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Alterations in gut microbiome in age- and diet-induced colorectal cancer (CRC) progression in a preclinical model.

223 Background: CRC is the third leading cause of cancer related deaths worldwide with age and diet among the strongest risk factors. Emerging evidence suggests gut microbiome plays important role in CRC and is highly impacted by the exposome primarily the food intake. Since diet and age plays an important role in gut microbiome diversity, the present study aimed to investigate the alterations in the gut microbiome in young versus old mice harboring CRC allografts and fed with different diets. Methods: Two cohorts of C57BL/6 including young (n = 9, age = 6 weeks) and old (n = 9, age = 20-24 months) mice were implanted with 1x10 6 MSI (microsatellite instable) CRC MC38 tumor cells. Mice in both cohorts were randomized into three different diet groups: normal diet (ND; standard chow), high-fat (HF) and calorie-restricted (CR: 30% reduction in total calories). Mice were housed individually under standard laboratory conditions. Mice fecal samples were collected and subjected to DNA isolation (ZymoBIOMICS-96 MagBead DNA Kit), followed by metagenomic shotgun and whole genome sequencing (ZymoBIOMICSe and Illumina NovaSeq, respectively). P ≤ 0.05 were considered as statistically significant. Results: Fecal microbiome analysis showed that old microbiome has higher alpha diversity compared to the young mice. No statistically significant differences in were found in microbiome diversities between the diet groups. Pairwise permanova results showed statistically significant differences between microbiomes of old vs. young groups ( P : 0.001), CR vs. HF groups ( P : 0.012) and HF vs. ND groups ( P : 0.021). ANCOM-BC analysis determined the differentiating features and microbial functional pathways in the young mice compared to the old mice group and in different diet groups with relative abundance differences of larger than log 10 2. Bacteroides thetaiotaomicron ( P : 1.43E-39) and Parabacteroides goldsteinii ( P : 2.20E-23) were enriched in young and old groups, respectively. Akkermansia muciniphila ( P : 0.008) was significantly enriched in ND compared to CR group. Lactococcus lactis ( P : 9.94E-160) and Lachnospiraceae bacterium A4 ( P : 4.95E-10) were significantly enriched in HF compared to ND diet groups and vice-versa, respectively. Among the functional pathways, CMP-legionaminate biosynthesis I ( P : 2.38E-13) and L-arginine biosynthesis IV (archaebacteria) ( P : 4.77E-11) were the most significantly enriched in young and old groups, respectively. Conclusions: Our findings highlight the differential diversity and microbial features of gut microbiome in age- and diet-induced CRC progression. Collectively, alteration in diet and age of the host lead to changes in gut microbiota which has a direct impact on activation of specific signaling pathways, metabolism and local and systemic immune responses, which may in turn affect chemosensitivity and outcome in CRC

Cysteine import via the high-affinity GSH transporter Hgt1 rescues GSH auxotrophy in yeast

Landscape of metastatic colorectal cancer (CRC) using comprehensive circulating tumor DNA (ctDNA) next-generation sequencing (NGS) in India: Expanding beyond RAS and RAF.

49 Background: Traditional testing in mCRC primarily focuses on RAS and RAF mutations. However, a broader range of emerging biomarkers, collectively termed the "Pressing panel" (PP), identifies patients with RAS/RAF wild-type (wt) tumors who may particularly benefit from anti-EGFR therapy. Comprehensive liquid biopsies provide a non-invasive method for identifying traditional and emerging biomarkers. Limited genomic data, including the prevalence of PP alterations (alts), is available for mCRC patients in India tested by ctDNA NGS. Methods: We reviewed the results of Guardant360 (Guardant Health, Inc.) ordered for patients with mCRC as part of routine clinical practice in India through July 2024. NGS analyzed plasma samples at a CLIA-certified, CAP-accredited central laboratory. Guardant360 analyzes ctDNA for mutations (mts), insertions and deletions, amplifications (amps), and fusions in up to 83 genes, including PP genes, i.e., KRAS, NRAS, BRAF, ERBB2, PIK3CA, PTEN, AKT1, ALK, ROS1, NTRK, RET, and MSI status. The Indian cohort's prevalence of PP mts was compared to that from other countries in Asia and Middle East (AME). Timing of testing relative to line of therapy was unknown. Results: Among 145 samples from India, ctDNA was detected in 92% (n=134). Median age was 59 years, with women comprising 40%. The median turnaround time from blood collection to result was 7 days. The mean mts count per sample was 5, and the median variant allele frequency was 1.5%. Frequent mts were in APC (53%), KRAS (56%), and SMAD4 (13%), while amps of EGFR (16%) and FGFR1 (9%) were common. Clinically relevant fusions were observed in 3% of patients. KRAS, NRAS, and/or BRAF V600E alterations were found in 63% of both India and AME samples. PP alts were identified in 24% and 27% of Indian and AME patients, respectively. Most frequent PP alts included PIK3CA (15%), PTEN (3%), and MET amp (2%). The prevalence of most of the PP alts was similar between the Indian and AME cohorts (Table), with minor differences observed in PIK3CA (15% vs 18%) and MSI-High (3% vs 1%). In patients with RAS/RAF wild-type lacking EGFR-amp, 9.5% (India) and 18% (AME) harbored at least one PP alt. Conclusions: This study highlights the role of liquid CGP for characterizing the mutational landscape and identifying PP mts for patients from India with advanced CRC. Pressing panel alterations. PP Alteration INDIA % (n=134) AME % (n=720) ERBB2 Amp 1% 2% MET Amp 2% 3% ALK Fusion 0% 0% ROS1 Fusion 0% 0% NTRK1 Fusion 1% 0% RET Fusion 0% 1% ERBB2 Mut 1% 2% PIK3CA Mut 15% 18% PTEN Mut 3% 3% AKT1 Mut 0% 1% MSI-High 3% 1%

Real-world impact of matched targeted therapy on survival in advanced biliary tract cancer: An international collaborative study.

536 Background: The prognosis of advanced BTC remains poor. Although targeted agents have expanded late-line options, many patients (pts) become ineligible for these therapies after progressing on first-line treatment. Herein, we examined the real-world impact of targeted therapy on survival in advanced BTC. Methods: In this international collaborative study between the Mayo Clinic (US) and the National Cancer Center East (Japan), we included pts with advanced BTC with comprehensive tumor molecular profiling who had received at least 30 days of systemic therapy. Pts were categorized into 3 groups: 1) non-actionable, 2) pts with alterations who received matched targeted therapy at any point during their treatment (matched group), and 3) those with mutations who did not receive matched therapy (unmatched group). OS was calculated from the start date of first-line therapy until death and compared among three subgroups using Cox regression models. Results: Of 932 pts, 366 (39.3%) had an actionable alteration, and 135 of these received matched therapy. 566 (61.7%) did not have an actionable alteration (Table). The most common alterations were somatic BRCA1/2 (N=106, 11.4%), HER2 amplification (N=65, 7%), FGFR2 fusion (N=61, 6.5%), KRAS G12C/D (N=46, 4.9%), and IDH1 (N=38, 4.1%). 78.7% of FGFR2 fusions were found in Caucasian pts, whereas BRCA1/2 (97.5%), HER2 (78.5%), and KRAS G12C/D (67.4%) alterations were more prevalent in Asian pts. The median OS was significantly longer in the matched group (21.4 months; 95% CI 18.4-27.9) compared to the unmatched group (14.6 months; 95% CI 12.8-17.6) and the non-actionable group (17.2 months; 95% CI 15.5-19.0). The 36-month OS rate was 33% in the matched group vs. 7% in the unmatched group (p < 0.0001). After adjusting for age, gender, prior surgical resection, primary tumor location, and country of origin, matched targeted therapy remained a strong independent predictor for improved OS (HR 0.61; 95% CI 0.48-0.79). Conclusions: These real-world findings suggest that matched targeted therapies significantly improve survival in advanced BTC, underscoring the need to incorporate them earlier in the treatment course and address barriers to treatment access. The regional prevalence of actionable alterations should also be considered when developing new targeted therapies. Patient baseline characteristics stratified by actionable alterations and targeted therapy. Non-actionable(N=566) Unmatched group(N=231) Matched group(N=135) Site, n (%) Japan 409 (72%) 166 (72%) 50 (37%) US 157 (28%) 65 (28%) 85 (63%) Age at Dx > 65, n (%) 324 (57%) 122 (53%) 54 (40%) Female, n (%) 235 (42%) 92 (40%) 77 (57%) Primary tumor location (category), n (%) Intrahepatic 217 (43%) 115 (55%) 99 (76%) Extrahepatic 150 (30%) 39 (19%) 17 (13%) Gallbladder 142 (28%) 54 (26%) 14 (11%) Prior surgical resection, n (%) 220 (42%) 74 (34%) 48 (37%)

Current status of physicians’ perception of HCC conversion/downstaging therapy: A nationwide survey in China.

585 Background: Conversion or downstaging therapy for intermediate and advanced unresectable hepatocellular carcinoma (HCC) has emerged as a significant exploring area of clinical practice and research in recent years. Nonetheless, there exists considerable variability in both the selection criteria for patients undergoing conversion therapy and the regimens selected for conversion across different regions and medical institutions. The present study aims to elucidate the current clinical application of conversion therapy in China, as well as to identify the considerations that physicians take into account when selecting eligible patients for conversion therapy and determining the appropriate conversion modality. Methods: Physicians meeting predefined inclusion criteria were invited to complete an online questionnaire from January to July, 2024. The collected data were subsequently pooled and analyzed descriptively. Results: A total of 120 valid questionnaires were retrieved, mainly form surgical (69.2%, n=83) and interventional (30.8%, n=37) departments. Generally, the study showed that approximately 51% of stage Ib-IIIa patients will be selected for the treatment goal of conversion or downstaging, and the overall successful rate as meeting criteria for surgical resection after treatment was 36%. Three primary factors were prioritized by physicians for determination of conversion therapy: the type of portal vein tumor thrombus (PVTT) (97%, 116/120), the future liver volume (90%, 108/120), and Child-Pugh classification (90%,108/120). In the specific physician group who selected the following attributes, patients classified as Child-Pugh A (82%, 89/108) or Child-Pugh B7 (66%, 71/108), those with tumor diameter exceeding 5 cm (92%, 98/106) and Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1 (89%, 76/85) were most frequently selected for conversion therapy. Additionally, study showed that patients presenting with Vp1-2 (72%, 83/116) and Vp3 (71%, 82/116) could also be considered for conversion therapy. Currently, the prevalent treatment approach of conversion therapy involves a combination of local and systemic therapies, which is utilized in approximately 73% of cases. Among systemic treatment methodologies, the combination of Lenvatinib and immunotherapy is the most widely adopted by physicians. Besides, higher ORR was the foremost consideration for 83% (99/120) of physicians, followed by rapid response (68%, 82/120), adherence to guidelines and consensus (63%, 76/120), and lower tumor progression rate (58%, 70/120). Conclusions: This study elucidates the current status of conversion therapy for HCC in China. The findings underscore the necessity for optimizing conversion modalities and advancing standardized practices in the application of conversion therapy.

Real-world (RW) experience with atezolizumab + bevacizumab (A+B) for the treatment of unresectable HCC (uHCC): A multicenter study.

537 Background: A+B is the preferred first-line (1L) standard of care for uHCC, with emerging RW evidence supporting its use in a broad patient (pt) cohort. We evaluated pt characteristics, clinical and treatment outcomes in pts treated at five U.S. institutions: Mayo Clinic, Houston Methodist, Moffitt Cancer Center, Mays Cancer Center, and University of Arizona. Methods: This is a retrospective study of uHCC pts who initiated A+B after January 1, 2019. De-identified pt data were extracted by treating oncologists. Overall survival (OS) and real-world progression-free survival (rwPFS) were assessed using Kaplan-Meier methods for all pts and for a “trial-like” subgroup with characteristics similar to those in the IMbrave150 trial (ECOG performance status [PS] 0-1, Child-Pugh [CP] class A, albumin-bilirubin [ALBI] grade 1-2). HCC-related hospitalizations were evaluated within 1 year of A+B initiation. Results: A total of 300 eligible pts were treated with 1L A+B (median age 68 years, 79% male, 79% White, 82% BCLC C, 44% viral etiology,12% ECOG PS >1). Liver function was CP A in 73% (36% A5, 31% A6, 6% not reported), CP B in 26% pts (15% B7, 7% B8, 5% B9), and CP C in 2 (<1%) pts. Compared with CP A, more CP B pts had characteristics of compromised liver function (CP A vs B: cirrhosis: 61% vs 91%; ascites: 7% vs 46%; encephalopathy: 4% vs 17%; esophageal varices: 14% vs 32%), bile duct invasion (2% vs 11%), and ECOG PS>1 (8% vs 22%), all Ps<0.001. Over a median follow-up of 8.7 mos, 244 (81%) pts discontinued A+B, primarily due to disease progression. Toxicity-related treatment discontinuation and hospitalizations due to treatment-related adverse events (TRAE) were similar between the two groups (Table). Median OS (mOS) was 14.4 mos (95% CI: 12.3, 18.2) and median rwPFS was 6.8 mos (95% CI: 5.8, 8.4). In the trial-like subgroup (n=194), mOS was 19.5 mos (95%CI: 14.6, 24.7) and median rwPFS was 8.8 mos (95% CI: 7.6, 12.1). In the CP B subgroup, mOS was 5.6 mos (95% CI: 4.6, 11.3) and median rwPFS was 3.1 mos (95% CI: 2.4, 5.8). Conclusions: This study demonstrates the RW outcomes of 1L A+B in a diverse pt cohort. Results from the “trial-like” pts further confirm the reproducible efficacy of A+B in clinical practice. Although pts with CP-B had higher hospitalization rates due to disease progression or symptoms, consistent with their underlying liver complications, they had similar rates of toxicity-related treatment discontinuation and TRAE-related hospitalizations compared to CP-A. Further characterization of safety for A+B in CP B pts within a prospective, controlled trial is warranted. N (%) CP A (n=219) CP B (n=79) Treatment discontinuation* 167 (76) 75 (95) Atezolizumab-related toxicity 20 (12) 13 (17) Bevacizumab-related toxicity 26 (16) 16 (21) Hospitalization* 87 (40) 58 (73) Symptom-related 42 (48) 35 (60) Progression 8 (9) 11 (19) TRAE 7 (8) 6 (10) *P-value comparing CP A vs CP B <0.001.

New subgenera of Ellipteroides Becker (Tipuloidea: Limoniidae) and their phylogenetic implications

Crucial role and conservation of the three [2Fe-2S] clusters in the human mitochondrial ribosome

Immunotherapy for MSI-H colorectal cancer with isolated peritoneal metastases.

187 Background: NCCN guidelines recommend immunotherapy for MSI-H colon cancer (CC) with isolated peritoneal metastases (iPM); however, limited data support its benefit. This study aimed to evaluate the impact of immunotherapy in this population. Methods: Patients diagnosed with MSI-H CC with iPM from 2016-2019 were selected from the NCDB. Patients who received immunotherapy were compared to those who did not. Overall survival was assessed using Kaplan-Meier analysis and multivariate Cox proportional hazard regression. The trend of immunotherapy utilization from 2016-2020 was analyzed using the Cochran-Armitage test. Results: We analyzed a cohort of 444 patients, with 161 (36%) receiving immunotherapy. Patients in the immunotherapy group were, on average, younger (63 vs. 71 years; P<0.001), with balanced gender distribution between groups. Among those who received immunotherapy, 70% were treated as a first-line agent, and 30% after chemotherapy. Immunotherapy was more commonly administered in the adjuvant setting (66%) compared to neoadjuvant (7%) or without surgery (27%). Immunotherapy was associated with significantly longer median survival (33.6 vs. 14.9 months; P<0.001). In multivariate analysis, immunotherapy was associated with improved overall survival, whether given as a first-line agent (HR 0.54, 95% CI 0.39-0.74; P<0.001) or second-line after chemotherapy (HR 0.59, 95% CI 0.37-0.94; P=0.03). Additionally, primary tumor resection (HR 0.44, 95% CI 0.32-0.60; P<0.001), but not metastatectomy (HR 0.96, 95% CI 0.71-1.29; P=0.8), was associated with prolonged survival. Patients who received both immunotherapy and primary tumor resection (n=118) had a median survival of 43.8 months. From 2016 to 2020, the utilization of immunotherapy in this cohort increased from 29% to 37% (χ^2=0.23, P=0.63). Conclusions: Utilization of immunotherapy remains low in MSI-H CRC with iPM and did not change significantly during the study period. Immunotherapy is associated with improved overall survival and should be considered for appropriate candidates. The combination of primary tumor resection and immunotherapy yielded the best overall survival.

Genomic analysis of paired primary and metastatic pancreatic ductal adenocarcinoma tumors.

758 Background: The genomics of pancreatic ductal adenocarcinoma (PDAC) have been increasingly understood allowing for improvements in treatment, yet the clinical relevance of PDAC evolution is less well studied. The aim of this study is to evaluate genomic differences and clinical correlations between primary pancreatic tumors and paired metastases using a targeted sequencing panel. Methods: Patients who underwent surgical resection for PDAC with recurrent disease who had targeted genomic sequencing of both the primary tumor and a metastasis were included. Genomic alterations were determined using a panel of cancer-related genes (MSK-IMPACT). OncoKB was used to annotate driver alterations. MATH scores were used to quantify intratumoral heterogeneity. Comparison between paired samples was performed and association with clinical variables was assessed. Results: There were 55 patients included; 20% (n=11) received neoadjuvant therapy, 91% (n=50) had adjuvant therapy and 36% (n=20) had adjuvant radiation. The most common sites of metastasis sequenced were lung (36%, n=20), liver (35%, n=19) and local (13%, n=7). There was concordance between the first site of recurrence and site sequenced in 93% (n=51) of cases with a median time between resection and biopsy of recurrence of 25 months. The most commonly altered genes are KRAS (96%), TP53 (83%), CDKN2A (40%), SMAD4 (25%) and RNF43 (13%). The majority of alterations are shared between the primary tumor and metastasis. Clonal mutations were defined as cancer cell fraction (CCF) >0.8. The majority of shared mutations are clonal; 52% of mutations are clonal in both the primary and metastasis, and clonality is preserved in 76% of shared mutations in metastases. The most commonly shared alterations are in driver genes and the majority are clonal- TP53 (80%), KRAS (78%), CDKN2A (77%) and SMAD4 (64%). The proportion of clonal mutations among drivers is higher than variants of unknown significance (p=0.005). There are 31 mutations private to the metastasis in 19 patients, 12 of which are clonal (39%). Mutations private to the metastasis are more common in patients who received adjuvant systemic therapy (p=0.035); however this was not seen when comparing patients who received adjuvant radiation to those who did not (p=0.38). MATH scores are higher in the metastasis as compared to the primary in all patients (p=0.0096), including those who received adjuvant treatment (p=0.002), indicating increased intratumoral heterogeneity in metastases. Conclusions: A targeted sequencing panel demonstrates that the majority of driver mutations are clonal and preserved between the primary tumor and metastasis. Additional private mutations and increased intratumoral heterogeneity are noted in metastasis, and our data suggests that this may be associated with exposure to systemic therapy.

Diverse stromal phenotypes at spatial resolution in colorectal cancer peritoneal metastasis.

218 Background: Peritoneal metastases (PM) in colorectal cancer (CRC) portend a poor prognosis. We sought to elucidate spatially resolved molecular features facilitating transcoelomic dissemination and progression. Methods: 50 PT, 116 PM and 37 primary normal samples from 96 patients were retrieved and profiled with digital spatial profiling (GeoMx DSP, Nanostring Technologies). Through unsupervised clustering, we characterized the microenvironment of tumor-stroma compartments and studied the roles of stromal phenotypes in promulgating tumorigenesis. These findings were orthogonally validated through spatial proteomics (multiplex IHC [mIHC] - COMET, Lunaphore Technologies) of 10 paired PT-PM samples retrieved from 6 patients. Results: A median of 37 region of interests (ROIs) (IQR: 32-38) were selected from a total of 9 tissue microarray (TMA) slides. A total of 269 ROIs (181 tumor, 88 stroma) from PM samples, 45 ROIs (34 tumor, 11 stroma) from PT samples and 28 (all stroma) ROIs from primary normal samples were retrieved and profiled. Through consensus clustering of stroma ROIs, we identify a fibro-collagenous and immune infiltrated stromal phenotype (stromal cluster [SC] 2) characterized by increased cancer associated fibroblasts (CAFs), memory B cells, M2 macrophages and T-cell exhaustion. Patients with SC2 stroma had poorer survival (p=0.036). SC2 stroma was also observed to support adjacent tumor compartments with enriched oncogenic pathways such as TGF-beta, TNF-alpha, hypoxia and JAK-STAT. Through discriminatory gene expression profiles, we developed a 20-gene composite bidirectional signature of SC2. The prognostic significance of the SC2-signature was externally validated through several cohorts including TCGA and MSI-H only cohorts. Next, by inspecting mIHC retrieved immune cell type densities across ROIs, we confirmed a similar phenomenon in which two distinct stromal clusters were found – one being fibroblast infiltrated but T-cell depleted (SC2-like, n=67 ROI) and another which is T-cell infiltrated but fibroblast depleted (SC1-like, n=104 ROI). Diverging spatial distributions of T-cells and fibroblasts between SC1 and SC2-like stroma was appreciated as well. Between both PT and PM, we find close clustering of T cells in SC1-like stromal compartments and fibroblasts in SC2-like stromal compartments. Conclusions: We describe SC2, a pro-tumorigenic stromal phenotype characterized by increased CAFs, T cell exhaustion and is associated with poor prognosis in CRC PM.

A single arm phase II trial of trastuzumab deruxtecan in patients with gastrooesophageal adenocarcinoma cancer who are ctDNA and HER2 positive: DECIPHER.

TPS512 Background: Oesophagogastric adenocarcinoma (OGA) is globally prevalent and frequently advanced at presentation. Less than 50% of patients with operable OGA are cured when treated with multimodality therapy. Patients in the UK with operable OGA, are treated with FLOT prior to and following surgery. However, patients who have circulating tumour DNA (ctDNA) in their blood after surgery have worse survival than ctDNA negative patients. Therefore, use of novel treatment approaches aiming to cure this micrometastatic disease are considered a rational and appropriate treatment approach. Trastuzumab deruxtecan (T-DXd), a novel HER2-targeting antibody drug conjugate, is licensed to treat advanced, previously treated HER2 positive OGA. Therefore, there is a need to evaluate T-DXd in resectable HER2 and ctDNA positive OGA, where options are limited. Methods: Co-ordinated by the Cancer Research UK Southampton Clinical Trials Unit, DECIPHER is a single arm, multicentre, phase II trial testing the effect of T-DXd on reducing micrometastatic disease burden in HER2 positive OGA patients who are ctDNA positive after chemotherapy and surgery. To be eligible, participants must have been treated with chemotherapy before surgery for at least 6 weeks and must have recovered from surgery with no evidence of metastatic disease on post-surgical imaging. HER2 positive patients are recruited to the tissue testing stage of the trial prior to surgery. Patients who are ctDNA positive after surgery will be treated with T-DXd at a dose of 6.4 mg/kg intravenously every 21 days for a maximum of 8 cycles or until disease recurrence. If required, patients may dose reduce, but no dose re-escalation will be permitted. A clinically validated, personalised, tumour-informed ctDNA assay (signatera, Natera, Inc.) will be utilised to detect ctDNA in patient plasma samples. The primary endpoint is the percentage of patients who are ctDNA negative after 4 cycles of treatment. Secondary endpoints include ctDNA clearance after each cycle, disease free survival, overall survival, quality of life and frequency of adverse events. DECIPHER (NCT05965479) opened in April 2024 and will run in approximately 15 UK secondary care hospitals with the aim of recruiting 25 evaluable patients (recruitment to the tissue testing stage is currently 27 on 23-Sep-2024). Clinical trial information: NCT05965479 .

Exploring the thermal-induced optical nonlinearity of crude oil via spatial self-phase modulation technique

Inositol phosphates dynamically enhance stability, solubility, and catalytic activity of mTOR

A randomized phase 2 study of an individualized neoantigen-targeting immunotherapy in patients with newly diagnosed metastatic microsatellite stable colorectal cancer (MSS-CRC).

LBA13 Background: Neoantigen-targeting immunotherapy aims to provide therapeutic benefit to patients by generating potent neoantigen-specific T cells. GRANITE is an immunotherapy regimen that uses chimpanzee adenovirus and self-amplifying mRNA vaccines encoding patient-specific neoantigens in combination with immune checkpoint inhibitors. Preliminary efficacy was noted in MSS-CRC (Palmer et al Nature Medicine 2022) and this regimen is being assessed in a randomized Phase 2 study in 1L metastatic MSS-CRC (NCT05141721). Methods: Patients (pts) with 20 neoantigens based on the EDGEÔ prediction model were randomized 1:1 to receive the GRANITE regimen in addition to 1L standard of care (SOC) (GRANITE vaccine arm), or 1L SOC alone (control arm). Results: Baseline demographics and disease characteristics were balanced between arms. As of 15 Oct 2024, GRANITE pts had an improvement in PFS relative to control pts (HR=0.73, 90% CI [0.44, 1.21]). In this study, high and low disease burden groups were identified using baseline ctDNA assessed by Gritstone’s validated, highly sensitive, tumor-informed assay. Patients with low disease burden benefited more than those with high disease burden, consistent with emerging data suggesting neoantigen-targeting immunotherapy having greater activity in minimal disease settings (e.g., adjuvant setting). Furthermore, in the low disease burden group at the most recent study visit, more patients were free of progression with very low ctDNA levels (ie, below the limit of quantification of the assay) in the GRANITE arm, 41% (7/17), versus the control arm, 21% (3/14). The greater proportion of GRANITE patients both free of progression and with very low ctDNA, suggests potential further separation of PFS cuves with additional follow up. Neoantigen-specific T cell responses were observed in 100% of patients in the GRANITE arm with evaluable PBMC samples (17/17 assessed by ex vivo and in vitro stimulation ELISpots). Molecular responses based on a reduction in ctDNA at a single timepoint was similar between arms (39% in GRANITE and 40% in control arms). Most common (≥20%) treatment-related adverse events (TRAE) included pyrexia and influenza like illness and no pts discontinued due to a TRAE. Conclusion: This randomized study shows GRANITE may benefit patients, especially those with low burden disease, in this front line setting of metastatic MSS-CRC that has not benefitted from immunotherapy. Updated analysis will be presented. Clinical trial information: NCT05141721 .

Safety and biomarker assessment of ST316, a novel peptide antagonist of ß-catenin, in patients with advanced solid tumors.

286 Background: Constitutive activation of ß-catenin, resulting in its nuclear accumulation and deregulated transcriptional activity, is a key event in colorectal cancer (CRC). Additionally, pathway mutations correlate with immune exclusion in CRC and across different tumor types. Disruption of the interaction of ß-catenin and its co-activator BCL9 is sufficient to suppress oncogenic ß-catenin transcriptional activity, without impacting its homeostatic functions in normal tissue. ST316 is a first-in-class, cell-penetrating peptide antagonist of the ß-catenin and BCL9 interaction. Preclinical evaluation revealed significant bioavailability and potent activity in CRC models with no impact on ß-catenin homeostatic functions such as intestinal stem cell survival or bone morphology. Methods: A phase 1-2 (P1-2) escalation-expansion study has enrolled patients (pts) with advanced solid tumors likely to harbor abnormalities in the Wnt/ß-catenin pathway, to assess the safety, pharmacokinetics (PK), biomarker and preliminary activity of ST316, and to recommend a P2 dose (RP2D). Paired biopsies were collected when feasible and assessed for drug penetration and pharmacodynamic biomarkers. Peripheral blood (PB) collected pre- and post-treatment was assessed by flow cytometry for polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Results: As of Sep.24, 2024; 23 pts with CRC (N=14), NSCLC (N=4), PDAC (N=2), or Breast and Ovarian cancer (N=1, each), were treated in 6 cohorts (0.5-12mg/kg) with IV ST316, once weekly. Treatment related AEs were observed in 17/23 pts and were mostly low grade, except for 2 G3 AEs that resolved: Fatigue (1) and ALT/AST elevation (1). No dose-limiting toxicities (DLTs) were observed. Single agent ST316 showed disease stabilization in 4 pts. PK analysis showed dose-proportional increases in Cmax and AUC for doses up to 8 mg/kg. IHC analysis showed substantial tumor penetration of ST316 in all analyzed samples and evidence of a treatment-induced redistribution of β-catenin in a subset of pts. PB analysis indicated high baseline levels of the ß-catenin-driven immunosuppressive PMN-MDSCs , followed by a significant decrease after ST316 exposure (p<0.005). The RP2D selected for combination cohorts in CRC is 8mg/kg; additional PD assessments are ongoing. Conclusions: Monotherapy ST316 was well-tolerated with dose-proportional PK and substantial tumor uptake. Pharmacodynamic analyses demonstrate mechanistic evidence of antagonism of ß-catenin signaling, including redistribution of ß-catenin subcellular localization and significant depletion of the ß-catenin-driven immunosuppressive PMN-MDSC population. Based on these data, ST316 advanced into P2 in CRC pts in combination with SoC in 2 nd and 3 rd line. Clinical trial information: NCT05848739 .

Investigating communication barriers impacting postoperative decision regret in patients with pancreatic ductal adenocarcinoma.

698 Background: Patient communication barriers are associated with worse quality of care and clinical outcomes. However there are limited data exploring their impact on shared decision-making (SDM) in the preoperative setting, especially for pancreatic ductal adenocarcinoma (PDAC). This study investigates the impact of patient communication barriers on patient-physician communication surrounding the decision to pursue pancreatectomy. Methods: This cross-sectional study investigates the impact of communication barriers on the degree of decisional regret (DR) in patients with PDAC who have undergone curative-intent resection at least 6 months prior to study recruitment. Patients completed validated surveys assessing communication preferences, SDM participation, and DR. Health literacy was assessed by the BRIEF Health Literacy survey. Groups were stratified by presence or absence of DR, assessed by the Decisional Regret Scale (DRS). Characteristics and survey scores were compared by chi-square and independent t-test. 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 surgery with 5 patients expressing moderate to severe regret (DRS ≥25). Baseline characteristics were similar between groups. There were no significant differences in neoadjuvant or adjuvant treatments, or operative characteristics. Both groups reported high participation in preoperative SDM (average score 34.47 ± 9.67 in DR group vs 36.08 ± 8.88, P=0.567). Despite similar levels of education between groups, those expressing regret had a lower level of health literacy (14.68 ± 4.10 vs 17.35 ± 2.07, P=0.016). Fewer patients also identified English as their primary language in the DR group (78.9% vs 100%, P=0.026). While most patients preferred an active role in the final decision making process, fewer patients in the DR group reported this happening in actuality (ƙ= 0.635 vs ƙ=0.934). Conclusions: Almost half of patients expressed some regret pursuing surgery for PDAC. Despite similar educational backgrounds, a higher proportion of those expressing regret did not identify English as their primary language and had lower health literacy. While there was high participation in SDM, there was greater discordance between preferred and actual roles in the final decision making process. This identifies an important disparity to address in future preoperative discussions.

Pembrolizumab and stereotactic radiotherapy combined in subjects with advanced HCC: A phase II study (PEMRAD).

602 Background: Combination approaches of immune-checkpoint inhibitors and locoregional therapies have an increasing role in advanced HCC. Methods: The PEMRAD phase II trial investigated the efficacy of combination pembrolizumab and stereotactic body radiation (SBRT) following progression on sorafenib. Patients with advanced HCC, ECOG 0-1 and Childs-Pugh A were eligible. Patients received pembrolizumab on day 1 followed by SBRT starting Day 2 and delivered in five fractions. Pembrolizumab was continued every 21 days until progression, unacceptable toxicity or patient withdrawal. The primary endpoint was objective response rate (ORR) as measured by RECISTv 1.1. hypothesizing an increase to 40% with the combination. Tissue and liquid biopsies were collected for correlative analyses including multiplex IHC, longitudinal CyTOF and dynamic cytokine changes. Results: The trial was stopped early due to a shift in the treatment landscape. Between March 2018 and March 2023 18 patients of a planned 22 patients were enrolled and treated with combination therapy. Of these 10 (55%) had evidence of macrovascular invasion (MVI) and 15 (83%) had extrahepatic disease; viral hepatitis was the underlying etiology in 50%. The ORR was 41% meeting the proposed endpoint. Median number of cycles of pembrolizumab was 7.5 (2-35) .The median number of lesions treated by SBRT was 3 (1-5) and the median dominant gross tumour volume was 184 cc (IQR 69-285). The median PFS was 5.4 (2.8-9.9) months and median OS 12.6 (5.7-25.8) months. Of the 10 patients with macrovascular invasion 5 (50%) had evidence of a vascular thrombus response by RECIST criteria including 1 complete response. Treatment related adverse events ≥ grade 3 were reported in 5 patients (28%). One death due to myocarditis was attributed to treatment. Conclusions: In a poor prognostic group of patients in the second line setting, the combination of SBRT and pembrolizumab demonstrated high ORR and may have a specific role in patients with MVI. Correlative analyses will be presented at the meeting. Clinical trial information: NCT03316872 .

Research on maximum power point tracking of photovoltaic power generation based on improved hybrid optimization algorithm

The cobalamin processing enzyme of Trichoplax adhaerens