Wu, Christina

TPS3678 Background: Advanced and metastatic colorectal cancer (CRC) remains an area of significant unmet clinical need, particularly for patients with MSS/MSI-L tumors. In recent years, there have been several advancements in the treatment of solid tumors with T cell engagers. Our ATLAS scRNA-seq based discovery platform identified LY6G6D as a highly-specific tumor-associated antigen in advanced and metastatic CRC. CBI-1214, a CD3 bispecific T cell engager targeting LY6G6D with potent in vitro and in vivo activity even at low LY6G6D expression levels of ~300 copies/cell ( Yigit B et al, AACR 2025 ), is being developed for the treatment of patients with advanced or metastatic MSS/MSI-L CRC. Methods: This ongoing, open-label FIH study (CBI-1214-001) is being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of CBI-1214 and to determine the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) in participants with advanced or metastatic MSS/MSI-L CRC who have exhausted at least one prior line of systemic treatment and do not qualify for available targeted treatment options for actionable genomic alterations. Additional eligibility criteria include: at least 18 years of age, measurable disease (as defined by RECIST v1.1), available archival tumor tissue sample or a fresh tumor sample, ECOG PS 0 or 1, as well as adequate hematologic and organ functions. Patients whose CRC tumor tissues have been identified as dMMR or MSI-H are excluded. The study is conducted in two parts: Part 1 dose escalation, which starts with Part 1a as accelerated dose escalation, followed by Part 1b escalation, which is based on a modified toxicity probability interval (mTPI-2) design, and Part 2, which is designed as a randomized dose optimization study to select the final recommended phase 2 dose (RP2D). For both parts of the study, the study intervention is administered as monotherapy, given as an intravenous (IV) infusion, in 21-day treatment cycles, with a step-up option. After an up-to-28-day screening period, eligible patients receive study medication and are followed for their entire treatment period plus a follow-up period of approximately 90 days. The study is open for recruitment in the United States (NCT07321106). Clinical trial information: NCT07321106 .

830 Background: Immune checkpoint inhibitors (ICIs) are standard therapy for MSI-H GI cancers. Lynch syndrome, caused by germline mutations in mismatch repair (MMR) genes, leads to MSI-H tumors and robust ICI responses, but its effect on irAEs remains poorly defined. Clarifying this risk may inform treatment selection and toxicity monitoring. Methods: We retrospectively reviewed MSI-H or MMR-deficient (dMMR) GI cancer patients (pts) treated with ICIs across Mayo Clinic (AZ, MN, FL) from January 2017 to June 2025. Eligible pts were identified using Mayo Data Explorer. Demographics, treatment, and irAEs (graded per CTCAE v5.0) were collected. Lynch status was determined by germline testing when available. Logistic regression estimated odds ratios (ORs) for any grade and grade ≥3 irAEs, adjusting for age, cancer type, prior chemotherapy, and treatment regimen. Results: A total of 209 pts with dMMR/MSI-H GI cancer were included: 61 with Lynch syndrome and 148 without. Lynch pts were younger (median 58 vs 76 years, p < 0.001) and more likely to have received prior chemotherapy (62% vs 43%, p = 0.009). Colorectal cancer was the predominant cancer type (74%), but Lynch pts had proportionally more non-colorectal GI cancers (15% vs 2.7%, p = 0.007). Overall, 29% of pts experienced an irAE, with rates significantly higher in Lynch vs non-Lynch pts (43% vs 24%, p = 0.005). The most frequent irAEs were gastrointestinal, endocrine, and dermatologic, followed by hepatic and pulmonary events. Grade ≥3 irAEs occurred in 16% overall, with no significant difference between groups (p = 0.124). In adjusted models, Lynch syndrome was independently associated with a higher risk of any grade irAE (OR 2.14, 95% CI 1.09 - 4.19, p = 0.026), while risk of severe irAEs was not increased (OR 1.55, 95% CI 0.64 - 3.59, p = 0.316). Lynch syndrome pts were more likely to have combination therapy (17% vs 6.8%, p = 0.029). However, there were no differences observed in any grade irAE between monotherapy and combination immunotherapy (OR 1.36, 95% CI 0.49 - 3.54, p = 0.535). Conclusions: Lynch syndrome is associated with a higher prevalence of any-grade irAEs among dMMR/MSI-H GI cancer pts treated with ICIs, though severe events were not increased. Incorporating Lynch status into immunotherapy planning may improve risk stratification and guide regimen selection.

776 Background: Surgery is the only potentially curative option for PC. However, only a minority of patients (pts) undergo resection with current perioperative (periop)-chemotherapy (CT). In the absence of phase III trials, selection between mFOLFIRINOX and gemcitabine/nab-paclitaxel (gem-nab) is based on limited evidence. We assessed whether NGS–based tumor profiling can guide tailoring of CT. Methods: pts with resected PC (resectable, borderline resectable, and downstaged locally advanced) that underwent Tempus xT, xF (DNA), and/or xR (RNA) testing were selected (89% tissue, 11% blood). Most samples (73%) were collected post-CT. Samples were stratified by KRAS status into KRAS -mutated ( KRAS mut) and KRAS wild-type ( KRAS wt). PD-L1 IHC was reported as tumor proportion score (TPS). Primary endpoint was median overall survival (mOS) defined from CT initiation to death with censoring of pts alive at the last follow-up or at a study cutoff of 5 years. Secondary endpoint was molecular profiling by KRAS status. Pearson chi-square and Wilcoxon rank-sum tests were used for descriptive comparisons; univariate Cox regression and log-rank tests (p<0.05) for survival. Results: We included 1,325 pts (median age 66 years [IQR 59–72]) with resected PC [stage II (15%), stage III (12%) and stage I (10%), unknown (62%)]. 95% had adenocarcinoma. Pts received neoadjuvant (50%), neoadjuvant plus adjuvant (26%), neoadjuvant with indeterminate adjuvant allocation (13%) or adjuvant CT (11%). First-line periop-CT was mFOLFIRINOX in 73% and gem-nab in 27% (median duration 4.3 months (mo) [range, 2.6–6.7]). KRAS mutations were present in 75% (G12X 91%: G12D 44%, G12V 34%, G12R 21%, G12C <1%). mOS was 26.7 mo (95%CI, 22.4-35.7) in the total cohort; KRAS mut pts showed a clinically meaningful worse mOS compared to KRAS wt [24.1 vs 35.7 mo; HR 1.61 (95%CI, 0.98 - 2.63); p=0.06]. In the KRAS G12D pts, mFOLFIRINOX showed a trend towards longer mOS compared to gem-nab [17.79 vs 14.53 mo; HR 0.75, (95% CI, 0.56 - 1); p=0.050]; no significant differences were observed in other KRAS subgroups. Compared to KRAS wt, KRAS mut pts were enriched for TP53 (76% vs 22%; p<0.001), SMAD4 (28% vs 5.8%; p<0.001), CDKN2A (33% vs 8.5%; p<0.001), MTAP deletions (7.7% vs 1.2%; p<0.001), and chromatin-regulator alterations ( ARID1A 7.8% vs 1.2%; p<0.001; KMT2C 2.5% vs 0.6%; p=0.034). KRAS wt pts were enriched for BRAF V600E (1.5% vs 0%; p<0.001). PD-L1 TPS ≥1% was more frequent in KRAS mut compared to KRAS wt (11.0% vs 8.1%; p=0.033). Conclusions: KRAS status does not predict benefit from mFOLFIRINOX vs gem-nab in resected PC. Interestingly, resected PC showed a higher prevalence of KRAS wt compared to the metastatic setting. KRAS status is associated with distinct profiles of potentially targetable co-alterations. These findings may suggest the integration of genomic profiling in clinical trials to develop biomarker-driven tailored strategies in the early stage.

679 Background: DNA-damaging agents improve outcomes in metastatic pancreatic cancer (mPC) with homologous recombination repair (HRR) deficiency, albeit use is limited to 6-9% of patients (pts) with BRCA1/2 or PALB2 mutations. We hypothesized that BRCA/PALB2 wildtype mPC may exhibit platinum sensitivity driven by altered HRR gene expression. We correlated HRR gene RNA profiles with real-world overall survival (rwOS) following first-line (1L) platinum therapy (PT). Methods: Tempus Lens, a platform used to query multimodal data from millions of de-identified patient records in the Tempus Database was used to identify mPC pts with wildtype somatic BRCA1/2 and PALB2 who had Tempus xT DNA and xR RNA testing. RNA-seq data were normalized to correct for assay/batch effects, quantified as transcripts per million (TPM) and reported as log2(TPM+1) for 17 HRR genes and GATA6 . Pts were classified as high and low expressors based on the top and bottom quartile gene expression. Pts were grouped as PT-treated (received 1L PT) or PT-naïve (never received PT). Real world overall survival (rwOS) was calculated from 1L start to death or loss to follow up. Risk set adjustment was applied to mitigate immortal time bias. Median rwOS was estimated using Kaplan-Meier and univariate Cox models. A multivariate Cox Proportional (CoxPh) model included PT use, RAS status, and expression of genes (as continuous variables). Results: Among 1,068 pts, the median age was 66 years and 609 (57%) received 1L PT. In low RAD51 expressors, PT-treated pts (n=136) had significantly longer rwOS than PT-naïve (n=112): 11.4 months (95% CI, 7.8–13.8) vs 8 months (95% CI, 5.5–9.0); p=0.028. In contrast, in high RAD51 expressors, rwOS was similar between PT-treated (n=150) and PT-naïve (n=97): 7.9 vs 6.9 months (p=0.236). High GATA6 expression was also associated with improved rwOS in PT-treated pts vs PT-naïve: 13.5 vs. 9.3 months; p=0.011. In multivariate analysis, increased GATA6 expression remained a positive predictor of rwOS (HR 0.82; 95% CI, 0.76–0.88; p<0.001), and high RAD51 expression was associated with shorter rwOS with PT (HR 1.18; 95% CI, 1.01–1.39; p=0.043). Conclusions: In BRCA/PALB2 wt mPC, transcriptomic profiling identified low RAD51 and high GATA6 expression as predictors for improved rwOS when treated with PT. Integrating these biomarkers may improve development of DNA-damaging therapies beyond canonically defined HRD. Hazard ratios of mPC mortality by selected HRR genes estimated by multivariate CoxPh models. HR 95% CI p value 1L PT (vs PT-naïve) 0.87 0.75, 1.00 0.054 BRCA1 1.15 0.98, 1.35 0.079 BRCA2 0.89 0.77, 1.04 0.14 GATA6 0.82 0.76, 0.88 <0.001 NBN 0.97 0.81, 1.15 0.7 RAD51 1.18 1.01, 1.39 0.043 RECQL4 0.94 0.84, 1.04 0.2 Any RAS mutation 1.43 1.14, 1.81 0.002

599 Background: Biliary tract cancers (BTC) remain aggressive malignancies with limited treatment options. Alterations in PIK3CA are implicated in tumor progression across solid tumors, but their prognostic impact in BTC remains unclear. We investigated the association of PIK3CA alterations(alt), alone and in combination with TP53 and ARID1A , with survival outcomes in advanced BTC. Methods: We conducted a retrospective analysis of 1,079 patients with advanced BTC treated with first-line chemotherapy (CT) or chemoimmunotherapy (CIO) across three sites in the USA, Japan, and Brazil. Genomic profiling was performed using next-generation sequencing on tissue and/or liquid biopsy samples. Survival outcomes were estimated by Kaplan-Meier analysis, with comparisons by log-rank testing and hazard ratios (HR) derived from Cox regression models. Results: PIK3CA alterations were identified in 11% (123/1,079) of patients. The median age at diagnosis was 68 yrs (range, 20–79), with 50% (62/123) female. The most common primary site was intrahepatic in 43.1% (53/123) while majority of patients received CT only 92.5% (111/123). When analyzed with TP53 , 68 pts had PIK3CA/TP53 co-alterations(co-alt), 501 had TP53 alt, 55 had PIK3CA alt alone, and 455 had neither PIK3CA nor TP53 alt (WT/WT). Overall survival (OS) was significantly worse in patients with PIK3CA alt, particularly in the setting of TP53 co-alt. Median OS (mOS) was 22.6 months(m) (95% CI, 20.4–24.8) for PIK3CA/TP53 WT, 15.9 m (95% CI, 11.6–18.5) for PIK3CA alt /TP53 WT, 14.6 m (95% CI, 13.1–19.5) for PIK3CA alt/ TP53 alt, and 17.1 m (95% CI, 15.5–18.8) for TP53alt/PIK3CA WT (p<0.001). In analyses with ARID1A , 32 pts had PIK3CA/ARID1A co-alt, 91 had ARID1A alt only, 120 had PIK3CA alt only, and 836 were WT/WT. PIK3CA/ARID1A co-alt tumors had a mOS of 12.8 m (95% CI, 9.1–NE) compared with 19.3 m (95% CI, 18.1–20.9) in PIK3CA WT /ARID1A WT (p=0.009). Multivariate analysis identified PIK3CA alt (hazard ratio [HR] 1.37, 95%CI 1.09–1.72; p=0.008), PIK3CA alt/ TP53 alt (HR 1.52 95% CI, 1.11–2.07; p=0.008), ARID1A alt/ PIK3CA WT (HR 1.40, 95% CI 1.08-1.82, p=0.011), and metastatic status (HR 1.82, 95% CI 1.52-2.19, P<0.001) as independent prognostic factors for shorter OS. Conclusions: In advanced BTC, PIK3CA alt were associated with significantly worse overall survival, particularly when co-occurring with TP53 or ARID1A alt. These findings establish PIK3CA as a prognostic biomarker of poor outcome and highlight the need to explore PI3K-targeted therapeutic strategies in BTC.

103 Background: Clinicians spend significant time extracting and synthesizing information to risk-stratify and make adjuvant chemotherapy (AC) recommendations for CRC. By automating parts of this process, LLMs could help reduce documentation burden and variability in decision-making. Methods: We selected 144 stage III, pMMR CRC patients treated at Mayo Clinic (2017–2021). HIPAA-compliant Gemini-2.0-Flash-001 and GPT-4o extracted clinical variables (age, neuropathy grade, pathological stage) from EHRs and generated AC recommendations. Two approaches were compared: (1) a rule-based algorithm with nested if/else statements translating variables into NCCN-based recommendations, and (2) a dynamic LLM agent generating recommendations using a structured prompt informed by NCCN guidelines. Concordance with treating physicians was assessed, with disagreements reviewed by a blinded GI oncologist. Results: The dataset included 144 patients with median age 67 (IQR 66–68), 48.6% female. The LLM pipeline extracted neuropathy grade with 100% accuracy and pathological T/N stages with 99.3% accuracy. Concordance with physician recommendations was 93.1% for the rule-based algorithm and 62.5% for the LLM agent. In discordant cases, blinded adjudication by a GI oncologist favored the algorithm and LLM agent over physicians in most cases (Table 1). Conclusions: This exploratory work shows LLM agents can reliably extract variables and generate evidence-based treatment recommendations for stage III CRC. The high rate of expert preference for LLM recommendations in discordant cases is intriguing but limited by small sample size and possible adjudicator bias. Discordant physician recommendations reflect the complexity of decision-making, including patient preferences, performance status, comorbidities, and subtle findings not fully captured in EHRs. Rather than replacing judgment, we envision LLMs as decision support tools—analogous to an advanced trainee reviewing charts and presenting evidence-based recommendations to the attending physician with ultimate authority. Larger multi-institutional studies with multiple adjudicators are needed to validate these findings and clarify AI’s role in oncology. Patient characteristics, LLM extraction accuracy, and concordance with physician recommendations. Metric Result Total patients 144 Median age (IQR) 67 (66-68) Female (%) 48.6% LLM extraction accuracy – Neuropathy grade 100% LLM extraction accuracy – Pathological T and N stages 99.3% Primary Concordance – Rule-based algorithm vs. physician 93.1% Adjudicator preference of rule-based algorithm over treating physician for discordant cases 100% Concordance – LLM agent vs. physician 62.5% Adjudicator preference of LLM agent over treating physician for discordant cases 82.0%