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Prognostic value of tumor regression grade (TRG) in patients with gastric/gastroesophageal junction cancer treated by peri-operative chemotherapy and surgery: A single-center experience (Institut Mutualiste Montsouris, Paris, France).

486 Background: Management of locally advanced gastric and gastroesophageal junction (GOJ) cancer relies on peri-operative chemotherapy and radical surgery. Response to neoadjuvant chemotherapy can be evaluated by Mandard Tumor Regression Grade (TRG) performed on the removed specimens. The aim of this study was to investigate the prognostic value of TRG, in terms of post-surgical disease-free survival (DFS) and overall survival (OS). Methods: Retrospective analysis of all consecutive patients (Jan 2010 to Dec 2021) who underwent oncological gastrectomy for gastric or GOJ adenocarcinoma after neoadjuvant chemotherapy was performed. TRG was evaluated according to Mandard classification, ranging from 1 (complete pathological response) to 5 (absence of response), TRG 1-2 being considered as “good responders” and TRG 3-5 as “bad responders”. Univariate and multivariate analysis were performed for DFS and OS. Results: One hundred and ninety-nine patients were included, 157 treated with FOLFOX and 42 with FOLFOX + Taxanes (either FLOT or FOLFOX + Abraxane). TRG 1-2 was observed in 30% in patients (pts) treated with FOLFOX and 24% in pts treated with FOLFOX + Taxanes. With a median follow-up over 5 years (yrs), median DFS and OS were not reached (DFS rates at 3, 5 and 10yrs of 66.5%, 64.1% and 55.7%, respectively; OS rates at 3, 5 and 10yrs of 75.6%, 66.8% and 60.4%, respectively). In univariate analysis, TRG 1-2 was significantly associated with favorable outcome compared to TRG 3-5 in terms of DFS (HR 2.4, p-value 0.0056) and OS (HR 2.6, p-value 0.0061), as well as ECOG at diagnosis (0 vs. 1), ypT stage (yp T0-2 vs. yp T3-4), ypN stage (ypN- vs. ypN+), tumor localization (antrum + body vs. cardia + esophagus), and lymphatic, vascular and peri nervous embolisms (negative vs. positive) for both DFS and OS. However, in multivariate analysis (selection backward Cox-model), only ypT stage and vascular embolisms for DFS, and ypT and ypN stages for OS were found to be independent prognostic factors. Conclusions: Although TRG is a prognostic factor in patients with gastric or GOJ cancer, it does not appear as an independent factor for DFS and OS in this series of 199 pts. These results raise the issue of “good responder” definition, especially for TRG 3. Prognostic impact of TRG needs to be investigated for patients treated with combination of immune checkpoint inhibitors and chemotherapy in neoadjuvant regimens.

Results from a phase 2 study of triplet blockade of the IL-27, PD-(L)1, and VEGF pathways with casdozokitug (casdozo, CHS-388) in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (uHCC).

605 Background: Casdozo is the first in class and only clinical-stage IL-27 targeting antibody, which induces increased serum IFN-γ and NK cell gene activation, leading to reversal of IL-27-mediated immune suppression. A phase (Ph) 1 study demonstrated a favorable safety profile and antitumor activity of casdozo alone and in combination with PD-1 blockade in indications with known high levels of IL-27 pathway activation, including HCC (NCT04374877). This open-label Ph 2 trial examined the potential antitumor activity and safety of casdozo with PD-L1 and VEGF blockade in uHCC (NCT05359861). Updated clinical and biomarker data are presented. Methods: Patients (Pts) with untreated uHCC received casdozo 10 mg/kg, atezolizumab (atezo) 1200 mg, and bevacizumab (bev) 15 mg/kg IV Q3W. Primary endpoints were safety and tolerability, with key secondary endpoints of investigator-assessed ORR by RECIST1.1 and mRECIST, PFS, and OS. Results: As of Sept 4, 2024, 30 pts received casdozo/atezo/bev. Most pts were male (77%), Asian (67%), had viral etiology (53% HBV, 17% HCV), and poor-prognosis disease assessed by metastatic spread (67%) and/or macrovascular invasion (13%). Median follow-up was 15 months (mo). Median time on therapy was 8 mo. The most common (>20%) adverse events related to any study drug were proteinuria (43%), hypertension (27%), fatigue (23%), and diarrhea (20%); Grade ≥3 events occurred in 67%, with only hypertension (20%), arising in >10% of pts. Treatment-emergent adverse events (TEAEs) resulting in any study drug discontinuation occurred in 30% of pts. No treatment-related deaths were reported. In the 29 RECIST1.1 response-evaluable pts, ORR was 38% with 17% of pts achieving a CR (5 CRs, 6 PRs); mPFS (95% CI) was 8.1 mo (1.9, 13.6); landmark PFS rates at 6, 12 and 18 mo were 58.6%, 36.1% and 27.1%, respectively; mDoR (95% CI) was NR (6.1, -). In the 28 pts evaluable for mRECIST, ORR was 43% (5 CRs, 7 PRs); mPFS (95% CI) was 8.4 mo (2.0, 14.5); mDoR was NR (12.7, -). mOS (95% CI) was 19.9 mo (14.2, -); the 12-mo survival rate (95% CI) was 85% (65, 94). More than 40% of pts remain on study, and 16.7% remain on study treatment. Available archival tissue of responders expressed IL-27+ TAMs by IHC, including tumors of viral and nonviral etiologies. Conclusions: Triplet blockade of IL-27, PD-(L)1, and VEGF pathways with casdozo/atezo/bev continues to show a manageable safety profile with promising antitumor activity in uHCC that warrants continued exploration. Toxicity was consistent with the known profiles of the agents, with no new safety signals identified. Biomarker analysis to evaluate immune response and associations of IL-27 pathway and clinical outcomes is ongoing. Additional clinical studies of casdozo in combination with toripalimab are planned. Clinical trial information: NCT05359861 .

Preliminary results of the ALTER-E009 study: Efficacy and safety of anlotinib combined with radiotherapy in patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC)—A multicenter, multi-cohort retrospective exploratory study.

361 Background: Therapeutic options for metastatic esophageal squamous cell carcinoma (ESCC) primarily involve immunotherapy combined with chemotherapy. For locally advanced ESCC, concurrent chemoradiotherapy (CRT) or radiotherapy is the standard, though outcomes remain suboptimal. Targeted therapies, particularly anti-angiogenic agents, hold promise to enhance CRT efficacy. Anlotinib, a multi-target anti-angiogenic agent inhibiting VEGFR, PDGFR, FGFR, and c-KIT, has shown potential to enhance radiotherapy by alleviating tumor hypoxia. This multicenter, retrospective study evaluates the efficacy and safety of anlotinib combined with radiotherapy in locally advanced or metastatic ESCC. Methods: This study screened patients (pts) with locally advanced or metastatic ESCC treated with anlotinib (8-12 mg, p.o., qd, d1-14, q3w) and radiotherapy from June 2018 to June 2024. Two cohorts were included: Cohort 1 (metastatic ESCC) and Cohort 2 (locally advanced ESCC). Cohort 2 was divided into an observational group (OG, anlotinib + radiotherapy ± chemotherapy) and a control group (CG, radiotherapy ± chemotherapy). Radiotherapy doses for primary lesions were 45-60 Gy (1.8-2.2 Gy per fraction), while metastatic lesions received either standard fractionation (≥45 Gy) or stereotactic body radiotherapy (SBRT, ≥3 Gy per fraction, total dose ≥30 Gy). Chemotherapy regimens were not restricted. Cohort 1 aimed to enroll 50 pts, while Cohort 2 included 100 in the OG and 200 in the CG. The primary endpoint was overall survival (OS), with secondary endpoints including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and safety. Results: By September 10, 2024, 128 pts had been enrolled: 34 in Cohort 1 and 94 in the OG of Cohort 2. In Cohort 1, all 34 pts (100%) were stage IVB, with a median OS of 24.0 months (95% CI: 12.44-35.60) and a median PFS of 9.2 months (95% CI: 7.60-10.80). The 24-month OS and PFS rates were 54.0% (95% CI: 27.20-74.73) and 30.8% (95% CI: 10.21-54.53), respectively. ORR was 52.9% (95% CI: 35.1-70.2), with 1 complete response (CR) and 17 partial responses (PR), DCR was 88.2% (95% CI: 72.5-96.7). In Cohort 2, 50 pts (53.2%) were stage III, and 28 (29.8%) were stage IVA. The median OS is not yet mature, but the median PFS was 20.1 months. The 36-month OS and PFS rates were 61.9% (95% CI: 46.12-74.34) and 48.4% (95% CI: 29.58-64.87). ORR was 46.8% (95% CI: 36.4-57.4), with 6 CRs and 38 PRs, DCR was 95.7% (95% CI: 89.5-98.8). Safety data collection is ongoing. Conclusions: Anlotinib combined with radiotherapy exhibited promising efficacy in locally advanced or metastatic ESCC, though further data are needed to confirm these preliminary findings.

Grand roles for microproteins

Multicenter, retrospective, observational study of outcomes of treatment for unresectable neuroendocrine tumors G3 of gastroenteropancreatic or unknown primary origin.

660 Background: The 2017 edition of the WHO classification categorized neuroendocrine neoplasms (NEN) as neuroendocrine tumors (NET) G1, G2, G3, and neuroendocrine carcinoma (NEC). Prior to 2017, NET G3 was categorized as NEC in the WHO 2010 classification. Platinum-based chemotherapy, commonly used as first-line treatment for these tumors, shows suboptimal efficacy for NET G3. Additionally, large-scale studies and robust evidence on chemotherapy outcomes for NET G3 are lacking. We investigated chemotherapy regimens for NET G3 and evaluated their outcomes. Methods: We included 73 patients (pts) who were clinically and pathologically diagnosed with unresectable NET G3 of gastroenteropancreatic or unknown primary origin and who started chemotherapy between Jan 2011 and Dec 2019. Clinical data were collected retrospectively and analyzed for regimen selected, treatment efficacy, and prognostic factors. A central pathological review was conducted if tissue samples were available. Results: The median age of pts was 65 years (range 27-85 years), with 45 being male. Among the pts, 49 had pancreatic NETs, 10 had gastrointestinal NETs, and 14 had NETs of unknown primary origin. The median Ki-67 index was 30% (range 20-70%). Twenty-seven patients (37%) had received prior treatment, such as surgery or local therapy. A central pathological diagnosis was confirmed NET G3 in 42 out of 44 patients (95%). Primary treatment regimens were NET-based (somatostatin analogues, everolimus, sunitinib, streptozocin-based chemotherapy, and capecitabine and temozolomide [CAPTEM]) and NEC-based (platinum-based chemotherapy) in 54% and 44% of patients, respectively. NET-based regimens were selected in 36% and 78% of pts, respectively, before and after publication of the WHO 2017 classification. The overall response rate (ORR) was 16% for NEC-based regimens and 19% for NET-based regimens. However, when focusing on NET-based chemotherapy (streptozocin-based and CAPTEM), the ORR was 54%. Median progression-free survival (PFS) was 118 days (95% confidence interval [CI]: 60-337 days) for NET-based regimens and 229 days (95%CI: 133-426 days) for NEC-based regimens. Median overall survival (OS) was 841 days for NET-based regimens (95%CI: 480-989 days) and 658 days (95%CI: 455-1144 days) for NEC-based regimens. There were no significant differences in PFS or OS between the regimens. In multivariable analysis, hepatic tumor volume >25% was a negative predictor of PFS, and NSE ≥16.3 ng/mL was a negative predictor of OS. Conclusions: Since the introduction of NET G3 in the WHO classification, NET-based regimens have become the preferred treatment choice. Although there were no significant differences in PFS or OS between the regimens, the NEC-based regimens was limited. Pts with high hepatic tumor volume or elevated NSE levels had a worse prognosis.

Preliminary results from the multicenter, randomized phase III trial (SCIENCE): Comparing chemotherapy plus sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy for neoadjuvant treatment in resectable locally advanced esophageal squamous cell carcinoma.

LBA329 Background: Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (CRT) followed by surgery is the standard treatment for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC). Despite significant advancements in therapeutic strategies, the rate of recurrence remains high. Therefore, this multicenter, randomized, Phase III trial (SCIENCE) aims to evaluate and compare the efficacy of nCT and nCRT plus Sintilimab, and nCRT alone in patients with resectable LA-ESCC. Methods: Eligible patients with thoracic ESCC and had not received any prior treatment. Patients were clinically staged as locally advanced (cT1N2-3M0 or cT2-4aN0-3M0). Participants were randomized in a 1:1:1 ratio to one of three neoadjuvant treatment groups: Group A: Sintilimab combined with nCT (nab-paclitaxel plus carboplatin) for two cycles. Group B: Sintilimab combined with concurrent nCRT (nab-paclitaxel plus carboplatin chemotherapy and radiotherapy using IMRT/IGRT totaling 41.4 Gy). Group C: Concurrent nCRT alone. Surgical resection was planned 6-8 weeks after the completion of neoadjuvant therapy. The co-primary endpoints were pathological complete response (pCR) rate, and event-free survival (EFS), evaluated by investigators according to RECIST 1.1 criteria. Results: Between November 2022 and June 2024, 146 patients were enrolled and randomized into three groups: Group A (n = 46), Group B (n = 45), and Group C (n = 55). The majority of patients were male (89.7%; 131/146), with most clinical stage III disease (72.6%; 106/146) and tumors located in the middle thoracic esophagus (51.4%; 75/146). All patients completed the neoadjuvant treatment and underwent surgical resection and achieving a 100% R0 resection rate. The pCR rates differed significantly among the groups, with Group A achieving a pCR rate of 13%, Group B 60%, and Group C 47.3%. Both Group B and C demonstrated significantly higher pCR rates compared to Group A, with Group B versus Group A showing a difference of 47% (95% CI, 27.8–62.2; OR = 10; 95% CI, 3.7–30.8; P < 0.0001) and Group C versus Group A showing a difference of 34.2% (95% CI, 16.4–49.1; OR = 6; 95% CI, 2.3–17.8; P = 0.0005). No perioperative deaths were reported. Treatment-emergent adverse events (TEAEs) of any grade were observed in 50% of patients in Group A, 86.7% in Group B, and 85.5% in Group C. Additionally, the incidence of Grade 3 or higher TEAEs during neoadjuvant treatment was 8.7% in Group A, 31.1% in Group B, and 36.4% in Group C. Conclusion: This Phase III trial demonstrates that nCRT, with or without Sintilimab, significantly enhances pCR rates compared to nCT with Sintilimab in LA-ESCC, without increasing surgical risks. Ongoing monitoring of EFS is necessary to validate these results. Clinical trial information: NCT05244798 .

Conversion effects of PD-1 inhibitor camrelizumab (Cam) combined with Nab-POF regimen in patients (pts) with initially unresectable locally advanced or limited metastatic gastric or gastroesophageal junction adenocarcinoma: FDZL-001 trial.

334 Background: For initially unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, the prognosis is poor and chemotherapy is the main treatment option. The AIO-FLOT3 Trial suggested that conversion therapy might improve outcome in pts with limited metastatic gastric cancer (GC). We conducted this prospective, single-arm, phase II trial to improve conversion efficacy of PD-1 inhibitor Cam combined with Nab-POF regimen (nab-paclitaxel , oxaliplatin, fluorouracil) in pts with initially unresectable locally advanced or limited metastatic gastric or gastroesophageal junction adenocarcinoma. Methods: Eligible pts received Cam 200mg, nab-PTX 125 mg/m 2 , oxaliplatin 85 mg/m 2 or with trastuzumab if Her2 positive, each was an IV followed by fluorouracil 2400 mg/m 2 as a 48-h continuous IV on day 1, every 2 weeks. Patients were assessed for tumor response and surgical feasibility every 3 cycles, and if confirmed feasible for surgical resection by both surgical and medical experts after 6 cycles, they would undergo surgery within 3-6 weeks. The primary endpoint was R0 resection rate. Results: In total, 53 pts were enrolled up to 01/2024. 52 pts were evaluable. 50% are younger than 65 years of age. Male was 73.1%. The metastatic sites included liver 46.2% (24), retroperitoneal lymph nodes 40.4% (21), Krukenberg 5.8% (3), and locally advanced unresectable tumors 21.2% (11). 4 pts (7.7%) were dMMR/MSI-H and 10 (19.2%) were Her2 positive. ORR was 88.5% (46/52) and DCR was 98.1% (51/52). 45(86.5%) pts were assessed as resectable. 3 pts (6.8%) refused surgery and 3 (6.8%) were cCR under observation. The R0 resection rate was 75.0% (39/52). CR rate was 23.1% (cCR, 5.8%; pCR,17.3%). The mPFS was not reached (95% CI = 17.0-NE), and the mOS was not reached (95% CI = 25.4-NE), either. The 3-year PFS and OS rate were 56.9% (95% CI = 45.7%-86.3%) and 62.8% (95% CI = 41.6%-78.0%), respectively. The 3 cCR pts have survived utill the last follow-up date of 07/2025 without tumors for 17, 29, and 34 months, respectively. Pts tolerated treatment well, although all pts experienced treatment-related adverse events (AE). Grade 3/4 AEs were 42.3% (22/52) and neutrophil decrease was the most common at 36.5%. 10 patients (19.2%) experienced immune related AEs (irAEs), and 2 of them experienced grade 3 irAEs. Conclusions: The PD-1 inhibitor Cam combined with the Nab-POF regimen safely induced a high conversion rate with very high R0 resection and high 3-year PFS and OS rates, preliminarily demonstrating promising effects, providing a new conversion drug treatment option for pts with initially unresectable locally advanced or limited metastatic advanced GC. These findings warrant further prospective, randomized controlled investigations. Clinical trial information: NCT04510064 .

Assessing impact of postoperative outcomes and quality of life on decisional regret after resection of pancreatic ductal adenocarcinoma.

699 Background: Surgery is potentially curative for patients with localized pancreatic ductal adenocarcinoma (PDAC). Given the high rate of complications, decline in quality of life (QoL) postoperatively, and high rates of recurrence, clear preoperative communication and expectation setting is critical. This study investigates clinical outcomes that affect postoperative decisional regret (DR) in patients with PDAC. Methods: This mixed-methods study investigates the impact of clinical outcomes and QoL on the degree of DR in patients with PDAC who have undergone curative-intent resection at least 6 months prior to study recruitment. Patients completed validated surveys assessing DR and QoL by the European Organization for Research and Treatment of Cancer (EORTC). Groups are stratified by presence or absence of DR, assessed by the Decisional Regret Scale (DRS). Characteristics and survey scores were compared by chi-square, independent t-test, and median test. Narrative responses were thematically analyzed. Given significant findings, results of this interim analysis are reported below. Results: 45 patients met inclusion criteria and completed all questionnaires. 19 (42.2%) patients expressed regret about their decision to pursue curative-intent surgery, with 5 patients expressing moderate to severe regret (DRS ≥ 25). There was no significant difference in median postoperative timing of survey completion between groups (56 months in DR group vs 34 months, P=0.465). Baseline characteristics, medical treatments, and operative approaches were similar. Both groups had similar recurrence rates at time of survey completion. While 30 and 90 day readmission rates were similar, a greater proportion of the DR group had 30 day complications (42.1% vs 15.4%, P=0.045). Those expressing regret reported poorer physical functional status (mean score 79.30 ± 18.84 vs 92.31 ± 10.27, P=0.011) and greater impact on social activities (mean score 67.54 ± 33.55 vs 84.67 ± 19.19, P=0.038). Thematic analysis of narrative responses revealed that a majority of patients expressed a strong desire to have a greater focus on potential QoL changes during preoperative discussions. Conclusions: Patients expressing postoperative DR experienced more 30 day complications, and still report lasting effects on their current physical status and social activities. This emphasizes the importance of thorough preoperative counseling on surgical risks and potential changes in postoperative QoL so that patients may make the best informed decision.

Chemotherapy selection for advanced or metastatic pancreatic cancer using machine learning models trained with multi-center datasets.

738 Background: Several factors must be considered when selecting the chemotherapeutic regimen for advanced or metastatic pancreatic cancer. The decision between FOLFIRINOX and Gemcitabine/Nab-paclitaxel (GnP) as the first-line therapy is challenging, as survival is influenced by the efficacy and toxicity profiles of these treatments, along with individual patient characteristics and therapeutic vulnerabilities. This study aims to facilitate the selection of an appropriate first-line regimen for advanced or metastatic pancreatic cancer by employing machine learning (ML) methods trained on multi-center datasets. Methods: Our study is based on a cohort of 191 patients who underwent systemic chemotherapy for advanced or metastatic pancreatic cancer at the Gangneung Asan Hospital and Asan Medical Center in South Korea between 2014 and 2023. The dataset consisted of 17 types of demographic and clinical characteristics, as well as time-course of response and survival outcomes. We divided the cohort into training and test groups (4:1) in a stratified manner. ML models predicting overall survival (OS) were trained on the former group using the CatBoost method. The models utilizing a minimal subset of variables were selected with respect to ROC-AUC during 5-fold cross validation. A patient was classified as having high risk to a therapy when the predicted probability of death following treatment initiation was above the threshold value as determined during training of the respective model. Results: The median age of the entire cohort was 62 years, with 64% being male. The ML models achieved ROC-AUCs of 0.81 and 0.82 when predicting early death within 12 months following the initial administration of FOLFIRINOX or GnP, respectively. The predictive accuracies of the models were 0.77 and 0.80 for the unseen datasets from the two treatment groups, respectively. The median OS of the high- versus low-risk groups of FOLFIRINOX predicted by the ML models were significantly different (9 vs 15 months, P <0.0001), with a hazard ratio (HR) of 2.8. Similarly, the median OS of the high- and low-risk groups of GnP were significantly different (9 vs 18 months, P <0.01, HR of 2.5). We observed that 27% of the patients predicted as high risk to FOLFIRINOX therapy were predicted as low risk to GnP and vice versa for 32% of the patients predicted as high risk to GnP therapy. Conclusions: We developed ML models to compute the probability of early death following FOLFIRINOX or GnP therapy from routinely collected data of the patients with advanced or metastatic pancreatic cancer. After confirming robust predictive performance with multi-center datasets, we believe that these models may assist clinicians in selecting a first-line regimens, potentially enhancing personalized treatment strategies for this challenging disease.

Molecular and clinical determinants of targeted therapy (TT) outcomes in biliary tract cancer (BTC): Analysis of a prospectively maintained next generation sequencing (NGS) biorepository.

555 Background: BTCs are genomically diverse. TT have established antitumor activity in a subset of pts that harbour actionable alterations; however, most patients (pts) do not respond to or experience acquired resistance on TT. We sought to explore genomic mechanisms of response across the spectrum of BTCs. Methods: We leveraged a prospectively maintained cohort of pts with histologically confirmed BTC who underwent molecular profiling using an FDA authorized, targeted, NGS assay. Additional clinicopathologic information was retrospectively extracted with an aim to describe the genomic profile and clinical actionability using OncoKB, to explore outcomes for pts treated with TT, and to nominate innate and acquired genomic mechanisms of resistance. Results: N = 1254 pts had molecular profiling: 61.2% intrahepatic (iCCA), 16.8% extrahepatic cholangiocarcinoma (eCCA), 22.1% gallbladder cancer (GBC). MSI high was observed in 2.1% and the median TMB was 3.3 (range: 0-74.6 muts/mb). Among MSS tumors, the most frequently altered genes were TP53 (36%), CDKN2A (21%), ARID1A (18%), KRAS (17%), and IDH1/2 (16%). Genomic profiles differed significantly based on anatomic subsite. Oncogenic drivers were mostly clonal except for ERBB2 amplifications and mutations, which were subclonal in 19%, and 28% of cases respectively. OncoKB level 1/2 events observed in 32.2% (iCCA 40%, eCCA 15%, and GBC 22%). Progression-free survival (PFS) for pts with these oncogenic drivers: IDH , FGFR2 , ERBB2, BRAF V600E , MSI high , and TMB high from start of matched TT (N=164) is listed in the table. Clinical factors or co-occurring genomic alterations did not impact outcomes. Profiling of paired pre- and post-progression samples (N=25) nominated pathway reactivation in FGFR2 , BRAF , NTRK, and ERBB2 driven tumors with emergence of recurrent oncogenic FGFR2 , RAS , MEK , and MET alterations, respectively, as well as off target MYC amplification and CDKN2A loss. Loss of the oncogenic driver at progression was only observed for ERBB2 driven tumors. Conclusions: Acknowledging the limitations of the study design, matched TT in a real-world, prospectively maintained cohort offers meaningful PFS, most notably in those pts with MSI high BTC treated with immunotherapy. In those with acquired resistance to TT, alterations predicted to reactivate the primary oncogenic pathway were identified. ERBB2 heterogeneity and loss is predicted to be a mechanism of resistance to HER2 targeted therapy. Outcomes for BTC treated with matched TT. Target Median PFS, months (95% CI) IDH1/2 (N = 72) 4.2 (2.9-6.8) FGFR2 (N=37) 7.4 (6.5-9.4) ERBB2 (N =22) 8.2 (2.95-16.7) MSI high (N = 14) NR (10.15-NR) TMB high (N=12) 2.69 (1.64-NR) BRAF V600E (N=7) 16.6 (3.7-NR)

Impact of baseline alterations in HER2-pathway oncogenic drivers on response to anti-HER2 therapy in patients (pts) with HER2-amplified advanced colorectal cancer (aCRC).

243 Background: HER2-amplified aCRC is associated with poor prognosis despite new anti-HER2 regimens. Insight on biomarkers that predict response to these therapies is limited. This study aims to evaluate whether baseline alterations in oncogenic drivers along the HER2 pathway predict response to anti-HER2 therapy in HER2-amplified aCRC. Methods: In this international multi-center study involving Mayo Clinic, Duke Cancer Institute and National Cancer Center Hospital East (Japan), we collected baseline genomic alterations from tissue or blood samples using next-generation sequencing (NGS) prior to anti-HER2 therapy initiation. We defined PIK3CA, RAS, RAF, MAP2K, and MET as oncogenic drivers of resistance within the HER2 pathway. Overall survival (OS) was evaluated with the Kaplan-Meier method and a log-rank test was used to compare median OS (mOS) between pts with and without alterations in the above genes. A chi-square test (significance level 0.05) was performed to compare overall response rate (ORR) and disease control rate (DCR). Results: We identified 39 pts with HER2-amplified aCRC and baseline NGS. Median age was 57 (range 30-77), 54% were male. Baseline alterations in HER2 pathway oncogenic drivers were identified in 17 pts (43.5%). 18 (46%) received monoclonal antibodies (mAbs) plus tyrosine kinase inhibitors, 12 (30%) received dual mAbs and 7 (18%) received trastuzumab deruxtecan. The mOS was 41.9 months (mos) (95%CI 23.7-60.1) for other alterations vs 24.2 mos (95%CI 14.1-34.3) in pts with HER2 pathway alterations (p = 0.1). ORR was 47% vs 41% (p = 0.7) and DCR 82% vs 73% (p = 0.4), for pts with HER2 pathway alterations and without HER2 pathway alterations, respectively. 4 pts receiving trastuzumab/tucatinib had complete response, none of which had HER2 pathway alterations. Conclusions: Pts with baseline alterations in oncogenic drivers of the HER2 pathway had clinically worse outcomes compared to pts without such alterations despite receiving HER2-targeted therapy, though results lacked statistical significance. Larger studies are needed to confirm the lack of benefit from anti-HER2 therapy in this subgroup.

Comparison of long-term outcomes for neoadjuvant chemoradiation (NA-CRT) followed by surgery versus (V) definitive chemoradiation (D-CRT) in localized gastroesophageal cancer (GEC): A single-center analysis.

371 Background: The therapeutic approach in locally advanced GEC is evolving. NA-CRT followed by surgery has been recommended based on the CROSS trial. The SANO trial reports active surveillance may be an alternative in clinically complete response after D-CRT in both squamous cell carcinoma (SCC) and adenocarcinoma (AC). SCC and AC in GEC are different diseases with differences in tumor location, etiology, and biology. Despite the evolving landscape, there still may be a role for both CROSS and SANO approaches. In our large observational cohort study, we sought to compare the long-term outcomes in localized GEC across all histological subtypes treated with NA-CRT+Surgery V D-CR+Surveillance. Methods: A retrospective analysis comparing NA-CRT + surgery V D-CRT in localized GEC between 2007-2023 treated at the Princess Margaret Cancer Centre was completed. Baseline characteristics including age, gender, race, performance status and Charlson Comorbidity index (CCI) were reviewed. The primary and secondary endpoints were overall survival (OS) and disease-free survival (DFS), respectively and to compare these outcomes in both histologies. Cox proportional hazards analysis and Kaplan-Meier methods were employed. Outcomes were adjusted for baseline characteristics. Results: There were 529 patients (pts) included, 321 (61%) received NA-CRT+Surgery and 208 (39%) D-CR+Surveillance. Median age was 64yrs, 75% were male and 66% had N1+ disease. The proportion of pts with SCC treated with NA-CRT+Surgery and D-CR+Surveillance was 25% and 63%, respectively. There was a statistically significant difference in median OS and DFS between pts who received NA-CRT+surgery and D-CRT+surveillance (Table). Multivariate regression analysis shows a significant association between OS and age (adjusted HR 1.02, p=0.005), male sex (HR 1.55, p=0.003) but no significant association between OS and CCI (HR 1.1 p=0.36). In our subgroup analyses, there was no statistically significant difference in OS (p=0.33) and DFS (p=0.18) between SCC and AC. However, this was significant in D-CRT (OS p<0.0001, DFS p<0.001) favoring SCC. Conclusions: In contrast to the SANO trial, we found that NA-CRT+surgery was associated with a significantly better OS and DFS compared to D-CRT when subtypes were combined. However, in the D-CRT subgroup, SCC was associated with improved OS and DFS compared to AC. Thus, we continue to recommend current approaches in SCC. Awaited updates from SANO will inform whether active surveillance may also be appropriate in pts with AC subtype. Median (95% CI)NA-CRT Surgery Median (95% CI)D-CRT Log-rank test p-value OS (mo) 28.2 (15.1, 57.6) 15.6 (7.7, 33.7) P=<0.0001 DFS (mo) 17.9 (9.6, 40.8) 9.4 (5.0, 20.7) P=<0.0001 pathCR (%) 14 - R0 resection (%) 89 -

Fruquintinib combined with FOLFIRI/mFOLFOX6 as second-line treatment in patients with RAS-mutant metastatic colorectal cancer (mCRC): A multicenter, open-label, phase II study.

151 Background: Anti-angiogenic drugs combined with chemotherapy could bring good clinical benefit to patients (pts) with mCRC, but the efficacy in pts with RAS mutant mCRC was limited. Fruquintinib is a highly selective oral inhibitor of vascular endothelial growth factor receptors (VEGFRs -1, -2, and -3) and was approved for previously treated mCRC. Our study was to explore the efficacy and safety of fruquintinib combined with FOLFIRI/mFOLFOX6 in the second line treatment of RAS-mutant mCRC (NCT05634590). Methods: Eligible pts with histologically confirmed RAS-mutant mCRC who had received first-line standard chemotherapy regimens were included in the study, and pts received Fru (4 mg, p.o. qd, 3 weeks on/1 week off, q4w) plus FOLFIRI/mFOLFOX6 (d1-15, q4w) until disease progression, unacceptable toxicities, or withdrew consent. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS)and safety. Results: As of Aug 30, 2024, 25 eligible pts were enrolled and received at least one time treatment. Baseline characteristics included median age (66.0 [range: 35-73]), female/male (56.0% / 44.0%), ECOG PS 1(68.0%), left-sided and right-sided colon (72.0% / 28.0%), liver metastasis (64.0%), prior anti-VEGF therapies (76.0%). 14 pts had received at least one tumor assessment. Five pts achieved partial response (PR), 9 pts achieved stable disease (SD), and the ORR was 35.7% (5/14) (95% confidence interval [CI]: 12.8-64.9), the DCR was 100.0% (14/14) (95% CI: 76.8-100.0). Compared to liver metastases, the ORR was higher without liver metastases (42.9% [95%CI 9.9-81.6]). The median PFS was 6.41 months (95% CI: 6.37 - NA), and median OS was not reached yet. In the subgroup analysis, Median PFS was also longer without liver metastases pts than with liver metastases (8.84 mo vs 6.41 mo; HR=1.230; 95%CI 0.2462-6.148; p=0.7775). Additionally, Grade ≥3 treatment-emergent adverse events (TEAEs) included platelet count decreased (18.2%), hypertension (9.1%) and neutrophil count decreased (9.1%). Conclusions: Fruquintinib combined with FOLFIRI/mFOLFOX6 as second-line in patients with RAS-mutant mCRC achieved a promising clinical benefit, with a manageable safety profile. This trial is ongoing and more updated clinical data will be presented in the future. Clinical trial information: NCT05634590 .

A comparative study of dosage strategies in HIPEC: BSA-based vs fixed dose methods.

832 Background: Peritoneal metastases commonly occur in ovarian, gastric, and colorectal cancers, significantly contributing to patient morbidity and mortality. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is a promising approach for managing peritoneal surface cancers. This procedure involves cytoreductive surgery to remove visible tumors, followed by the perfusion of heated chemotherapy (41-42°C) directly into the peritoneal cavity. HIPEC addresses the limitation of systemic chemotherapy, which often fails to penetrate the peritoneal cavity effectively. HIPEC dosing may either be a flat-fixed dose or be calculated based on Body Surface Area (BSA). BSA can be determined using three methods: actual BSA (based on weight and height), ideal BSA (based on sex and height), and adjusted BSA (considering lean and fat mass). Methods: A retrospective chart review was conducted on 151 metastatic cancer patients at UVMMC. Patient BMI, weight, and height at diagnosis were collected to calculate BSA values (actual, adjusted, and ideal) for estimating a hypothetical chemotherapy dosage. Statistical analysis using SPSS involved linear mixed models and paired t-tests to compare Mitomycin-C dosages between a fixed dose (40 mg) and a BSA-derived dose (30 mg/m²). Results: The average dosage of Mitomycin-C differed significantly depending on whether the dose was calculated using actual, adjusted, or ideal BSA. The largest discrepancy in dosage was observed between the actual BSA method and the flat-fixed dose, with an average difference of 16 mg. The smallest difference in dose was between the adjusted and ideal BSA methods. When stratifying by BMI, the greatest variation in Mitomycin-C dosage was found among overweight and obese patients (BMI ≥ 25). For these patients, the average dosage difference between the flat fixed dose and the actual BSA dose was 20 mg. In comparison, in patients with a BMI under 18.5 (underweight) the actual BSA dose was comparable to the fixed dose. Conclusions: Different institutions utilize a variety of dosing strategies for the HIPEC procedure. Differences in BSA calculation methods and perfusate volumes (literature values of 2, 3 and 4 L is most common) contribute to the complexity of establishing standardized dosing. The significant dosing variations observed, especially in overweight and obese patients, are of concern, as 70% of the U.S. population has a BMI ≥ 25. Our study demonstrates significant variability in HIPEC chemotherapy dosing, especially among patients with higher BMI. The discrepancy between BSA-based methods and flat-fixed doses may impact treatment efficacy and toxicity. Standardizing dosing approaches is important to ensure consistent therapeutic outcomes and patient safety.

Real-world outcomes of targeted therapies and local interventions in BRAF V600E–mutated metastatic colorectal cancer: A single-center retrospective study.

203 Background: Metastatic colorectal cancer (mCRC) patients with BRAF V600E mutations, especially those with microsatellite stable (MSS) tumors, have poor prognoses. Chemotherapy has limited efficacy in this subgroup, especially for second-line or subsequent-line treatments. Current research is increasingly focusing on the integration of targeted therapies and local interventions, but real-world evidence remains scarce, particularly from Asian cohorts. This study leverages real-world data to evaluate the impact of novel therapeutic combinations, including triplet and doublet targeted therapies, alongside local treatments in this high-risk patient population. Methods: This retrospective study includes MSS-type mCRC patients with BRAF V600E mutations treated at the Sixth Affiliated Hospital of Sun Yat-sen University between April 2014 and May 2024. Patients receiving targeted therapies were stratified into three groups: Triplet group (BRAF, EGFR, and MEK inhibitors, including Dabrafenib, Cetuximab and Trametinib), Doublet group (BRAF and EGFR inhibitors, including Dabrafenib and Cetuximab or Encorafenib and Cetuximab), and Doublet target-chemotherapy group (BRAF and EGFR inhibitors combined with chemotherapy, including Vemurafenib, Irinotecan, and Cetuximab). Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and objective response rate (ORR). Results: Among 239 enrolled patients, 58 received targeted therapy and 68 underwent conventional chemotherapy as second-line treatment. 63.5% (80/126) of these patients underwent local interventions, including primary tumor resection, metastasectomy, CRS±HIPEC, and liver ablation. Targeted therapy demonstrated significantly improved mPFS compared to conventional chemotherapy (5.5 vs. 4.2 months, HR = 0.44; 95% CI: 0.29-0.68, p < 0.001). OS did not differ significantly between the two treatment arms (12.7 vs. 12.1 months, HR = 0.80; 95% CI: 0.50-1.25, p = 0.330). In the triplet group, ORR, mPFS, and mOS were 21%, 5.8 months and 18.0 months, respectively, showing a trend towards enhanced efficacy compared to the other targeted therapy groups, albeit without statistical significance. Patients who received targeted therapy (n=35) or chemotherapy (n=45) in combination with local interventions demonstrated significantly prolonged OS compared to those without local therapy (mOS: 22.3 vs. 9.6 months; HR = 0.19; 95% CI: 0.09-0.42; p < 0.001 and 14.3 vs. 10.9 months; HR = 0.53; 95% CI: 0.29-0.98; p = 0.042, respectively). Conclusions: Optimal treatment for BRAF V600E mCRC remains under investigation. This study suggests that combining targeted therapies with selective local interventions may significantly improve patient survival in this challenging subgroup, warranting further prospective evaluation.

Short-course radiation(SCRT) followed by 6 cycles of cadonilimab plus mFOLFOX6 as neoadjuvant therapy for patients with locally advanced rectal cancer (LARC): A multicenter, single arm, phase II trial (NeoCaCRT).

LBA210 Background: Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is recommended for mismatch repair-proficient (pMMR) or microsatellite stability(MSS) LARC. Recent studies have shown that anti-PD-1/PD-L1 in combination with CRT can improve pathological complete response (pCR) compared to CRT in the neoadjuvant setting. This trial aims to investigate the efficacy and safety of SCRT followed by cadonilimab, a first-in-class anti-PD-1/CTLA-4 bispecific antibody, plus mFOLFOX6 in patients (pts) with LARC. Methods: Eligible pts aged 18-79 years with pMMR/MSS, nonmetastatic, stage cT3-4N0 or cT1-4N1-2 rectal adenocarcinoma located below the peritoneal reflection were enrolled and given SCRT (25Gy/5F) followed by 6 cycles of cadonilimab (6mg/kg, q2w) plus mFOLFOX6. The primary endpoint was pCR. Secondary endpoints included clinical complete response (cCR), major pathological response (MPR), disease-free survival (DFS), overall survival (OS), safety and quality of life. The exploratory endpoint explored potential biomarkers related to response. Results: From April 2023 to May 2024, 27 pts were enrolled and received at least 1 dose of treatment. As of data cutoff date of October 20, 2024,median follow-up was 9.7 months (IQR 5.4–18·8)，and all pts received study treatment, and 24/27(88.9%) underwent R0 resections (one delayed surgery due to chemotherapy-related pneumonia, while the other two were assessed unresectable). The primary endpoint was met with a pCR of 37%(10/27)(95% CI, 19.4%–57.6%) and MPR of 55.6%. A cCR of 22.2%(6/27) was observed, and among them, 83.3%(5/6) still received local excisions. The T downstaging was observed in 59.3%(16/27) while N downstaging in 66.7%(18/27). Grade 3–5 adverse events occurred in 5 (18.5%) of 27 pts; the most common were diarrhea (ten [37%]),nausea (ten [37%]) and fatigue (ten [37%]), and neutropenia (seven [26%]). Drug-related serious adverse events occurred in eight (30%) of 27 patients. No new safety signal was identified. Conclusions: In pts with pMMR/MSS LARC, neoadjuvant SCRT with cadonilimab plus mFOLFOX6 resulted in promising pCR rates with intolerable toxicities. Follow up continues. These data deserve further investigations in a phase III randomized trial. Clinical trial information: NCT05792735 .

The influence of depression on esophageal cancer outcomes: Using the National Inpatient Sample (NIS) 2021.

338 Background: Esophageal cancer (EC) remains a challenging malignancy with high morbidity and mortality rates. Depression is prevalent among cancer patients and has been shown to affect various clinical outcomes. This study aims to evaluate the impact of depression on mortality, length of stay (LOS), and hospitalization charges in patients with esophageal cancer using data from the NIS. Methods: We conducted a retrospective, population-based study using the NIS data to analyze patients diagnosed with esophageal cancer. Depression was the primary exposure variable using the appropriate ICD-10 code. We applied survey-weighted descriptive statistics, logistic regression, and linear regression models to assess outcomes, adjusting for demographic and clinical factors, including age, sex, race, comorbidities (Charlson Comorbidity Index), hospital teaching status, and regional characteristics. Results: A total of 40,855 patients with esophageal cancer were included, with 11.4% (n = 4,855) having a concurrent diagnosis of depression. The unadjusted mortality rate for the cohort was 9.18%, with depressed patients showing a lower mortality rate (6.45% vs. 9.53%, p = 0.0018). After adjusting for covariates, depression was associated with significantly lower in-hospital mortality (adjusted OR 0.63, 95% CI 0.48–0.83, p = 0.001). While the unadjusted mean length of stay (LOS) was slightly higher in depressed patients (7.66 vs. 7.25 days, p = 0.132), adjusted models showed no significant difference (β = 0.42 days, p = 0.132). Depression was associated with lower unadjusted total hospitalization charges ($92,321 vs. $104,156, p = 0.023), and in adjusted analyses, depressed patients incurred significantly lower costs (β = -$10,327, 95% CI -$19,233 to -$1,421, p = 0.023). Significant predictors of increased hospitalization charges included teaching hospital status (β = $34,029, p < 0.0001) and large hospital size (β = $38,481, p < 0.0001). Conclusions: Depression, while common among patients with esophageal cancer, was unexpectedly associated with lower in-hospital mortality, despite a longer length of stay and higher comorbidity burden. This suggests that depressed patients may receive more comprehensive or prolonged care, which could contribute to their reduced mortality risk. Additionally, despite extended hospital stays, these patients incurred significantly lower hospitalization costs, indicating possible differences in resource utilization or treatment intensity. These findings highlight the complex relationship between mental health and cancer outcomes, emphasizing the need for further research to explore the mechanisms behind these associations and to better tailor care for esophageal cancer patients with depression.

The impact of prediabetes on cerebrovascular risk among patients with gastrointestinal malignancies.

817 Background: Cancer screening ingastrointestinal (GI) malignancies has translated into an improvement in overall survival due to detection at an earlier stage. The majority of survivors (up to 67%) are over the age of 65. The impact of metabolic profiles on cerebrovascular events amongst this population of cancer survivors is unclear. Methods: Data from the NIS database from 2016 to 2020 were reviewed for patients with seven GI malignancies. Analysis was performed based on the presence or absence of prediabetes using ICD-10 codes. Baseline characteristics, comorbidities, and cerebrovascular outcomes were studied in these 2 cohorts. Results: 1,532,250 hospitalizations of patients with seven GI malignancies, namely colorectal cancer (CRC), pancreatic cancer, hepatocellular carcinoma (HCC), gastric cancer, small intestinal cancer, cholangiocarcinoma, and esophageal cancer, were evaluated and divided into two subgroups: prediabetics (15,610) and non-prediabetics (1,516,640). Prediabetics with GI malignancies as compared to non-prediabetics with GI malignancies were noted to be older (67.7 years vs. 65.64 years), with higher total hospitalization charges (USD 87,267 vs. USD 80,173), greater rates of elective admissions (34.92% vs. 25.89%) but a lower length of stay (6.018 days vs. 6.53 days). Prediabetic patients with GI malignancies were noted to have a higher prevalence of obesity (18.64% vs. 7.69%), dyslipidemia (52.99% vs. 26.16%), and hypertension (49.59% vs. 39.37%). Prediabetics with CRC, as compared to non-prediabetics, had higher adjusted odds ratios (aORs) of occlusion/stenosis of precerebral or cerebral arteries not leading to cerebral infarction, and cerebral infarction, with aORs of 2.03 (95% CI 1.24-3.30, p 0.004), and 1.63 (95% CI 1.01-2.63, p 0.045) respectively. Additionally, prediabetics with pancreatic cancer had a higher aOR of cerebral infarction as compared to non-prediabetics, with aOR of 2.42 (95% CI 1.70-3.44, p<0.001). Conclusions: Prediabetic patients with CRC had higher aORs of cerebral infarction and occlusion/stenosis of precerebral arteries not leading up to cerebral infarction, and prediabetics with pancreatic cancer had twice the risk of cerebral infarction as compared to non-prediabetics. This study highlights the impact of prediabetes, a modifiable risk factor, on cerebrovascular outcomes in patients with GI malignancies.

A multicenter, open-label, first-in-human study of TYRA-200 in advanced intrahepatic cholangiocarcinoma and other solid tumors with activating <i>FGFR2</i> gene alterations (SURF201).

TPS646 Background: Approved Fibroblast Growth Factor Receptor (FGFR) inhibitors have demonstrated clinical benefit in locally advanced or metastatic cholangiocarcinoma harboring oncogenic FGFR2 fusions or other rearrangements. However, the emergence of acquired resistance mutations limits the clinical activity and duration of responses to currently available inhibitors. TYRA-200 is an orally bioavailable FGFR1/2/3 inhibitor designed to specifically address these clinically observed acquired resistance alterations in FGFR2. Methods: SURF201 is a single arm, multicenter, open-label, first-in-human, dose escalation and expansion study designed to investigate TYRA-200 in patients (pts) with advanced intrahepatic cholangiocarcinoma and other solid tumors with primary activating FGFR2 gene alterations and on-target acquired known FGFR2 resistance mutations. The study is being conducted in two parts. Part A dose escalation uses an i3+3 design and is evaluating the safety, tolerability, and the pharmacokinetic profile of TYRA-200. Part B dose expansion will further characterize the safety profile and evaluate the preliminary anti-tumor activity of TYRA-200 by RECIST v1.1 in pts with unresectable locally advanced/metastatic intrahepatic cholangiocarcinoma who have previously received an FGFR inhibitor(s) and have developed acquired FGFR2 kinase domain resistance mutations. The study is currently planned for approximately four centers in the US and is actively enrolling (NCT06160752). Clinical trial information: NCT06160752 .

Epigenetic discovery by enzyme activity profiling