Citations

399 Background: The standard of care for resectable GEA adenocarcinomas is perioperative chemotherapy with the FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) regimen. Recent studies investigating the addition of checkpoint inhibitors (CPIs) to perioperative chemotherapy have shown mixed results. An NMA can leverage both direct and indirect comparisons to evaluate the relative efficacies of available regimens in this setting. Methods: MEDLINE, EMBASE, Scopus, Web of Science and CENTRAL were searched until August 27th, 2025. Eligible studies included phase 3 randomized trials evaluating perioperative or neoadjuvant chemotherapy +/- CPIs ± radiation in resectable GEA. The primary outcomes were disease-free survival (DFS) and overall survival (OS). Hazard ratios and 95% confidence intervals (CIs) were estimated using a frequentist NMA framework. Results: Fifteen trials including 8072 patients were analyzed. For DFS, perioperative durvalumab + FLOT (dFLOT) ranked highest (P-score = 0.99), followed by FLOT (P-score = 0.84) (HR for dFLOT vs. FLOT was 0.71, 95% CI 0.58-0.86). dFLOT also ranked higher than perioperative pembrolizumab + cisplatin and fluorouracil/capecitabine (KN-585), though this comparison was not statistically significant (HR 0.65, 95% CI 0.40-1.04). Compared with CROSS, dFLOT showed superior DFS (HR of 0.48, 95% CI 0.36-0.63). For OS, dFLOT ranked the highest (P-score=0.95) and was superior to CROSS (HR 0.57, 95% CI 0.42-0.77). While dFLOT appeared favorable versus FLOT (HR 0.78, 95% CI 0.62-0.98), this finding was primarily driven by MATTERHORN, which did not meet its prespecified OS significance boundary (P = 0.03 vs threshold P < 0.0001), and the proportional hazards assumption was violated. Similarly, no significant OS difference was observed between dFLOT and the KN-585 arms (HR 0.75, 95% CI 0.45-1.23). Conclusions: In this NMA, perioperative FLOT remained the benchmark regimen for resectable GEA. dFLOT has shown promising early results, ranking the highest for DFS and showing favorable, but not statistically definitive OS trends in comparison to FLOT. Importantly, the network enabled indirect comparisons not tested in head-to-head trials, demonstrating that dFLOT ranked above pembrolizumab+CF/CX (KN-585) without reaching statistical significance, and also outperformed CROSS. However, these findings should be interpreted with caution, as they are primarily driven MATTERHORN data in which OS did not cross the prespecified threshold and proportional hazards assumptions were violated. Perioperative immunotherapy combinations appear promising, but final MATTERHORN results and further confirmatory studies are needed before dFLOT can be considered as a new standard of care.

392 Background: PAC+RAM is the standard second-line therapy for advanced GEA. However, PAC-related neuropathy is a major challenge, particularly since many pts have pre-existing neuropathy from prior platinum exposure. An effective “neuropathy-free” regimen remains an unmet need. We evaluated FTD-TPI+RAM as an alternative to PAC+RAM. Methods: This multi-center, randomized, phase II study enrolled GEA pts who progressed on or were intolerant to fluoropyrimidine+ platinum therapy. Pts were randomized to FTD-TPI+RAM (Arm A) or PAC+RAM (arm B) at a 1:1 ratio. The primary endpoint was progression-free survival (PFS), defined as time interval between randomization date and the date of disease progression or death; Secondary endpoints included overall survival (OS) and adverse events (AEs). The design hypothesized non-inferiority (NI) of Arm A to Arm B with a NI margin of hazard ratio 1.19. 90 PFS events from 116 pts provide 80% power with a one-sided alpha of 0.15. The interim futility analysis, conducted in December 2024 with 20 events, did not cross the futility boundary (Z statistic ≥ 1.172 ) and continued enrolling pts. The trial closed enrollment in March 2025 due to slow accrual. At the time of interim analysis, 20 events had occurred and the Z statistic was 0.4532. Final analysis included the 29 pts that were eligible, consented, randomized, and received any protocol treatment. Results: Among 29 pts (15 Arm A; 14 Arm B), baseline characteristics were balanced (in Arms A vs B, median age 64 vs 63; 80% vs 85.7% male; 86.7%% vs 78.6% White; 80% vs 78.6% ECOG 1). At data freeze of 8/4/2025, 26 PFS events were reported. Median PFS was 3.2 vs. 3.9 months in Arm A vs. Arm B (HR 1.37, 95% CI 0.61-3.02). NI was not demonstrated (Z =0.34, threshold for NI<-1.036). Median OS was 8.4 vs. 10.7 months, in Arms A and B, respectively. Grade ≥3 AEs occurred in 93% (Arm A) vs 71% (Arm B) with hematologic AEs occurring more frequently in Arm A than Arm B (53% vs 29%). Peripheral sensory neuropathy (any grade) occurred more frequently in Arm B (86%) vs. Arm A (47%). Conclusions: Although NI was not achieved due to early closure and small sample size, FTD-TPI+RAM was relatively safe and associated with less neuropathy compared with PAC+RAM. This regimen warrants further evaluation for pts in whom neuropathy limits taxane use. Clinical trial information: NCT04660760 .

381 Background: In RATIONALE-306 (NCT03783442), patients (pts) with LA unresectable or metastatic ESCC who received TIS (intravenously, 200 mg, every 3 weeks) + CT (platinum + fluoropyrimidine or paclitaxel) had longer median overall survival (OS) than pts who received PBO + CT at the interim analysis; improvement was maintained after a ≥3-year follow-up. Post hoc analyses in the PD-L1 TAP ≥1% subgroup showed clinically meaningful improvement with TIS + CT. These data supported the US FDA approval for unresectable or metastatic ESCC. Here we report the subgroup analysis of pts who had LA ESCC with PD-L1 TAP score ≥1%. Methods: Pts who had LA unresectable ESCC with PD-L1 TAP score ≥1% were included in this post hoc analysis. Efficacy outcomes (OS, progression-free survival [PFS], objective response rate [ORR], duration of response [DoR]) and safety were analyzed. Results: At data cutoff (Feb 28, 2022), of 649 pts randomized, 63 had LA ESCC with PD-L1 TAP score ≥1% (TIS + CT n=31; PBO + CT n=32; median age 67.0 years; 85.7% male). At median follow-up (TIS + CT 24.4 months; PBO + CT 24.5 months), efficacy with TIS + CT was improved vs PBO + CT (Table) and was consistent with the intent-to-treat (ITT) population. Efficacy was maintained after a ≥3-year follow-up (data cutoff: Nov 24, 2023; Table). Conclusions: In this post-hoc analysis, the median OS for pts receiving TIS + CT exceeded two years. The regimen was well tolerated. While the findings require validation in future clinical trials, first-line TIS + CT is an encouraging option for pts who have LA unresectable ESCC with PD-L1 TAP score ≥1%. Clinical trial information: NCT03783442 . Interim Analysis 3-Year Follow-up TIS + CT (n=31) PBO + CT (n=32) TIS + CT (n=32) e PBO + CT (n=31) f Median OS, mo(95% CI) 25.6 (15.3, NE) 11.5(9.0, 21.8) 25.6 (15.3, NE) 12.3(9.0, 21.8) HR (95% CI) a 0.36 (0.17, 0.77) – 0.50 (0.26, 0.95) – Median PFS, a mo(95% CI) 13.2(6.8, NE) 6.7(4.2, 9.7) 13.2(6.8, 27.7) 6.7(4.2, 9.7) HR (95% CI) a 0.46 (0.22, 0.96) – 0.47 (0.23, 0.96) – ORR, b,c n (%) 18 (58.1) 10 (31.3) 19 (59.4) 10 (32.3) Median DoR, b,d mo(95% CI) Not reached (8.4, NE) 5.7 (1.5, 9.6) 22.1 (6.1, NE) 5.7 (1.5, 9.6) a Stratified. b Investigator assessed. c Unconfirmed. d Based on unconfirmed ORR. e One patient’s disease status at baseline was changed to LA after interim analysis. f One patient’s disease status at baseline was changed to metastatic after interim analysis. NE, not estimable.

380 Background: KRAS amplifications (amp) occur in ~2% of solid tumors, representing a high unmet need for effective targeted therapies. BI3706674 binds to GDP-bound KRAS and locks KRAS protein in an inactive form. In preclinical models, BI3706674 has shown potent inhibition of KRAS-amp tumors. Methods: This is a Phase Ia/b trial (NCT06056024) to explore the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of BI 3706674 in patients (pts) with unresectable or metastatic KRAS wild type amp or KRAS G12V mutated (mut) solid tumors. The trial aimed to define the maximum tolerated dose (MTD). Pts (ECOG 0 -1) received BI 3706674 daily per os at 50 - 1200 mg doses. Dose escalation (DE) was guided by a Bayesian logistic regression model. This report focuses on KRAS wt amp pts from Phase Ia (DE). Results: As of 31 July 2025, 46 pts had received BI 3706674. Pts (n=15/46) with KRAS wt amp tumors had upper gastrointestinal tract (uGI) cancer [n=9: gastric (GAC;n=5), oesophageal (EAC; n=2), gastroesophageal junction (GEJC; n=2) cancers], Cholangiocarcinoma (n=1), colorectal (CRC; n=4), and ovarian (OC; n=1) cancers. Pts were treated at 200 mg (n=2), 400 mg (n=1), 800 mg (n=5), 1200 mg (n=7) doses; males: n=11; ECOG 1: n=10; median age - 62 years (range 38–83); median number of prior treatment lines was 3 (range 1-6). AEs were reported in 15 pts (100%), including 12 pts (80%) with treatment-related AEs (TRAE). High-grade AEs (Grade 3-5) were reported in 10 pts (66.7%), including 4 pts (26.7%) with TRAEs. SAEs were reported in 7 pts (46.7%), including 2 pts (13.3%) with TRAEs. The most-frequent AEs were mostly low-grade (Grade 1-2) diarrhoea (10 pts, 66.7%), nausea (10 pts, 66.7%), and vomiting (9 pts, 60.0%), often reported as TRAE. Two dose limiting toxicities were observed in 1200 mg group: nausea (Grade 3) and vomiting (Grade 3). MTD was not reached. BI 3706674 PK parameters followed the predicted non-linear PK model; dose dependent systemic exposure reached plateau at 800 mg. 12/15 pts with KRAS wt amp tumors, including 10/12 pts in 800 – 1200 mg groups, were efficacy evaluable; Disease control rate (DCR) was 58.3% (7/12 pts): 3/ 12 pts with partial response (PR), 4/12 had stable disease (SD), 5/12 pts - disease progression (PD). In 800 – 1200 mg groups 1 - OC, 2 – CRC pts achieved SD. PK/PD/efficacy correlation data is pending. Conclusions: BI 3706674 showed a tolerable safety profile and clinical efficacy in pts with KRAS amp tumors. Study results provide clinical proof of concept. KRAS wt amp is a druggable target and KRAS-targeting treatment is active in KRAS wt amp uGI cancer pts. Clinical trial information: NCT06056024 . Anticancer activity of BI 3706674 in efficacy evaluable pts with KRAS wt amp tumors. All pts, 200 – 1200 mg, N=12 Pts with uGI cancers,800 – 1200mg, N=7 ORR, n (%) 3* (25%) 3* (43%) SD, n (%) 4 (33.3%) 1 (14%) DCR, n (%) 7 (58.3%) 4 (57%) PD, n (%) 5 (41.7%) 3 (43%) *Tumor shrinkage: -60.3%, -34% and 34.3%.

378 Background: RATIONALE-305 (NCT03777657) enrolled the highest number of pts with PM among similar trials and stratified pts with advanced GC/GEJC by presence of PM. We used statistical modeling to evaluate the impact of varying PM levels on outcomes with TIS+CT. Methods: We randomized adults with GC/GEJC (1:1) to TIS or placebo (PBO) + CT. Primary endpoints: OS in intent-to-treat (ITT) population and pts with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥5%. We weighted pts using the method of moments to match a hypothetical population to ITT, with the same distribution of sex, primary tumor location, PD-L1 (TAP score <5% vs ≥5%), number of metastatic sites (0-2 vs 3+), and liver metastasis. PM representation was set from 20% to 45%. Weighted OS, PFS, and objective response rate (ORR) were estimated. Results: Of 997 pts enrolled, 434 (43.5%) had PM. Among pts with PD-L1 TAP scores ≥5% (54.8%), 39.7% had PM, and among pts with scores ≥1% (88.9%), 43.6% had PM (data cutoff Feb 28, 2024). Fewer pts with (+) PM had PD-L1 high tumors (TAP score ≥5%: 50.0%) and more had primary stomach tumors (86.6%) compared to those without (-) PM (58.4% and 75.5%). TIS+CT improved OS, PFS, and ORR in ITT and in pts +/- PM vs PBO+CT (Table). Across 20%–45% PM, TIS+CT showed consistent benefit, with stable HRs for OS and PFS (20% and 45% shown). TIS+CT showed survival benefits in pts with PM and PD-L1 TAP score ≥5% (OS: HR=0.71; PFS: HR=0.65) and ≥1% (OS: HR=0.79; PFS: HR=0.79) vs PBO+CT. ORR was higher with TIS+CT vs PBO+CT in pts + PM and PD-L1 TAP scores ≥5% (47.3% vs 30.8%) and ≥1% (44.2% vs 33.2%). Conclusions: Our analysis showed that lowering PM representation marginally improved OS and ORR, underscoring the poor prognosis of peritoneal disease. In RATIONALE-305, TIS+CT provides clinically meaningful response and survival benefits irrespective of PM, with higher responses in PD-L1+ GC/GEJC. Clinical trial information: NCT03777657 . Arm(95% CI) ITT + PM - PM 20%+ PM 45%+ PM OS, months TIS+CT 15.0 (13.6, 16.5) 12.3 (10.6, 14.3) 17.3 (15.0, 20.3) 15.4 (13.9, 18.0) 15.0 (13.5, 16.5) PBO+CT 12.9 (12.1, 14.1) 11.8 (10.5, 13.0) 14.0 (12.6, 16.0) 13.1 (12.3, 14.5) 12.8 (12.1, 14.1) HR 0.79 (0.69, 0.91) 0.78 (0.64, 0.96) 0.79 (0.65, 0.95) 0.81 (0.69, 0.95) 0.79 (0.69, 0.90) PFS, months TIS+CT 6.9 (5.7, 7.2) 5.8 (5.6, 7.3) 7.0 (5.7, 8.4) 6.9 (5.7, 7.3) 6.9 (5.7, 7.2) PBO+CT 6.2 (5.6, 6.9) 5.7 (5.3, 6.9) 6.9 (5.7, 7.1) 6.5 (5.6, 7.0) 6.2 (5.6, 6.9) HR 0.79 (0.68, 0.91) 0.80 (0.64, 0.98) 0.77 (0.64, 0.94) 0.79 (0.67, 0.94) 0.79 (0.69, 0.91) ORR, % TIS+CT 47.3 (42.9, 51.8) 43.6 (37.0, 50.5) 50.2 (44.2, 56.2) 48.0(42.9, 53.1) 47.3 (42.8, 51.8) PBO+CT 40.5 (36.2, 45.0) 32.2 (26.0, 39.0) 46.8 (40.9, 52.8) 43.1(38.1, 48.3) 40.3(36.0, 44.8) ORR difference, % 6.8 (0.6, 12.9) 11.4 (2.3, 20.3) 3.4 (-4.9, 11.6) 4.9 (-2.2, 11.9) 6.9 (0.8, 13.0)

373 Background: Recent studies have demonstrated encouraging outcomes with neoadjuvant ICIs in pts with localized deficient mismatch repair (dMMR) and/or microsatellite instability-high (MSI-H) GEC, prompting discussions around the feasibility of nonoperative management (NOM). However, current evidence is largely from phase 1 and 2 clinical trials with limited sample sizes. Thus, the efficacy and safety of neoadjuvant ICI in this pt population remain subject to ongoing debate. Methods: We conducted a systematic review and meta-analysis of prospective and retrospective studies evaluating neoadjuvant ICIs in pts with localized dMMR/MSI-H GEC according to the PRISMA guidelines. The primary outcomes were pathological complete response (pCR) and complete clinical response (cCR) rates. cCR was defined as no evidence of residual disease on tumor-specific imaging and on endoscopy with biopsy. Secondary outcomes included major pathologic response (MPR) rates and the incidence of grade 3–4 immune-related adverse events (irAEs). Proportions with 95% confidence intervals (CI) were used to pool event rates for occurrence of cCR, pCR, MPR and grade 3-4 irAEs. The DerSimonian and Laird random-effects model was used. NOM was assessed as part of the qualitative analysis. Results: 20 studies comprising 396 pts treated with neoadjuvant ICIs were included. Three studies utilized double ICI blockade (PD-1/ PD-L1 inhibitor plus CTLA-4 inhibitor), while the remaining studies primarily utilized monotherapy with a PD-1 inhibitor, with or without chemotherapy. Overall, 320 (81.0%) underwent surgical resection. The pooled pCR rate was 41.6% (95% CI, 33.1%–50.8%), cCR 63.8% (95% CI, 45.6%–78.8%), and MPR 64.2% (95% CI, 49.1%–76.9%). The pooled incidence of grade 3–4 irAEs was 5.1% (95% CI, 0.6%–12.2%). Subgroup analysis showed higher pCR with ≥3 months versus <3 months of ICI (50.2% [95% CI 42.2–58.3] vs 28.4% [18.9–40.2]; χ²=8.69, p=0.003). Forty-four pts were managed with NOM, two experienced early local regrowth over median follow-up ranging from 11.5 to 28 months. Conclusions: Neoadjuvant ICI therapy appears to be a safe and effective therapeutic strategy for pts with localized dMMR/MSI-H GEC. Neoadjuvant ICI exposure for ≥3 months seems to yield higher pCR rates than <3 months. The high and prolonged cCR rates support the nonoperative strategy in selected patients with dMMR/MSI-H GEC.

334 Background: Sarcopenia, or decreased skeletal muscle mass, has been associated with worse surgical and oncologic outcomes across multiple malignancies. This study investigates the impact of sarcopenia on outcomes after multimodal therapy for esophageal cancer. Methods: Retrospective observational cohort study including adult patients who underwent neoadjuvant therapy followed by esophagectomy for primary esophageal cancer from January 2000 - December 2021. A fully automated abdominal segmentation using deep convolutional neural network was utilized to calculate skeletal muscle index (SMI) from preoperative CT scans performed at our institution. Males with SMI <52.4 cm 2 /m 2 and females with SMI <38.5 cm 2 /m 2 at any point before surgery were classified as sarcopenic. The relationship between sarcopenia and patient demographics, operative details, and complications were explored using chi-square tests. The relationship between sarcopenia and disease-free survival and overall survival were investigated using parsimonious multivariable analysis retaining variables with p-value <0.05 using backward selection method. Results: We identified 200 patients meeting the study criteria with 142 (71%) having sarcopenia at any time prior to surgery. Patients with sarcopenia were significantly older [65.2 (59.6, 71.2) vs 63 (53.6, 67.5), p = .023] and more likely to have had open surgery [129 (90.8%) vs 46 (79.3%), p = .034]. There were no significant differences in sex, history of diabetes, coronary artery disease, renal disease, smoking, cancer type, cancer stage, tumor size, tumor location, or margin status between sarcopenic groups ( p > .05). Sarcopenic patients were significantly more likely to require blood transfusion ≥3 units after esophagectomy [79 (55.6%) vs 8 (13.8%), p < .001] or to experience complications requiring surgical intervention [36 (24.6%) vs 7 (12.1%), p = .048]. Multivariate analysis revealed that sarcopenia was associated with disease-free and overall survival (Table). Conclusions: Sarcopenia is a prognostic factor in patients undergoing multimodal therapy for esophageal cancer. Interventions that aim to prevent decreases in SMI after initiating neoadjuvant therapy should be investigated. Multivariate analysis with sarcopenia predicting outcomes. Disease free survivalHR (95% CI) p-value Overall survivalHR (95% CI) p-value Age 1.04 (1.02, 1.06) < .001 1.04 (1.02, 1.07) < .001 Epicenter Middle Upper 1.88 (1.21, 2.86)3.16 (1.67, 5.98) .001.005< .001 1.96 (1.26, 3.04)4.00 (1.90, 8.44) < .001.003< .001 Stage Stage II Stage III Stage IV 1.88 (0.95, 3.71)2.90 (1.46, 5.75)16.02 (6.12, 41.93) < .001.069.002< .001 1.65 (0.83, 3.25)2.76 (1.37, 5.55)10.14 (4.03, 25.53) < .001.151.005< .001 Cancer type - - 1.76 (1.03, 3.02) .039 Transfusion > 3 pRBC - - 1.54 (0.99, 2.40) .057 BMI prior to cancer diagnosis - - 0.98 (0.94, 1.01 .208 Sarcopenic 1.76 (1.16, 2.67) .007 1.64 (1.04, 2.60) .033

331 Background: The relationship between plant-based dietary patterns and upper gastrointestinal (GI) cancers remains unclear. The Healthful Plant-Based Diet Index (hPDI) is a tool that measures adherence to plant-based diet and generates “scores” for clinical comparison. We conducted a systematic review and meta-analysis to examine the association between hPDI and the risk of esophageal and gastric cancers. Methods: A PubMed search identified relevant studies reporting on the association between hPDI and upper GI cancers. Reference lists were manually searched for additional studies. Study selection followed PRISMA guidelines, and quality was assessed using the Newcastle–Ottawa Scale (NOS). Pooled risk estimates were calculated using inverse-variance fixed-effects models, with subgroup analyses by cancer type. Sensitivity analyses were conducted using leave-one-out approach and by switching between fixed- and random-effects models. Forest plots and funnel plots were generated with RevMan 5.4, while Begg’s and Egger’s tests for publication bias were performed using Stata 15. Results: A total of four studies were included, all with high NOS scores. Overall, higher hPDI scores were associated with a significantly lower risk of upper GI cancers (RR = 0.64, 95% CI: 0.56–0.75). In subgroup analyses, the inverse association was consistent for both esophageal cancer (RR = 0.66, 95% CI: 0.54–0.79) and gastric cancer (RR = 0.63, 95% CI: 0.50–0.79). Between-study heterogeneity was low (I² = 35%, P = 0.16). Publication bias assessment indicated no evidence of small-study effects, as Begg’s test was non-significant (P = 0.88) and Egger’s test showed no significant bias (P = 0.76). Sensitivity analyses confirmed the robustness of the findings, with consistent results after sequential exclusion of individual studies and when using random-effects models. Conclusions: Higher hPDI scores were associated with a significantly reduced risk of esophageal and gastric cancers, indicating that adherence to a healthy plant-based diet may reduce upper GI cancer risk. These findings highlight the potential role of dietary modification in upper GI cancer prevention.

292 Background: Fibroblast activation protein (FAP) has high expression in cancer associated fibroblasts (CAFs) in the tumor microenvironment of many solid tumor malignancies. [ 18 F]FAPI-74 is a fluorine-18 labeled FAP-targeting PET imaging tracer with promising characteristics for detection of malignant disease in a variety of cancers. In this multicenter prospective Phase 2 trial, we hypothesized that [ 18 F]FAPI-74 PET would have a high positive predictive value (PPV) for detecting FAP-expressing tumor tissue in a variety of gastrointestinal (GI) malignancies. Methods: This Phase 2 multicenter trial was conducted in the United States at MGH, MSKCC, BAMF, Northwell, UCLA and Mayo (NCT05641896). Eligible GI cancers in the study included hepatocellular carcinoma, cholangiocarcinoma, gastric, esophageal, pancreatic, and colorectal cancer. Each subject underwent one [ 18 F]FAPI-74 PET scan, and a tissue sample was obtained by biopsy and/or surgical resection. The imaging reads were performed centrally by experienced PET readers. The primary objective was to evaluate the PPV of [ 18 F]FAPI-74 PET in detecting FAP-expressing cells from patient collected tissues using centrally evaluated immunohistochemistry (IHC) with positivity defined by the sponsor as an H score higher than 50. The secondary objective was to evaluate the safety profile of [ 18 F]FAPI-74 and its PPV in detecting the presence of GI malignancies using histopathology as the standard of truth. Results: The trial was activated in May 2023, with the last patient imaged in Jan 2025. Of 103 subjects with GI malignancies, the primary site was gastroesophageal in 46 (45%), pancreatic in 22 (21%), colorectal in 17 (17%), hepatobiliary in 10 (10%) and of other GI origin in 8 (8%) cancers. 60 participants were male and 43 female. In total, 60 patients had viable and representative tissue data for efficacy analysis of primary and secondary endpoints. No serious adverse events were reported because of the investigational product. The PPV of [ 18 F]FAPI-74 PET to detect FAP-expressing cells using IHC was 100% (52/52). The sensitivity and specificity for the detection of FAP were 90% (52/58) and 100% (2/2) respectively. The PPVs of [ 18 F]FAPI-74 PET to detect cancer using histopathology as truth standard was 94% (49/52). The sensitivity for the detection of disease was 91% (49/54). Conclusions: The Phase 2 study in GI cancers demonstrates that [ 18 F]FAPI-74 PET detects FAP expression and presence of disease in cancers of the GI tract. PPV of 100% for primary objective and 94% for secondary objective were determined. These results support initiation of a Phase 3 study of [ 18 F]FAPI-74 PET in patients with GI cancers. In addition, [ 18 F]FAPI-74 PET’s reliability in visualizing FAP expression cells in the tumor microenvironment supports a further role in selection of patients for FAP-directed therapies. Clinical trial information: NCT05641896 .

210 Background: ERBB2/HER2 amplification defines a rare but clinically distinct subtype of colorectal cancer (CRC), associated with favorable responses to HER2-targeted therapies. In contrast, ERBB2/HER2 -mutant CRCs show limited therapeutic benefit, and their clinical and molecular features remain poorly defined. This study investigated the molecular and clinical features of ERBB2/HER2 -mutant CRCs to provide insight into the molecular basis of their differential therapeutic vulnerabilities compared to amplified CRC. Methods: CRC cases were identified from cBioPortal studies with available clinical and ERBB2/HER2 genomic data. After quality control and deduplication, the cohort included 4407 unique cases: 97 with driver mutation(s) only (2.2%), 86 with amplification only (2%), and 4224 wild-type (95.9%). Demographic, clinical, and molecular features, including microsatellite instability (MSI), tumor mutational burden (TMB), and alterations in 94 oncogenic pathway genes, were compared across groups. Statistical analyses used chi-square/Fisher’s exact tests for categorical data, Kruskal-Wallis tests for continuous variables, and the Benjamini-Hochberg correction for multiple comparisons. Odds ratios and FDR-adjusted p-values were calculated to assess associations. Results: Across groups, the distributions of gender, race, and primary cancer site (colon or rectal cancer) were comparable. However, significant differences were observed in age (mean 58.7 ± 15.0 years for ERBB2/HER2 -mutant, 55 ± 13.9 for amplified, and 59 ± 14.8 for wild-type; p = 0.035) and tumor sidedness (among ERBB2/HER2 -mutant cases: right-colon 30.8%, left-colon 15.2%; among ERBB2/HER2 -amplified: right-colon 12.1%, left-colon 37.9%, p = 0.011). KRAS alterations were significantly more common in ERBB2/HER2 -mutant CRCs (50.5%) compared with both amplified (19.8%) and wild-type (37.6%). MSI-H was detected in 34.5% of ERBB2/HER2 -mutant cases, whereas no MSI-H was observed among amplified tumors (p < 0.001). Expectedly, ERBB2/HER2 -mutant tumors exhibited a hypermutated phenotype, with significantly higher TMB (30.3 ± 45.5) and total mutation count (232.8 ± 926.0), compared to amplified (6.1 ± 9.7 and 15.3 ± 28.4) and wild-type (10.5 ± 20.3 and 126.3 ± 424.5; both p < 0.001). Conversely, ERBB2/HER2 -amplified tumors had the highest fraction of overall genomic alterations including chromosomal changes (0.24 ± 0.17 in amplified vs 0.14 ± 0.17 in mutants and 0.20 ± 0.16 in wild-type; p < 0.001). Hierarchical clustering demonstrated that ERBB2/HER2 -mutant tumors form a distinct molecular cluster, whereas amplified tumors cluster closely with wild-type CRC. Conclusions: ERBB2/HER2 - mutant and amplified CRCs show highly distinct genomic and clinical features, supporting the need for tailored treatment approaches.