ and were less likely to achieve a clinical response to NAT [complete response: 8% (ctDNA+) vs. 51% (ctDNA-), p=0.0017]. Of the 87 pts with post-NAT tp, 48 underwent surgery, 39.5% (19/48) of whom were ctDNA+ post NAT and had worse pathological response [TRG score >2 (ctDNA+) vs. 0-2 (ctDNA-), p<0.001]. The remaining 39/87 pts underwent NOM, of whom 21.9% (7/39) were ctDNA+ and had significantly worse EFS compared to ctDNA- pts (HR: 7.6, 95% CI: 1.9-31, p<0.001). Among the pts who underwent surgery + NAT (N=195), ctDNA was measured in the MRD window (2-12 weeks post-surgery, prior to adjuvant therapy) for 128. Of these, 14.8% (19/128) were ctDNA+ (MRD+). Clinical recurrence was observed in 79% (15/19) of MRD+ pts and in 11% (12/109) of MRD- pts. Notably, of the MRD- pts who clinically recurred, 83% (10/12) did convert to ctDNA+ on subsequent blood draws. MRD+ pts had significantly worse DFS compared to MRD- pts (HR: 18, 95% CI: 7.9-39, p<0.0001). Similar results were observed regardless of whether the pts received NAT (DFS; NAT: HR=13, 95% CI: 5.8-31, p<0.0001; no NAT: HR=12, 95% CI:5.29-7957, p<0.001). Conclusions: Post NAT ctDNA status is associated with clinical/pathological response and survival outcomes. As such, ctDNA can potentially guide treatment decision-making in rectal cancer pts. The post-NAT tp was prognostic of recurrence in pts who had NOM. In pts receiving surgery, ctDNA status in the MRD window was highly prognostic of outcomes. Further studies are warranted to evaluate ctDNA-guided management in the post NAT and NOM settings.

PURPOSE Mucinous neoplasms of the gastrointestinal tract are characterized by a propensity for metastasis to the peritoneum, resulting in peritoneal mucinous carcinomatosis (PMC). A subset of these tumors, most often originating in the appendix, harbor mutations in the GNAS oncogene. While the natural history of GNAS -mutant PMC varies, patient outcomes are generally poor, as is response to cytotoxic chemotherapy. The purpose of this study was to evaluate the clinical efficacy of single-agent palbociclib, a cyclin-dependent kinase (CDK)4/6 inhibitor, in patients with GNAS -mutant PMC. PATIENTS AND METHODS We enrolled 16 patients with PMC in a single-arm personalized cancer therapy trial. For all patients, tumor tissue and/or circulating tumor DNA genomic profiling using next-generation sequencing and, when possible, PD-L1 expression, tumor mutational burden, and microsatellite instability status was assessed. Twelve of 16 patients had previous disease progression on at least one previous line of chemotherapy. The primary tumor was appendix in 13 patients, unknown in two patients, and pancreas in one patient. Eleven cases were classified as low grade, and five as high grade. RESULTS In 13 of 16 patients, we observed a decrease in carcinoembryonic antigen (CEA), and in six patients, the CEA declined by >50%. As measured by clinical and modified peritoneal RECIST criteria, 50% of evaluable patients had stable disease after 12 months of palbociclib. At a median follow-up of 17.6 months, median survival has not been reached. Clinical response to CDK4/6 inhibition was mirrored in tumors with GNAS mutation and mucinous histology using an ex vivo preclinical platform. CONCLUSION CDK4/6 inhibition with palbociclib had clinical activity in PMC characterized by mutations in GNAS that was superior to that previously reported with cytotoxic chemotherapy. CDK4/6 inhibition is a novel therapeutic strategy worthy of further evaluation in this subgroup of gastrointestinal neoplasms.

356 Background: Autologous anti-claudin 18.2 (CLDN18.2) CAR T cell, satricabtagene autoleucel (satri-cel), was developed to treat solid tumors. We report the completed results of the Phase 1b ELIMYN18.2 study (Cohort A) in gastric/gastroesophageal junction (GC/GEJ) and pancreatic cancer (PC). Methods: This single-arm, open-label, Phase 1b/2 study (NCT04404595) evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced GC/GEJ or PC. Cohort A consisted of a modified 3+3 design. After a conditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel, patients were administered 1-3 cycles of satri-cel. The primary objectives were safety and determination of the recommended Phase 2 dose (RP2D). Adverse Events (AEs) were graded per CTCAE 5.0, objective response rate (ORR), and clinical benefit rate (CBR) including CR, PR, and ≥6-month SD were assessed by the investigator per RECIST 1.1. Results: As of May 14, 2023, twenty-four patients underwent leukapheresis in Cohort A. Nineteen patients (7 GC/GEJ and 12 PC) with a median of 3 (range: 1-8) prior therapeutic lines had satri-cel at three dose levels (DLs) between 250×10 6 and 600×10 6 cells. Seven patients received a 2nd dose and two patients received a 3rd dose of satri-cel at a median of 113 and 259 days, respectively, post-first infusion. All 19 patients experienced at least one AE. No DLTs occurred and 17 patients experienced cytokine release syndrome (CRS). Two cases of Grade 3 CRS were reported, and all other CRS were Grade 1 or 2. Two Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. All CRS and ICANS were resolved. No severe gastrointestinal-related AEs were found. No increased toxicities were reported after any reinfusion. No satri-cel treatment-related death occurred. For all patients, the best ORR was 26.3%, the median DOR was 3.7 months and the CBR was 42.1%. The median PFS was 5.2 months, and overall survival was 12.8 months (95% CI 5.7-NE) after leukapheresis, and the median PFS was 3.3 months, and overall survival was 8.9 months (95% CI 3.3-NE) after the first infusion. In the GC/GEJ group, the ORR was 42.9% (3/7), the median DOR was 6.9 months and the CBR was 57.1%. In the PC group, the ORR was 16.7% (2/12), the median DOR was 3.4 months and the CBR was 33.3%. An ORR of 42.9% (3/7) and a CBR of 71.4% were reported at the DL3 of 600×10 6 cells which was selected as RP2D. At DL3, one GC patient achieved a CR and two PC patients had PR, suggesting the PC group achieved an ORR of 40% (2/5) and the GC group achieved an ORR of 50% (1/2). In addition, tumor shrinkage was detected in 73.7 % (14/19) of patients. Conclusions: The safety profile and therapeutic efficacy of satri-cel were shown to be promising in heavily pretreated patients with CLDN18.2-positive advanced GC/GEJ and PC . In the Phase 2 study, the first patient with GC received satri-cel in May 2023. Clinical trial information: NCT04404595 .