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AGITG SPAR: A randomized, placebo-controlled, phase II trial of simvastatin in addition to neoadjuvant chemotherapy and radiation for rectal cancer.

141 Background: Retrospective clinical studies and preclinical studies demonstrated that statin use during preoperative (chemo)radiation (pCRT) for rectal cancer is associated with improved survival, response, and toxicity. Tumor regression following pCRT has strong prognostic significance and can be assessed using MRI-based tumor regression grading (mrTRG), including with non-operative management. SPAR was designed to prospectively evaluate the benefits of adding simvastatin (SIM) to pCRT on tumor regression and gastrointestinal (GI) adverse events (AE). Methods: SPAR is a double-blind randomized phase 2 trial investigating SIM/placebo (PBO) in addition to long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma. Stratification included trial site, clinical T stage (<4 vs 4), clinical N stage (<2 vs 2), either mesorectal fascia involvement (MRFI) or extramural venous invasion (EMVI) on MRI (yes vs no), and total neoadjuvant therapy (TNT): induction vs consolidation chemotherapy vs none. Study treatment was SIM 40mg/PBO daily for 90 days, starting 1 week prior to pCRT; recent statin use was excluded. Pelvic MRI was repeated 6-8 weeks after pCRT to determine mrTRG. An amendment in January 2022 allowed TNT with either induction or consolidation chemotherapy; the timing of post-pCRT MRI remained unchanged. The design was amended to open-label due to PBO supply issues. Primary objective: rate of centrally assessed grade 1-2 mrTRG. Secondary objectives include centrally assessed favorable pathologic TRG (pathTRG), safety and cancer outcomes. Analysis was by intention-to-treat. Results: Between April 2018 - November 2023, 135 of 222 planned participants from 17 sites in Australia and New Zealand were randomized (68 SIM; 67 no SIM). Recruitment was hampered by the COVID-19 pandemic and adoption of TNT as standard care before the protocol amendment. Participant characteristics: median age 59 years; 85 (63%) males; 118 (87%) T2-3 disease, 80 (59%) N0-1 disease; 55 (41%) MRFI or EMVI; 25 (19%) had TNT. Rates of grades 1-2 mrTRG with SIM vs no SIM were 38.5% and 29.7% (X 2 = 1.09, p = 0.30), respectively. There was no significant difference in rates of > grade 2 GI and non-GI AE. Four serious AE were recorded, none related to study treatment. Median follow-up was 3.2 years. 3-year local recurrence rates (LRR) were low: 1 (2.2%) and 3 (5.5%) with SIM vs no SIM, respectively (HR: 0.29, 95% CI: 0.03 to 2.67, p = 0.26). 3-year disease-free survival (DFS) with SIM vs no SIM was 84% and 72%, respectively (HR 0.48; 95% CI: 0.21–1.08, p = 0.07). Conclusions: The rates of favorable mrTRG, 3-year LRR and DFS were numerically better with the addition of SIM to pCRT, though the differences were not statistically significant. SIM was well tolerated. Interpretation is limited by reduced sample size and statistical power. PathTRG and other key outcomes will be presented at the meeting. Clinical trial information: ACTRN12617001087347 .

Effects of the delay of surgery in localized rectal cancer.

63 Background: The treatment landscape for localized rectal cancer has evolved significantly in recent years, with long-course neoadjuvant chemoradiation (CRT) and total neoadjuvant therapy (TNT) emerging as the primary options. However, the optimal timing of surgery remains an important clinical question, particularly in resource-limited settings where surgical delays can occur. Data from previous studies have shown conflicting results. This retrospective study aimed to assess the impact of delaying surgery beyond the longer interval used in previous studies, focusing on its effects on Pathologic Complete Response (pCR), DFS, and OS. Methods: We conducted a retrospective cohort study using electronic medical records from three centers in Brazil between the years 2013-2024. The study included 236 patients with localized rectal cancer treated with neoadjuvant CRT and/or chemotherapy. Patients were divided into two pre-specified groups based on the interval between the end of neoadjuvant therapy and surgery: ≤11 weeks and >11 weeks. The primary endpoint was DFS. Secondary endpoints were pCR rates, and OS. Descriptive statistics were used for population analysis, while the Kaplan-Meier method estimated DFS and OS, with comparisons made using the log-rank test. A Cox proportional-hazards model was used to estimate hazard ratios and 95% confidence intervals. Results: The median age of the study population was 62 years, with males comprising 56.4% of the sample. The majority of the sample consisted of stage III patients, making up 72.2%, followed by stage II patients at 25.8%, and stage I patients at 1.9%. Most patients (77.8%) had surgery more than 11 weeks after completing neoadjuvant therapy, with a median time to surgery of 16 weeks. The pCR rates did not significantly differ between the two groups (29% for ≤11 weeks vs. 21.5% for >11 weeks; p = 0.271). After a median follow-up of 30 months, the median DFS was not reached, and there was no significant difference between the groups (HR: 0.86; 95% CI: 0.48-1.5; p = 0.63). Similarly, the median OS was not reached, and no difference was observed between the groups (HR: 0.85; 95% CI: 0.47-1.54; p = 0.88). Conclusions: Delaying surgery beyond 11 weeks did not result in greater tumor downstaging in patients with localized rectal cancer. Furthermore, DFS and OS were not significantly impacted by extended intervals between neoadjuvant therapy and surgery.

Proteomic profiling identifies muscle-invasive bladder cancers with distinct biology and responses to platinum-based chemotherapy

Outcomes in management of locally advanced rectal cancer with total neoadjuvant therapy in an underserved population.

208 Background: The use of total neoadjuvant therapy is now standard of care and is favored when treating locally advanced rectal cancer but its treatment is seldom studied in an underserved population. Methods: A retrospective study was conducted on patients with Stage II and III locally advanced colorectal cancer treated with either total neoadjuvant therapy (TNT) followed by resection or conventional therapy (CT) with chemoradiation followed by surgery, with or without adjuvant treatment afterwards. Patients completed treatment between 2015 and 2023 at the Hartford Hospital Helen and Harry Gray Cancer Center at Hartford, Connecticut. Data collected included demographics, type of treatment, tumor location (high vs mid vs low) and pathological response to treatment spread out among the two groups. Propensity score matching was used to minimize baseline differences between the two groups, adjusted for age, gender, ethnicity and tumor location and Fisher’s exact test was performed to then check for significance. Results: Out of the 133 patients analyzed, 90 underwent TNT, and 43 received CT. The average age at diagnosis was 57.5 years (SD: 11.15). In the TNT group, 79 patients (87.7%) achieved either a partial or complete response (PCR), while 11 patients (12.3%) had No response (NR). Tumor locations in the TNT group were distributed as follows: 13.4% (n=12) had high tumors, 34.4% (n=31) had mid tumors, and 52.2% (n=47) had low tumors. In the CT group, 31 patients (72.9%) achieved PCR, while 12 patients (27.9%) had NR. Tumor locations in the CT group were distributed as follows: 9.3% (n=4) had high tumors, 51.2% (n=22) had mid tumors, and 39.5% (n=17) had low tumors. After propensity score matching and adjusting for demographic covariates, the TNT group demonstrated a higher proportion of responders compared to the CT group (p=0.048). Furthermore, 40% (n=36) of patients in the TNT group achieved a complete response, compared to 32% (n=14) in the CT group. Partial response rates were 39.5% (n=17) in the TNT group and 47.8% (n=43) in the CT group. Conclusions: TNT demonstrated superior pathological response rates compared to CT, which supports its growing role in the management of locally advanced rectal cancer even in this underserved population.

Young onset gastrointestinal cancer: A needs analysis.

383 Background: The global incidence of Young Onset ( YO) cancers diagnosed in adults under 50 years, is increasing for unknown reasons. YO Gastrointestinal (GI) cancers, which account for approximately 27% of newly diagnosed cancer cases and 37% of cancer deaths present distinct challenges in areas including sexual health, finance, career and family. We assessed the holistic needs of these patients through a mixed methods approach. Methods: A single institution needs analysis study was undertaken in YO GI patients diagnosed 2014-2024 through an anonymous survey and Focus Group Discussions (FGD). The surveys asked about their experiences of sexual health and function, psychosocial concerns, financial concerns, career developments and when in their cancer journey would they prefer to speak to a health care professional about these. FGD's used nominal group technique to deepen the analysis. Results: 88 participants responded via survey and 10 participated in a FGD. The average age at diagnosis was 43 years. 80% of participants reported they would have benefitted from a conversation about fertility, sexual health/function (82%) and financial supports (98%) at diagnosis. 93% of patients were out of work during cancer treatment with average length of time > 1 year. Conclusions: This needs analysis highlights the importance of specialised clinical pathways for young onset GI cancer patients focusing on these unique and complex needs. Financial supports, conversations regarding sexual health/function, fertility preservation and psychosocial support are critical areas requiring structured intervention. 2014-2024 young onset SJH. UGI ( N=233) Colorectal (N=275) Clinical Stage at diagnosis Oeso Stage 4 = 39% Gastric stage 4 = 26% Stage 3= 46% Stage 4 = 20% Treatment intent % Radical =54% Palliative =38% Radical/Palliative = 8% Radical =75% Palliative 25% Mortality rate 66% 25% GI Survey results ( N=236) Support offered Y/N Preferred timing of support Sexual health/ function No=85% Yes =15% 82% At diagnosis Financial support No=95%Yes= 5% 98% At diagnosis Fertility preservation No = 65% Yes=35% 80% At diagnosis

Impact of race on end-of-life care among patients with esophageal cancer.

337 Background: Esophageal cancer is an aggressive malignancy with rising incidence globally. Patients with advanced esophageal cancer suffer from a heavy burden of a wide array of symptoms including dysphagia and cachexia/anorexia, necessitating the need for focused symptom management and palliative care. Studies focused on other cancer types have shown that Black patients are more likely to receive aggressive care at end-of-life (EOL) and suffer from a decline in quality of life. We sought to investigate racial differences in EOL care among patients with advanced esophageal cancer in the US. Methods: The National Inpatient Sample (NIS) was queried to identify all hospitalizations with esophageal cancer utilizing ICD-10 codes C15x from 2016 to 2020. Hospitalizations of White and Black patients with documented inpatient mortality events were then extracted. Demographic and clinical data were analyzed using chi squared tests, independent sample t-tests, and binary logistic regression (adjusted for age, gender, and Charlson comorbidity index or CCI). Adjusted Odds ratios (aOR) are presented with 95% Confidence intervals (CI). Results: A total of 15,130 patients with esophageal cancer were included, of which 13,345 (88.2%) were White and 1785 (11.8%) were Black. Hospitalizations with White patients recorded higher age, more males, and higher comorbidities per CCI. Hospitalizations with Black patients had longer lengths of stay on average, higher total hospital charges, and significantly less likely to have a Do Not Resuscitate (DNR) code status (aOR 0.81, 0.74-0.9 95% CI). Rates of inpatient palliative care consultation at EOL were significantly lower among Black patients (aOR=0.53, 0.48-0.58 95% CI). Black patients were more likely to receive aggressive intervention at EOL demonstrated by rates of blood transfusion (aOR 1.9, 1.6-2.1 95% CI), mechanical ventilation (aOR 1.7, 1.5-1.8 95% CI), and vasopressor usage (aOR 1.4, 1.2-1.6 95% CI). Conclusions: We present a large retrospective analysis demonstrating significant racial disparities in EOL care amongst hospitalized patients with esophageal cancer. Black patients had longer lengths of stay, lower rates of palliative care consultation and DNR code status, and higher rates of aggressive interventions at EOL. These findings may have implications for improving health care decision making for EOL care amongst minority patients with esophageal cancer. WhiteN=13345 BlackN=1785 p-value Age (in years) 68.24±10.67 65.12±10.36 <.001 CCI 9.4±3.3 8.6±3.9 <.001 Mean length of stay (days) 7.5±11.3 10.4±22.8 <.001 Total Cost (In thousands of dollars) 108.6±231.0 141.9±388.5 <.001 Palliative Adjusted OR 60.9% 45.1% .53 (.48 - .58) <.001 DNR Adjusted OR 63.8% 58.0% .81 (.74 - .90) <.001 Blood transfusion Adjusted OR 13.0% 23.0% 1.9 (1.6-2.1) <.001 Mechanical ventilation Adjusted OR 31.4% 45.9% 1.7 (1.5-1.8) <.001 Vasopressor Adjusted OR 7.8% 10.6% 1.4 (1.2-1.6) <.001

The role of viral interaction in household transmission of symptomatic influenza and respiratory syncytial virus

Hepatotoxicity following external radiotherapy in patients with hepatocellular carcinoma treated with or without prior yttrium-90 radioembolization.

564 Background: A variety of local therapy options exist to treat Hepatocellular Carcinoma (HCC) including external radiotherapy (EBRT). Prior yttrium-90 (Y90) delivered transarterially is often a contraindication to EBRT in clinical trials and guidelines due to concerns of cumulative hepatotoxicity, though clinical data to suggest higher rates of hepatotoxicity is limited. This study examines hepatotoxicity profiles after EBRT with and without prior Y90 treatment using the ALBI grading system. Methods: Patients treated for HCC with EBRT from 2016 to 2024 with sufficient laboratory follow-up were retrospectively reviewed. Patients were classified into three ALBI grades based on ALBI scores: 1 (< -2.6), 2 (-2.6 < x < -1.39), and 3 (> -1.39). The total EBRT dose was defined using the EQD2 method (α/β = 10). The ALBI scores at 3- and 6-months post-EBRT were compared to baseline for patients with or without prior Y90 using paired t-tests. The main RT planning goal was ≥700 cc liver- (tumor volume+ Y90 volume) receiving ≤15 Gy. Results: 62 patients were treated with EBRT with (n=14) or without (n=48) prior Y90. At 6-months post-EBRT, 11 patients with prior Y90 and 39 patients without prior Y90 had appropriate laboratory follow-up. EBRT dose, technique, and baseline liver function are outlined in Table 1. The median time from Y90 to EBRT was 12.3 months (range 4-61 months). In patients with prior Y90, ALBI scores were similar at 3-mo (mean = -2.4 SD = 0.8, vs mean= -2.4 SD = 0.7, p= 0.60) and 6-mo (mean= -2.3 SD= 0.9, vs mean = -2.4 SD = 0.6, p= 0.653) post-EBRT compared to baseline, respectively. In patients without Y90, ALBI scores were clinically similar at 3-mo (mean = -2.2 SD = 0.7, vs mean= -2.3 SD = 0.6, p= 0.15) and 6-mo (mean= -2.1 SD= 0.8, vs mean = -2.3 SD = 0.7, p=0.021) post-EBRT compared to baseline, respectively. The proportion of patients with an increase in ALBI grade at 3- and 6-mo post-EBRT was similar regardless of prior Y90 treatment. In patients treated with Y90, 14.3% and 36.4% had an increase in ALBI grade at 3- and 6-months, respectively. In those treated without prior Y90, 21.3% and 35.9% had an increase in ALBI grade at 3- and 6-months, respectively. Conclusions: Patients with HCC treated with EBRT after Y90 appear to have a similar rate of hepatotoxicity defined by the ALBI grading system compared to patients treated without prior Y90. In well-selected patients, prior Y90 should not be an absolute contraindication for EBRT. Demographics and ALBI changes post-EBRT. EBRT alone (n = 48) EBRT after Y90 (n = 14) Median Age Years (range) 67.6 (17.9-84.3) 65.6 (55.1-85.2) Proton, IMRT/SBRT 22 (46%), 26 (54%) 9 (64%), 5 (36%) Baseline Child Pugh Score (A, B, C) 34 (70.8%), 10 (20.8%), 4 (8.4%) 11 (78.6%), 3 (21.4%), 0 (0%) Median EBRT EQD2 (range) 82 Gy (44-99) 82 Gy (67-86) Baseline ALBI Grade (1, 2, 3) 23 (47.9%), 20 (41.7%), 5 (10.4%) 6 (42.9%), 7 (50%), 1 (7.1%)

Real-world insights into immune-related adverse events (irAE) in gastrointestinal (GI) malignancies.

545 Background: This retrospective review aimed to examine the incidence and baseline characteristics (BLC) that irAE risk in patients with gastrointestinal (GI) cancers undergoing immune checkpoint inhibitor (ICI) therapy at our institution. Methods: GI cancer patients who received at least one dose ICI-only between 1/1/2017 and 7/31/2021 at the Ohio State University were included in the study. The BLC including hematological and chemistry labs were extracted with immune-related adverse events (irAE) details. Statistical analyses included descriptive statistics, chi-square test, logistic regression, and matched pairs t-tests were performed. Results: Our analysis included 198 patients (14 anal (Al), 65 hepatobiliary (HPB), 46 lower (LGI) and 74 upper (UGI)) with irAEs reported in 37 patients (19%). Median age of irAE-group was 67 years (range: 26 to 88) with 54% males and 86% Caucasians. Most of them (n=36) in had single agent ICI. Pneumonitis was most frequently (n=7) noted followed by dermatitis (n=), colitis (n=5), hypophysitis (n=5), and hepatitis (n=4). Relatively rare ones were hypothyroidism (n=3), nephritis (n=2), encephalitis (n=2), diabetes mellitus (n=1), neutropenia (n=1), and myasthenia gravis (n=1). In irAE-group, 18 (49%) required hospitalization (≥ grade 3) and 5 (14%) had irAE-related deaths. Complete recovery from irAEs was reported in 20 patients (54%), with 13 patients (35%) restarting ICI therapy. The irAE incidence in HPB group was significantly higher than other GI malignancies (HPB vs. LGI vs. Al vs. UGI = 46% vs. 24% vs. 16% vs. 14%, p=0.004). History of asthma (41% vs. 16% (p=0.004) and female gender (26% vs. 15%, p=0.04) increased irAE-risk; presence of liver (9 % 22%, p=0.04) and > 3 lung (8 vs. 21%, p=0.04) metastasis reduced the risk. Compared to non-irAE group, the irAE-group had significantly lower baseline (mean) whole blood cell count (WBC: 6.3 vs. 7.6 K/uL, p=0.02), neutrophil count (NC: 4.2 vs. 6.8 K/uL, p=0.04), and neutrophil-lymphocyte-count (NLR: 5.1 vs. 9.3, p=0.03), and lower albumin (3.7 vs. 3.5 mg/dL, p=0.02). A significant rise in NC (2.1 K/uL, p=0.0008), NLR (by 2.5, p=0.004), WBC (by 2.1 K/uL, p=0.002) from baseline was noted at irAE-incidence. Heterogeneity in the primary tumors and treatments received is a notable limitation of this analysis. Conclusions: Overall, the risk of irAEs in patients with GI cancers is relatively low, and certain BLC can predict their incidence.

Tinengotinib in patients with advanced, metastatic cholangiocarcinoma: Overall survival results and biomarker correlative analysis from a phase 2 clinical trial.

608 Background: Tinengotinib, a spectrum-selective multi-kinase inhibitor with unique binding properties to FGFR , potently inhibited FGFR2 fusion/rearrangement and acquired resistant/gatekeeper mutations in pre-clinical models and exhibited antitumor activity in cholangiocarcinoma (CCA) patients (pts) in phase 1/2 trials. Here we present the overall survival (OS) data and biomarker correlative analysis from a phase 2 clinical trial of tinengotinib in CCA. Methods: Eligible pts with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy with ECOG PS 0-1 were treated with tinengotinib 10 mg QD across four Cohorts: A1: FGFR2 fusion(s) with primary progression on previous FGFR inhibitor ( FGFR i); A2: FGFR2 fusion(s) with progression after prior response to FGFR i; B: FGFR alteration(s) without FGFR2 fusion(s); C: FGFR wild-type. Efficacy was evaluated per RECIST v1.1 and safety was assessed by CTCAE v5.0. Genomic alterations in circulating tumor DNA (ctDNA) were assessed by Foundation Medicine NGS panel at baseline, C3D1 and EOT. Planned correlative analyses of response (PR+SD>6 months) and PFS in pt subgroups based on ctDNA mutational status were performed. Results: 55 eligible pts were enrolled (18 in A1, 11 in A2, 13 in B, 13 in C) with median age 61.0 [range 24-81] years, ECOG PS 0 in 50.9% pts, 56.4% female, and 60.0% with ≥ 3 lines of prior therapy. Among 42 pts with FGFR alterations, 78.4% had ≥ 1 prior FGFR i, and 97.6% had prior chemotherapy. Median follow up time was 8.6 months (0.4-30.5). The median OS (months) was 17.1 (95%CI 7.5-19.5) in A1; not reached (95%CI 9.6, -) in A2; 18.0 (95%CI 9.6, -) in A1+A2; not reached (95%CI 8.0, -) in B; 6.5 (95%CI 4.8-16.4) in C. The OS rate in A, B and C was 100%, 91.7% and 75% at month 3; 83.7%, 83.3% and 66.7% at month 6, and 65.8%, 55.6% and 23.8% at month 12. Partial response was observed in 26% (10/39) of evaluable FGFR-altered pts (A1+A2+B). The safety profile was consistent with previous reports. The most common any-grade treatment-related AEs were hypertension (63.6%) and diarrhea (47.3%). Baseline ctDNA results were available in 46 pts, 35 in cohorts A+B and 11 in C. A positive correlation was shown in MED12 mutation vs response (P=0.03476). BCOR and ARID1A mutation were found to be negatively associated with PFS (P=0.01366 and P=0.0437). Acquired/secondary mutations at baseline were observed in cohort A, including V564F/I (3/24 and 5/24) and N549K/H (5/24 and 5/24); favorable anti-tumor activity was noted despite these resistant mutations, consistent with preclinical data. Conclusions: Tinengotinib has shown promising anti-tumor efficacy in CCA pts with FGFR fusion after prior FGFR i and in those with primary FGFR mutations. An ongoing randomized phase III study will investigate tinengotinib vs. chemotherapy in FGFR inhibitor refractory CCA (NCT05948475). Clinical trial information: NCT04919642 .

Prompt injection attacks on vision language models in oncology

Abstract Vision-language artificial intelligence models (VLMs) possess medical knowledge and can be employed in healthcare in numerous ways, including as image interpreters, virtual scribes, and general decision support systems. However, here, we demonstrate that current VLMs applied to medical tasks exhibit a fundamental security flaw: they can be compromised by prompt injection attacks. These can be used to output harmful information just by interacting with the VLM, without any access to its parameters. We perform a quantitative study to evaluate the vulnerabilities to these attacks in four state of the art VLMs: Claude-3 Opus, Claude-3.5 Sonnet, Reka Core, and GPT-4o. Using a set of N = 594 attacks, we show that all of these models are susceptible. Specifically, we show that embedding sub-visual prompts in manifold medical imaging data can cause the model to provide harmful output, and that these prompts are non-obvious to human observers. Thus, our study demonstrates a key vulnerability in medical VLMs which should be mitigated before widespread clinical adoption.

Real-world data of durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer: A Thailand multicenter observational study.

607 Background: Currently, durvalumab plus gemcitabine and cisplatin is a standard of care for patients with advanced biliary tract cancer (BTC). We aimed to evaluate efficacy and tolerability of durvalumab plus gemcitabine and cisplatin in real world experience in Thailand where there is high incidence of liver-fluke related cholangiocarcinoma (CCA). Methods: This is an observation study of patients with advanced BTC participating in the early access program of durvalumab since August 2023. Data were collected and analyzed for efficacy and toxicity. Results: Fifty patients participated the early access program in 14 centers across Thailand. Median follow-up time was 8.5 months. Median number of treatment cycles was 8.8 (1-16) cycles. Thirty six (72%) patients were alive and 8 (16%) patients were still on treatment. The mean age was 63 years, 60% were male and 92% were ECOG 0-1. There were 68% intrahepatic cholangiocarcinoma (CCA), 28% extrahepatic CCA and 8% gallbladder cancer. There were 29.5% objective response rate and 79.5% disease control rate. Median progression free survival (PFS) was 6.0 (95%CI 4.49-7.50) months. Eight (16%) patients were still on treatment with PFS more than 10 months. Grade 3 or 4 adverse events (AEs) were reported in 50% of patients. Most AEs were related to chemotherapy, there were 10% immune related AEs. Conclusions: In this real-world experience, durvalumab plus gemcitabine and cisplatin was efficacious and tolerable in Thai patients with advanced BTC.

Non-cancer-related deaths in patients with resectable locally advanced esophageal squamous cell carcinoma: A supplementary analysis of JCOG1109.

434 Background: Neoadjuvant docetaxel, cisplatin, and 5-FU (DCF) has become the standard treatment for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) in Japan, based on the result of JCOG1109. In this study, more non-cancer-related deaths were observed in the cisplatin, and 5-FU (CF) plus radiotherapy (CF-RT) arm compared to the CF and DCF arm. However, the details of these non-cancer-related deaths remain unclear. We aimed to evaluate the influence of neoadjuvant therapies on non-cancer-related deaths using the data from JCOG1109. Methods: We analyzed patients' characteristics, classification, time of onset, risk factors associated with onset, and cumulative incidences in patients with non-cancer-related deaths. Cumulative incidences of non-cancer-related deaths in each arm were estimated, considering cancer-related deaths as a competing risk. Risk factors were explored using multivariable Fine-Gray model with Firth penalization. Results: Among 601 enrolled patients, 164 in the CF arm, 169 in the DCF arm, and 173 in the CF-RT arm were completed the surgery. Of those, non-cancer-related deaths were observed in 19 (12%), 12 (7%), and 32 (18%) patients, respectively. Patient characteristics of non-cancer-related deaths in the CF/DCF/CF-RT arm were as follows: male, 89/92/88%; median age, 69/69/69 years old; ECOG PS 0, 89/100/97%; lower thoracic esophagus, 21/25/19%; previous history of ischemic disease of heart, 5/0/0%; brain, 0/0/0%; other malignancies, 5/8/0%; comorbidity of hypertension, 26/25/47%; COPD, 0/8/3%; thoracoscopic approach, 37/42/38%. The median follow-up time was 5.7 years (range, 0.3-10.4 years). The causes of non-cancer-related deaths in the CF/DCF/CF-RT arm were pulmonary, 4 (21%)/1 (8%)/10 (31%); cardiovascular, 1 (6%)/0/2 (6%); infectious, 2 (11%)/1 (8%)/3 (9%); other malignancy, 2 (11%)/3 (25%)/5 (16%); treatment-related, 0/1 (8%)/1 (3%), and the median time from surgery to onset of non-cancer-related death was 3.3/3.8/4.3 years, respectively. Cumulative incidences of non-cancer-related deaths after 3, 6, 9 years in the CF/DCF/CF-RT arm were 4.9/3.0/7.0%, 10.7/6.1/15.6%, 12.4/8.8/26.1%, respectively. In multivariable analyses, ≥ 65 years old (hazard ratio [HR]: 3.243, 95% confidential interval [CI]: 1.797–5.852, vs. < 65 years old), ECOG PS 0 (HR: 3.579, 95% CI: 1.148–11.162, vs. PS 1), and serum CRP ≥ 1.0 mg/dl (HR: 2.238, 95% CI: 1.003–4.995, vs. <1.0 mg/dl) were significantly associated with the onset of non-cancer-related deaths. Whereas the CF-RT arm was not significantly associated (HR: 1.600, 95% CI: 0.885–2.892, P = 0.12, vs. CF). Conclusions: The incidence of non-cancer-related deaths was relatively higher in the CF-RT arm, and pulmonary-related complications tended to be a particularly common cause of death.

Phase II single-arm, single-center clinical trial of all-trans-retinoic acid, bevacizumab, and atezolizumab in refractory microsatellite stable colorectal cancer.

TPS324 Background: A critical clinical challenge in microsatellite stable (MSS) metastatic colorectal (mCRC) patients is to identify strategies to overcome lack of response to immune checkpoint inhibitors. An immunosuppressive tumor microenvironment comprising myeloid-derived suppressor cells (MDSC), endothelial cells, regulatory T cells, tumor associated macrophages, and cancer associated fibroblasts promotes immune evasion and resistance to these agents. MDSCs are bone marrow derived myeloid cells that suppress T-cell function and promote tumor growth. Among all cancers, mCRC patients have one of the highest frequency of MDSC (CD11b+, CD33+, CD14+ HLA-DRneg) in blood (1). It was demonstrated that altering the MDSC% in the tumor microenvironment by ATRA and anti-VEGF therapy (bevacizumab) can enhance the effects of immune checkpoint inhibitors (2-4). The hypothesis of the current clinical trial is that the combination of ATRA, bevacizumab and atezolizumab will lead to a decrease in MDSC population in tumor microenvironment leading to a clinically meaningful improvement in response rates among refractory MSS mCRC patients. Methods: This is a single-arm, open-label, phase 2 clinical trial combining ATRA, bevacizumab, and atezolizumab in refractory MSS mCRC patients. It will enroll a total of 21 patients over 24 months at UT Southwestern Medical Center that are MSS by PCR or NGS testing or are proficient in immunohistochemical expression of all four mismatch repair enzymes (MLH1, MSH2, MSH6, PMS2). ATRA will be administered orally at 45 mg/m2/day in 2 divided doses on days 1-7 and repeated every 14 days; atezolizumab will be given intravenously on day 1 at 840 mg dose every 14 days, and bevacizumab will be administered intravenously on day 1 at 10 mg/kg dose every 14 days. The first six patients enrolled on this study will contribute to the safety lead-in phase of this study. The primary outcome is to assess the overall response rate by RECIST v1.1. Secondary outcomes include assessment of disease control rate and frequency of adverse events using CTCAE v5.0. Exploratory outcomes include assessment of PFS and OS and collecting blood and tissue samples at defined timelines to study the changes in the MDSC population among responders and non-responders (NCT05999812). 1. Kobayashi, M. et. al., Clin Cancer Res, 2019. 2. Mirza, N., et al., Cancer Res, 2006. 3. Tobin, R.P., et al., Int Immunopharmacol, 2018. 4. Tobin, R.P., et. al., Clin Can Res, 2023. Clinical trial information: NCT05999812 .

Electronic descriptors for designing high-entropy alloy electrocatalysts by leveraging local chemical environments

Machine learning–based liquid biomarker analysis from the NEONAX trial for response prediction to perioperative (PO) and adjuvant (A) gemcitabine/nab-paclitaxel in resectable PDAC (rPDAC).

755 Background: The phase II NEONAX trial examined PO and A gemcitabine/nab-paclitaxel (G/nP) efficacy for rPDAC pts with a comprehensive biomarker program. This translational study aimed at identifying liquid biomarker for early prediction of G/nP success in each treatment group (PO and A) and for the combined group using machine learning (ML). Methods: Pts from both study arms were stratified into groups based on Short- or Long-DFS ( n=80 pts total; PO n=42 pts; A n=38 pts). Blood plasma from selected G/nP naïve pts was analyzed by multiplexed ELISA (mELISA, 80-Plex ProcartaPlex Human Immune Response) and mass spectrometry (MS; feature list generation) and clinical data were acquired for each patient. For ML pts were divided into training (80%) and validation (20%) datasets. The Weka-based algorithm WrapperSubsetEval (WSE) with 8 different classifiers was used for feature selection. The best performing (highest accuracy, best ROC-AUC, minimal signature) classifier with the corresponding feature panel was selected by a 10x10-fold cross-validation (CV). Respective panels for all features combined as compared to clinical features and Ca19-9 blood levels were tested for performance via CV and bootstrap aggregating for training and validation datasets (10x with replacement). Results: The feature generation process generated 579 features from G/nP-naive pts (mELISA: 80; clinical data: 99; MS: 400). For response prediction of the whole rPDAC group to G/nP (S-/L-DFS), the ML-based flow identified a panel of 8 proteins from MS (SERPINA1, C1QB, KRT1, C4B, UBB, VCAM1, HPD, LYZ) and 3 proteins from mELISA (Galectin3, IL34, CCL4) combined with a logistic regression classifier. The predictive panel with the best performance for determining PO G/nP success was established using a kernel logistic regression classifier and included 2 proteins from mELISA (CXCL2, IL17A), 4 proteins from MS (C3, IGLV3-25, HLA-B, SHBG), and 2 clinical data (WHO grade, Na/Mg blood level ratio). The best performing biomarker for predicting success in A included 2 clinical data (tumor size at staging, hematocrit) and 1 protein from mELISA (IL22) and was established with a random forest classifier. All panels represented minimal feature signatures (rPDAC: 11; PO: 8; A; 3) and showed a high performance with ROC-AUC (training) > 0.90, ROC-AUC (CV) > 0.85, and ROC-AUC (validation) > 0.90. All panels described were superior compared to similar predictive signatures (with corresponding ML classifiers) for all clinical data or Ca19-9 blood levels. Conclusions: We show that minimal liquid biomarker signatures for early prediction of G/nP success in the NEONAX trial based on mELISA, MS and clinical data can be established by ML. The study shows the potential of ML for biomarker panel development and the value of mELISA/MS for generation of feature lists to use in ML. Clinical trial information: NCT02047513 .

Personalised use of repurposed non-anticancer drugs in colorectal cancer based on up-regulated signalling pathways: A real world cohort feasibility study.

833 Background: Targeting signaling pathways in colorectal cancers is a common therapeutic strategy. In addition to targeted drugs, non- anticancer drugs approved for use in other health conditions can inhibit key pathways. De novo tumor transcriptome analysis can identify patient-specific up- and down-regulated transcripts, based on which the corresponding repurposed drugs can be used in synergistic combinations with standard of care (SoC) regimens. Methods: This retrospective study was conducted on a real-world cohort of 459 colorectal cancer cases (218 females, 241 males; median age 56 years) who had taken Exacta multi-omics tumor profiling for selection of personalized treatments. Transcriptome analysis was performed as part of the evaluations to determine up and down-regulated gene transcripts for selecting targeted, endocrine, and cytotoxic anticancer agents as well as non-anticancer (repurposed) drugs and phytochemicals that could be used for tandem targeting of the dysregulated signaling pathways, as indicated in the table below. Results: Transcriptome analysis of this cohort revealed dysregulation of ≥1 pathway in 391 patients (85.2%). MAPKs (n = 244, 53.2%) and MMPs (n = 210, 45.8%) were most frequently upregulated. Celecoxib (n = 292, 63.6%), Atorvastatin (n = 255, 55.6%), and Doxycycline (n = 208, 45.3%) were the most frequently indicated repurposed drugs for targeting the identified dysregulated pathways. Potential indications for ≥1 repurposed drugs were seen in 353 patients (76.9%). Conclusions: Several cellular signaling pathways are known or potential therapeutic targets in cancers. The present study indicates that it may be possible to use multi-omics analyses to create personalized treatment strategies using a synergistic combination of repurposed drugs to potentiate the action of SoC systemic anticancer agents in colorectal cancer. Biomarkers for non anti-cancer drugs selection. Drug Biomarker/Gene Expression Aspirin PTGS2 (COX2) Atorvastatin HMGCR, MAPK Bromelain PTGS2 (COX2) Celecoxib PTGS2 (COX2), FZD, WNT, ΜΑΡΚ Chloroquine HMGB1 Curcumin MMP, BIRC5, BCL2 Doxycycline MMP Metformin MMP, BCL2, ΜΑΡΚ Quercetin FZD, WNT Resveratrol MMP, BCL2, PCNA, PTGS2 (COX2) Vitamin C SLC2A1 (GLUT1) Artesunate FZD, WNT, MMP, BCL2 Cannabidiol MMP Epigallocatechin gallate MMP, MAPK Mebendazole XIAP, MMP, MAPK

Clinical results of a phase 1 trial evaluating a HER2 directed CAR-T product selective for the tumor microenvironment (TME) in patients with GI and other solid tumor malignancies.

449 Background: A major limitation of CAR-T in solid tumors has been the inability to safely target antigens shared between healthy and malignant tissue. One approach to improving selectivity is to regulate CAR affinity through the unique metabolism of the tumor microenvironment (TME). This first in human trial evaluated an autologous (41BB) CAR-T product encoding a tumor metabolism regulated HER2 CAR. Methods: This Phase 1, dose escalation, basket trial evaluated the safety, tolerability, pharmacokinetics and efficacy in 12 patients (pts) with HER2 IHC 3+ / FISH + Stage IV r/r solid tumor malignancies (gastric, esophageal, colorectal, breast). They had failed multiple lines of therapy (66.7% patients had failed 4~10 lines of therapies previously). Dose cohorts of 3E5 (n=3), 1E6 (n=3), or 1E7 (n=6) CAR-T cells/kg were evaluated with a 28-day in-patient DLT observation period. Cell product was manufactured from whole blood, with a 12-day closed process and release on day 17. Lymphodepletion regimen was 500 mg/m 2 Cy and 30 mg/kg 2 Flu X 3 prior to infusion of CAR-T. Results: Data cutoff 09/16/24. All 12 patients were evaluable for safety and efficacy. No DLTs, ICANS or SAEs were observed. For HER2 positive normal tissues of special concern (e.g. cardiomyocytes), longitudinal functional, biochemical and clinical cardiovascular tests showed no signs of OTOT. One patient experienced Grade 2 CRS and recovered. No AE’s lead to study discontinuation. In one patient, there were two Grade 3 AEs attributed to product (neutropenia and hypoxia); both which resolved. With a median follow-up of 302 days for cohort 3, 12-month survival rate in this cohort is 83.3%, compared to the 12-month survival rate of 33.3% for cohorts 1 and 2 combined. Encouraging signals of efficacy were observed with an ongoing (at 24 wks) deep PR (100% reduction SLD) in a GC patient. The median peak copy number of CAR-T cells in peripheral blood (n=12) was 1,818 copies/µg DNA (range 403 – 10,466). Conclusions: The tumor metabolism regulated HER2 CAR-T product was generally well tolerated, with no DLTs, and evidence of radiologic objective response in patients with gastroesophageal cancer. Combined, the safety and activity observed in this study suggests that a previously challenging solid tumor antigen may be safely targeted by a CAR with affinity regulated by the metabolism of the TME. Enrollment for the study was complete as of 28-Feb-2024 (NCT04511871). Clinical trial information: NCT04511871 .

PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma

Comparison of demographics, mortality outcomes and resource utilization in early-onset versus later-onset pancreatic cancer: An analysis of the US National Inpatient Sample (NIS).

700 Background: Pancreatic cancer is associated with higher mortality, with 5-year relative survival of 12%. Early-onset pancreatic cancer (EOPC) is relatively uncommon and is seen in 5-12% of the cases. Recent studies indicate a rising trend in the incidence of EOPC. In this study, we categorized EOPC for ages less than 50 and later-onset pancreatic cancer (LOPC) for ages above or equal to 50 years. The aim of the study is to understand difference in demographics, mortality, and resource utilization between the two sub-categories of patients admitted to acute care hospitals in the United States. Methods: This is a retrospective cohort study of adult patients hospitalized with pancreatic cancer as the primary diagnosis at acute care hospitals across the United States in 2021, using the National Inpatient Sample (NIS) database. International Classification of Diseases, 10th Revision (ICD-10) codes were utilized to identify patients with a primary diagnosis of pancreatic cancer. The primary outcome is comparing demographics and in-hospital mortality between EOPC and LOPC. The secondary outcomes are length of stay (LOS) and total hospitalization charges. We performed multivariate logistic regression analysis to assess in-hospital mortality, LOS, and total hospitalization charges after adjusting for potential confounders such as sex, race, Charlson comorbidity index, hospital teaching status, and hospital region. Results: Our study included 38,654 patients with pancreatic cancer, of which 2,242 were EOPC and 36,412 were LOPC. The majority of the baseline characteristics were similar in both groups, except that EOPC has a higher Hispanic population (16.06% versus 8.77 %, p < 0.001), higher Medicaid as the payer source (28.28 % versus 7.32%, p < 0.001), and a more significant number of patients admitted to an urban teaching hospital (89.2 % versus 85.2%, p < 0.05) compared to LOPC subpopulation. No statistically significant difference in mortality was found between the two sub-categories (odds ratio 0.97, 95 % CI 0.60-1.5). Charlson index, hospital location, hospital bed size, and hospital region are independent predictors of mortality. There was no statistically significant difference between the two sub-categories for mean length of stay and total hospitalization charges. Conclusions: No significant difference was observed between EOPC and LOPC regarding in-hospital mortality, total length of stay, and total hospitalization charges. Our study highlights that EOPC disproportionately affects the Hispanic population and also a greater number of EOPC patients being admitted to urban teaching hospitals. Future research is needed to understand the disproportionate effect on the Hispanic population in the EOPC group and continued research in the domain, as the incidence of early-onset pancreatic cancer is expected to rise.