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Relationship of circulating tumor DNA (ctDNA) tumor fraction with prognosis in patients with metastatic pancreatobiliary cancer.

763 Background: Carcinomas of the pancreas and biliary tract are among the most lethal cancers. Currently, it is very difficult to predict individual patient outcomes with only general prognostic information available. Emerging evidence shows that baseline ctDNA tumor fraction (TF) is a prognostic factor for many tumor types, including metastatic pancreatic ductal adenocarcinoma (mPDAC). With an additional year of follow-up, we refresh our prior study of the prognostic value of ctDNA TF in mPDAC and extend the analysis to biliary tract cancers (BTC). Methods: A genomic dataset comprising patients who underwent ctDNA testing using FoundationOne Liquid or FoundationOne Liquid CDx as part of routine care was used to determine the distribution of ctDNA TF across pancreatobiliary cancer subtypes. A subset of patients was also included in the nationwide (~280 US cancer clinics, ~800 sites of care) de-identified Flatiron Health-Foundation Medicine clinico-genomic database, which was used separately for all other analyses. Clinical data were derived from the electronic health record. Real-world overall survival (rwOS) was evaluated by ctDNA TF while controlling for relevant covariates. In parallel, ctDNA TF cutoffs of ≥1% and ≥10% were evaluated. Exploratory analysis of trichotomized ctDNA TF at 1% and 10% was also performed. Results: In 8817 patients with pancreatobiliary carcinoma, 46.1% of PDAC and 41.9% of extra-hepatic cholangiocarcinoma patients had detectable levels of ctDNA TF, while patients with gallbladder carcinomas had the highest levels of ctDNA TF (median 0.8%). 470 patients with mPDAC and 89 patients with BTC were included in the outcomes analysis. High ctDNA TF was associated with clinical features linked to poor prognosis in mPDAC: Stage IV at diagnosis, pretherapy opioid prescriptions, high neutrophil-to-lymphocyte ratio and CA19-9 at baseline, and alterations in KRAS , TP53 , CDKN2A , or SMAD4 . In BTC, high ctDNA TF was associated with Stage IV at diagnosis and cholangiocarcinoma histology. Higher ctDNA TF in mPDAC was associated with significantly reduced rwOS for both cutoffs (1%: HR 1.55 [1.25-1.93], P < 0.001; 10%: HR 1.85 [1.42-2.41], P < 0.001). When ctDNA TF was trichotomized, higher ctDNA TF groups had reduced rwOS stepwise. Similar trends were observed in patients with BTC, but results were not statistically significant. Conclusions: ctDNA from pancreatobiliary carcinomas can be frequently detected and characterized in liquid biopsy while also assessing key genomic biomarkers. ctDNA TF was a prognostic biomarker for mPDAC, but not for BTC in this cohort. Detection of ctDNA associated with other clinical factors linked to poor outcomes. Cohorts given uniform treatment could possibly help further evaluate the ability of ctDNA TF to identify patients with more aggressive disease and inform future studies to personalize therapeutic decision-making.

FG-M108 plus capecitabine and oxaliplatin (CAPOX) for first-line treatment of CLDN18.2+/HER2- advanced gastric/gastroesophageal junction adenocarcinoma (GC): Update results of a phase I/II trial to determine RP2D.

431 Background: There exists unmet need for previously untreated pts with CLDN18.2+/HER2- advanced GC. FG-M108, an mAb specifically targeting CLDN18.2 and exhibiting enhanced ADCC activity, has the potential to benefit these pts. Methods: This phase I/II trial evaluated safety, pharmacokinetics and preliminary antitumor activity of FG-M108 plus CAPOX in previously untreated pts with CLDN18.2+/HER2- advanced GC, where FG-M108 was administered intravenously at 300 mg/m 2 or 600 mg/m 2 Q3W. Here we compare results of FG-M108 at 300mg/m 2 (Cohort A) with 600mg/m 2 (Cohort B) to establish RP2D. Results: As of August 28, 2024, 63 pts with CLDN18.2+ (IHC 1/2/3+≥10%) GC were treated, 70% of whom had CLDN18.2 Medium-High expression (CMH, IHC 2/3+≥40%). Baseline characteristics were comparable between Cohorts A & B. Increasing the FG-M108 dosage did not result in a higher incidence or severity of treatment-related adverse events (TRAE) overall. However, nausea and vomiting, identified as CLDN18.2 on-target toxicities, were significantly more frequent and severe in Cohort B compared to Cohort A.When 300 or 600 mg/m² of FG-M108 was administered intravenously Q3W, serum trough concentration exceeded the target drug concentration predicted by in vitro ADCC activity. The 300 mg/m² dose is expected to provide sufficient drug exposure as the effective dose.Moreover, in Cohort A, pts with CMH expression had a confirmed ORR of 78% (unconfirmed ORR=81%) and a median PFS of 11.0 months（95%CI 6.9-12.7）, significantly better than those in Cohort B. Based on safety, PK and efficacy trends, the RP2D was determined to be FG-M108 at 300mg/m 2 plus CAPOX. Conclusions: FG-M108 plus CAPOX had a manageable safety profile and promising antitumor activity in GC, with RP2D at 300mg/m 2 . A phase III trial is ongoing to confirm the efficacy of FG-M108 at 300mg/m 2 plus CAPOX as first-line treatment (NCT06177041). Clinical trial information: NCT04894825 . Cohort A n=52 Cohort B n=11 CMH % 71 64 Primary lesion-Stomach % 92 100 Metastatic organs ≥3 % 27 9 ORR/DCR with CMH % 81/97 57/86 PFS/DOR with CMH months 11.0/9.9 5.5/4.2 ≥G3 TRAE % 37 18 TRAE-Nausea % / ≥G3 Nausea % 38/2 64/9 TRAE-Vomiting % / ≥G3 Vomiting % 23/2 73/9

Structural basis of the bifunctionality of Marinobacter salinexigens ZYF650T glucosylglycerol phosphorylase in glucosylglycerol catabolism

Real-world safety of trastuzumab deruxtecan with gastric cancer: All-patient post-marketing surveillance study in Japan.

399 Background: Interstitial lung disease and pneumonitis (ILD/p) is an important identified risk in the Japanese risk management plan of trastuzumab deruxtecan (T-DXd). In Japan, an all-patient post-marketing surveillance (PMS) study was conducted to investigate the incidence of ILD/p and factors associated with its development among patients with gastric cancer treated with T-DXd in the real-world setting. Methods: This is an observational, multicenter, PMS study (jRCT2001200001) with an observation period of 12 months that enrolled all patients who initiated T-DXd treatment for HER2-positive unresectable advanced or recurrent gastric cancer between Sep 2020 and Dec 2021. All suspected ILD/p events reported by physicians were adjudicated by an independent ILD adjudication committee; events adjudicated as drug-related ILD/p were summarized. The factors associated with the development of adjudicated drug-related ILD/p were investigated using a Cox proportional hazards model. Effectiveness endpoints included best overall response rate according to the RECIST 1.1 and overall survival, which was estimated using the Kaplan–Meier method. Results: The safety analysis set included 1070 patients (77.4% male, 89.9% ECOG performance status ≤1) with median age of 70 years (range: 23-100). Median initial dose and treatment duration of T-DXd were 6.4 mg/kg (range: 3.1-6.4) and 3.9 months (range: 0.7-12.0), respectively.The incidence of any grade, grade ≥3, and grade 5 adjudicated drug-related ILD/p were 9.6% (n=103), 2.8% (n=30) and 1.2% (n=13), respectively. Within 24 weeks from onset, 73.8% of adjudicated drug-related ILD/p had resolved, were resolving, or resolved with sequelae.A multivariate analysis identified that medical history and/or comorbidity of ILD/p [hazard ratio (HR) = 3.372, 95% confidence interval (95% CI): 1.431, 7.840], radiation pneumonitis (HR = 8.523, 95% CI: 2.006, 36.215), COPD or emphysema (HR = 1.962, 95% CI: 1.032, 3.731) and age ≥75 years (HR = 1.648, 95% CI: 1.058, 2.567) were factors of interest associated with the development of ILD/p in patients with gastric cancer. The overall response rate at 12 months post-treatment initiation of T-DXd was 34.2%. Overall survival after 364 days post-treatment initiation of T-DXd was 43.8% (median survival time: 303.0 days). Conclusions: The results suggest that the risk of ILD/p in this PMS study does not differ from that in the Destiny Gastric-01 study, and no new safety concerns were identified. Medical history and/or comorbidity of ILD/p, radiation pneumonitis, COPD or emphysema and age ≥75 years were identified as factors of interest associated with the development of ILD/p in patients with gastric cancer. Further investigation into the identified factors of interest may offer insights into the development of ILD/p among T-DXd treated gastric cancer patients in Japan. Clinical trial information: jRCT2001200001.

Unraveling the role of interferon-stimulated neutrophils: A promising biomarker for immunotherapy efficacy and prognosis in gastric adenocarcinoma.

472 Background: Despite significant advancements in immunotherapy, the identification of effective predictive biomarkers for treatment response in gastric adenocarcinoma (GAC) remains a critical challenge. Discovering such biomarkers could enhance patient stratification and improve therapeutic outcomes. Methods: We conducted a comprehensive analysis of 18 specimens obtained from 10 GAC patients, both prior to and following immunotherapy. Utilizing single-cell RNA sequencing, we compared the cellular composition and functional phenotypes of these specimens, with particular emphasis on tumor-infiltrating immune cells and the identification of previously uncharacterized neutrophil subclusters. Results: Our analysis identified eight distinct neutrophil subclusters, including Neu01_S100A12, Neu02_VEGF, Neu03_CCL3_CCL4, Neu04_IL1β, Neu05_CXCR4, Neu06_IFN-Stimulated, Neu07_Proliferative, and Neu08_B-cell_related. Notably, the presence of IFN-Stimulated neutrophils was positively correlated with the efficacy of immunotherapy in GAC, a finding that was further validated through analyses of public datasets and in-house cohort studies employing multiplex immunohistochemistry. Additionally, IFN-Stimulated neutrophils served as prognostic indicators across multiple datasets. Investigations revealed that these cells engage in significant cellular communication with other immune components within the tumor microenvironment, including CD8+ T cells, macrophages, and B cells, thereby promoting a pro-inflammatory and anti-tumor phenotype. Importantly, pan-cancer analyses demonstrated the consistent prognostic and immunotherapy efficacy-predicting potential of IFN-Stimulated neutrophils across various cancer types. Conclusions: IFN-Stimulated neutrophils represent a promising biomarker for predicting immunotherapy response and patient prognosis in GAC. Our findings offer novel insights into the underlying mechanisms of immunotherapy and highlight potential avenues for personalized treatment strategies in the management of GAC.

A phase Ib study of immunotherapy with ex-vivo pre-activated and expanded CBNK cells in combination with cetuximab, in patients with colorectal cancer (CRC) with minimal residual disease (MRD): Final report.

176 Background: Colorectal cancer (CRC) is the second most common type of cancer. Even following successful curative treatment, patients often relapse, likely because of undetected micro-metastatic foci. Tumor-informed ctDNA testing has helped to identify those patients before they developed radiographic evidence of disease, introducing the concept of minimal residual disease (MRD) in solid tumors. No standard-of-care treatment options are available for MRD patients. Therefore, we have designed a phase IB trial of the combination of in vitro pre-activated and pre-expanded cord blood natural killer (pre-A+E CBNK) cells with cetuximab. We hypothesized that we could achieve CAR-like efficacy without genetic engineering, by pre-activating NK cells with inflammatory cytokines and by using antibodies to redirect NK cell specificity and antibody-dependent cellular cytotoxicity. The highly immunosuppressive CRC tumor microenvironment is understudied, and novel NK-cell therapy could be highly effective in MRD clearance. Methods: 15 patients with CRC-MRD were enrolled in this trial and completed treatment. All the patients received immunodepleting treatment prior to an infusion of pre-A+E CBNK cells, up to a dose of 1x10^8/kg. Patients were monitored inpatient for 24 hours after treatment for infusion-related reaction, and were then seen for toxicity follow-up in the outpatient clinic twice/week for 4 weeks (DLT window). Samples for correlative analysis were collected at different times. Results: 8/15 patients enrolled were female and 7 were male, age range 26-69. They all had no measurable radiographic evidence of disease and a positive ctDNA Signatera test at baseline. 11/15 were previously treated for metastatic disease; 13 patients had a history of metastases (including 7 liver, 2 lymph nodal, 2 peritoneal). All of them received 5-FU-based chemotherapy. 7/15 were RAS/RAF WT, 4/10 were KRAS mut, 1/10 had BRAF mutation, 1/10 had HER2 amplification. They were all pMMR. No DLT was observed, only 1 patient had G2 CRS requiring tocilizumab. 9/15 patients treated so far had ctDNA clearance at some point. One patient had negative ctDNA at 3 and 6 months, 4/15 were negative at d28 and 7/15 at d14. 4/15 patients have not met the 90-day time point yet. 10/12 patients analyzed up to the primary endpoint had decreased ctDNA over baseline CBNK cells in blood peaked 3 hours post-infusion and persisted at 3 days. Phenotype analysis of CBNK pre-post, donor NK and other immune cells is ongoing. Conclusions: Cetuximab in combination with pre-A+E CBNK is safe and showed promising results for the treatment of MRD-CRC. Clinical trial information: NCT050468 .

A first-in-human phase I trial with antibody drug conjugate ADCT-701 in neuroendocrine tumors and carcinomas.

TPS672 Background: Neuroendocrine neoplasms (NENs) consist of neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), which are rare malignancies found in various anatomical sites, including the gastrointestinal tract, pancreatic islets, lungs, and adrenal glands. Poorly differentiated NECs are classified as high-grade carcinomas that bear resemblance to small-cell lung cancer (SCLC). Treatment for poorly differentiated NECs typically follows small-cell carcinoma guidelines, utilizing platinum-based regimens; however, these patients experience a high risk of relapse and demonstrate a limited response to additional systemic therapies. Adrenocortical carcinoma (ACC) is another rare malignancy associated with a median survival of approximately 14.5 months post-diagnosis, and advanced disease management options show limited efficacy. Currently, no targeted therapies have demonstrated significant effectiveness for this condition. Preclinical investigations have indicated that Delta-like non-canonical notch ligand 1 (DLK1) is expressed in various neuroendocrine neoplasms, including ACC, SCLC, neuroblastoma, pheochromocytoma, and paraganglioma. ADCT-701, a humanized antibody targeting DLK1, has shown potential in suppressing tumor growth and enhancing survival across multiple cancer models expressing this marker. Methods: This Phase I dose escalation study (NCT06041516) aims to enroll adult patients with histologically or cytologically confirmed neuroendocrine neoplasms or malignant ACC with evaluable disease, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Participants will be part of a dose-finding trial. A 3+3 design is utilized to assess up to ten different dose levels of ADCT-701. Dose escalation continues unless dose-limiting toxicities occur, the maximum tolerated dose (MTD) is reached, or an optimal dose is established. The primary endpoint of the study is to ascertain the recommended phase 2 dose of ADCT-701 in patients with neuroendocrine neoplasms or malignant adrenocortical carcinoma. Secondary endpoints will assess safety, preliminary tumor activity, response rate, overall survival, pharmacokinetics, and the immunogenicity profile of ADCT-701. The trial aims to enroll up to 70 evaluable patients across a maximum of 10 dose levels. For further details, please refer to clinical trial information NCT06041516. Clinical trial information: NCT06041516 .

ID3 promotes erythroid differentiation and is repressed by a TAL1–PRMT6 complex

Real-world biomarker testing and first-line treatment patterns among locally advanced, unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma patients in the US.

348 Background: Advanced-stage gastric cancer and gastroesophageal junction adenocarcinoma (advG/GEJC) are leading causes of cancer-related morbidity and mortality. Chemotherapy is the traditional first-line (1L) therapy for patients in the advanced setting, with targeted and immunotherapy considered based on biomarker expression. This study aimed to describe real-world HER2 and PD-L1 testing practices and 1L treatment patterns among advG/GEJC patients. Methods: A retrospective cohort study was conducted among adult patients diagnosed with advG/GEJC between 01 Jan 2017 and 30 Jun 2023 usingthe US-based Flatiron Health electronic health record-derived de-identified database. HER2 and PD-L1 testing practices were evaluated prior to and up to 1-month post-1L treatment initiation or 6 months post-advG/GEJC diagnosis date in untreated patients. 1L treatment regimens were described overall and stratified by HER2 and PD-L1 expression. Results: Among 4,256 advG/GEJC patients, the average age was 67 years with the majority male (68%), non-Hispanic white (44%), and with metastatic disease (64%). Nearly three quarters (72%) of patients included received a HER2 test and 55% had a HER2 test with a valid result within the timeframe mentioned above. More than a quarter of patients (27%) received a PD-L1 test and 25% had a PD-L1 test with a valid result. PD-L1 testing before the approval of nivolumab in 1L (i.e. before 2021) showed testing at 19% (490/2,629; 17% with a valid result) and from 2021 onward at 40% (643/1,627; 37% with a valid result). Across the full cohort, half of the patients received chemotherapy alone (52%) and one quarter received no treatment (25%). Similar treatment patterns were observed in the subset of 1,117 patients who did not receive a HER2 or PD-L1 test; 54% received chemotherapy alone and 36% no treatment. Of the 340 patients who were tested for HER2 and were HER2 positive, half (52%) received trastuzumab combination therapy, 23% received chemotherapy alone, and 18% had no treatment. Of the 301 patients who received a PD-L1 test with a combined positive score (CPS) ≥5 from 2021 onward, 41% received immunotherapy, 34% received chemotherapy alone and 18% had no treatment. Prior to 2021, most patients with a PD-L1 test and CPS >5 used chemotherapy alone (57%; 132/233), 13% (31/233) received PD-L1 targeted therapies and 19% (43/233) received no treatment. Conclusions: This study describes a potential subset of US advG/GEJC patients who do not receive a HER2 or PD-L1 test and/or do not receive eligible targeted or immunotherapy as part of routine clinical practice. As precision medicine options continue to evolve, these data suggest an opportunity to further understand the drivers for biomarker testing as well as the factors impacting the use of biomarker-informed treatment options.

First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) vs chemo in patients (pts) with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC): 5-year (y) follow-up of Chinese pts from CheckMate 649.

392 Background: NIVO + chemo demonstrated clinically meaningful survival benefit and an acceptable safety profile vs chemo in previously untreated Chinese pts with advanced GC/GEJC/EAC from CheckMate 649, consistent with the overall study population. 1L NIVO + chemo is currently approved for pts with advanced non-HER2+ GC/GEJC/EAC in China and other countries. We report 5-y results of NIVO + chemo vs chemo in Chinese pts from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled regardless of programmed death ligand 1 (PD-L1) expression. Randomized pts received NIVO + chemo, NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 208 Chinese pts were randomized to NIVO + chemo or chemo. At 61-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). 5-y OS rate was 24% with NIVO + chemo vs 8% with chemo in pts with PD-L1 CPS ≥ 5 and 20% vs 7% in all randomized pts. Objective response rate (ORR) was higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). No new safety signals were identified with longer follow-up. Conclusions: NIVO + chemo continued to demonstrate clinically meaningful long-term survival benefit, more durable responses, and acceptable safety vs chemo in Chinese pts after 5 y of follow-up, consistent with earlier reports and with the overall study population of pts with advanced non-HER2+ GC/GEJC/EAC. These results further support NIVO + chemo as a standard 1L treatment option for Chinese pts. Clinical trial information: NCT02872116 . Efficacy PD-L1 CPS ≥ 5 All randomized NIVO + chemo(n = 75) Chemo (n = 81) NIVO + chemo (n = 99) Chemo (n = 109) mOS (95% CI), mo 15.5(11.9–21.1) 9.6(8.0–12.1) 14.3(11.5–16.5) 10.3(8.1–12.1) HR (95% CI) 0.57 (0.40–0.82) 0.63 (0.46–0.85) mPFS a (95% CI), mo 8.5(6.0–14.0) 4.3(4.1–6.5) 8.3(6.2–12.4) 5.6(4.2–6.8) HR (95% CI) 0.51 (0.34–0.76) 0.57 (0.41–0.80) ORR a,b (95% CI), % 68 (56–79) 48 (36–60) 66 (55–76) 45 (35–56) mDOR a,c (95% CI), mo 12.5 (7.2–23.4) 6.9 (3.9–8.5) 12.5 (7.2–17.7) 5.6 (4.4–8.3) a Per BICR. b In pts with measurable target lesions at baseline. c In responders. DOR, duration of response; m, median.

Investigation of synergistic effects in trials of combination therapies with immune-checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer.

405 Background: Combinations of immune checkpoint inhibitors (ICI) and chemotherapy (CT) have been approved for gastric cancer. However, there is a hypothesis that this combination may blunt antitumor immune responses because most chemotherapeutic agents also target lymphocytes. The primary objective was to investigate that the ICI and CT does not interfere each other’s therapeutic effects in advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) patients. Methods: The reconstructed individual patient data was electronically extracted from the Kaplan-Meier curve of phase III randomized controlled trials (RCTs). The observed PFS curve of each constituent monotherapies was used to estimate simulated PFS curves expected under a model of independent drug action. If the observed curve demonstrated significantly better PFS than simulated curve, the combination of ICI and CT may have a synergistic effect, implying a superior outcome compared to simply adding the component monotherapy. Results: The study included 2,538 unresectable advanced, recurrent, or metastatic GC or GEJC patients from three RCTs comparing pembrolizumab (KEYNOTE-061, KEYNOTE-062 and KEYNOTE-859). In patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater, the 1-year and median PFS of the observed and simulated curves were 28.0% vs. 27.9%, and 6.89 months vs. 6.88 months, respectively. One sample log-rank test showed no significant differences between the observed and simulated curves (p = 0.107). In the subgroups with PD-L1 CPS ≥10 or <1, the 1-year PFS of the observed and simulated curves was 34.7% vs 32.8%, and 28.5% vs 26.8%. Conclusions: The observed PFS of ICT involving pembrolizumab was comparable to the simulated PFS estimated from the data for each monotherapy regardless of the magnitude of PD-L1 CPS. Although it was not clear whether potential synergies existed for ICT, these findings at least suggest that the benefits of ICI and CT are not interfering each other, thereby providing theoretical support for the efficacy of ICT in patients with advanced GC or GEJC.

A cross-sectional analysis from a real-world cohort of patients with microsatellite instability colorectal cancer (MSI-CRC) with metastatic disease from the Spanish RETUD registry.

178 Background: Survival of microsatellite instability (MSI) metastatic colorectal cancer (mCRC) patients (pts) has remarkably increased with immune checkpoint inhibitors (ICI). Here, we present our real-world data regarding the management and clinical outcomes of a cohort of 214 MSI-mCRC patients included in the Spanish Group of Treatment of Digestive Tumors TTD Registry (RETUD). Methods: RETUD is a national, multicenter registry for gastrointestinal tumors from the Spanish TTD Group. In this cross-sectional analysis we evaluated a real-world cohort of MSI-mCRC pts diagnosed from 1 st January 2017 to 29 th April 2024. Baseline characteristics, treatments and treatment response are descriptively presented. Tumoral response was evaluated according to RECIST 1.1 criteria. First line progression-free survival (PFS) and overall survival (OS) analyzed by Kaplan-Meier method are presented along with 95% confidence intervals (CI). Results: Among 679 MSI-CRC pts included in RETUD, a total of 214 mCRC pts were evaluable. Pts’ age at diagnosis was 69.6 (26-96) years, and they were predominantly Caucasian (97.7%) and female (53.7%). Eastern Cooperative Oncology Group (ECOG) performance status was 0-1 for 168 (78.5%) pts. Seventeen (10.7%) pts presented Lynch syndrome. Main tumor biological characteristics are described at Table 1 and the molecular profile (when available) was: KRAS mutation (24.3%), NRAS mutation (3.5%) and BRAF v600E mutation (53.0%). Surgical resections: 158 (73.8%) pts for primary tumor and 42 (19.6%) pts for metastasis. First line systemic treatment was administered to 187 (97.1%) pts: 92 (49.2%) pembrolizumab, 83 (44.4%) chemotherapy (CT), 4 (2.1%) other ICIs, 8 (4.3%) not reported. With a median follow up period of 17.4 months, the median (95% CI) OS and first-line PFS of the total mCRC population were 32.6 (22-72.4) and 11.1 (8.2-17.9) months (m), respectively. In immunotherapy (IT) pts mOS was not achieved (22.0-NA) and PFS was 26.5 m (12.9-NA) while the mOS was 28.9 m (16.3-69.3) and PFS 7.5 (5.4-9.3) m in CT pts. The overall response rate (ORR) was 54.2% in IT pts vs. 37.3% in CT pts. Conclusions: The introduction of IT has changed the evolution of MSI-H mCRC management, offering a beneficial impact in the OS and PFS survival in contrast to other conventional therapies in a real-world context. Tumor characteristics at initial diagnosis of CRC. Stage at initial diagnosis of CRC I/II, n (%) 4 (1.9) / 26 (12.1) III/IV, n (%) 66 (30.8) / 118 (55.1) Location of primary tumor a , n (%) right colon /left colon /rectum 160 (74.8) /37 (17.3) /19 (8.9) Main metastatic location b , n (%) Liver 84 (39.3) Peritoneal 76 (35.5) Lymph 71 (33.2) Lungs 41 (19.2) a Pts with more than 1 primary tumor; the percentage may be over 100%. Data missing for 4 (1.9%) pts. b Pts with more than 1 metastatic site; the percentage may be over 100%.

A coplanar electrode operating mode for piezoelectric energy harvesting and self-powered sensing

Piezoelectric semiconductors have emerged as a prominent area of research in recent years due to their unique combination of piezoelectric and semiconductor properties. In this Letter, we propose a piezoelectric device structure featuring coplanar electrodes positioned above the piezoelectric layer. We have conducted a detailed theoretical analysis of the piezoelectric properties of this piezoelectric device. By utilizing a coplanar electrode piezoelectric mode, pressure applied to one electrode generates a potential difference between the two electrodes. Notably, the piezoelectric performance of the device can be adjusted by modifying its structure. Numerical simulations and experimental results indicate that the piezoelectric performance reaches an optimal value when the distance between the electrodes is equal to one-half of the electrode length. Additionally, we have developed a method to enhance the piezoelectric voltage output capability of the device under low load resistance conditions. Specifically, by introducing charge carriers into the piezoelectric layer from the doped silicon substrate, the device's resistance is reduced due to the Schottky contact. The piezoelectric operating mode proposed in this paper facilitates energy harvesting and self-powered sensing, distinguishing it from the d31 and d33 operational modes associated with traditional sandwich device structures, thereby allowing for more versatile device configurations.

Human α10 nicotinic acetylcholine receptor subunits assemble to form functional receptors

Second-line therapy with Nal-IRI/5-FU/FA after failure of gemcitabine/nab-paclitaxel in advanced pancreatic cancer (PC): Predictive role of 1st-line therapy (PREDICT) and impact of quality of life (QoL).

707 Background: Metastatic PC has the lowest survival rate of all malignant diseases and is the fourth most common cancer. QoL remains an unresolved issue in PC for patients (pts) after treatment failure of 1 st -line CTx (TTF1). Nanoliposomal irinotecan (Nal-IRI) with 5-FU/folinic acid (FA) increased survival of PC pts from 4.2 months (mo) to 6.1 mo as compared to 5-FU/FA alone, with a rate of toxicities that may impact QoL. PREDICT is an open label, single arm, multicenter Phase IIIb trial (NCT03468335) and examined 2 nd -line Nal/IRI/5-FU/FA for PC. Here we report on QoL during 2 nd -line Nal-IRI after failure of 1 st -line gemcitabine/nab-Paclitaxel (gem/nab-Pac). Methods: In this prospective trial, 151 patients with locally advanced or metastatic PC were treated with biweekly Nal-IRI/5-FU/FA (70 mg/m², 2400 mg/m², 400 mg/m²) after failure of gem/nab-pac (TTF1). Primary end point (EP) was the time to treatment failure of 2 nd -line therapy (TTF2) and has been reported elsewhere. Secondary EP were QoL and Health related quality of life (HR-QoL) which were evaluated using questionnaires (EORTC QLQC30, QLQ-PAN26, EQ-5D-5L). Evaluation of time to definitive deterioration of QoL (TDD) during 2 nd -line therapy, defined as the time from screening/baseline until loss of ≥10 points in the EORTC QLQ-C30 was compared to baseline. Results: QoL analyses were performed with all QoL evaluable subjects set (QAS). The QAS included 143 pts, of which 48 pts were included in TTF1 high (TTF of 1 st -line ≥213 d) and 49 pts in the TTF1 low (TTF ≤119 d) cohort, with 79 (54.1%) female and 67 (45.9%) male pts. Mean age was 68.2±8.9 years. Overall, a low global health status / QoL mean score was observed at baseline for TTF1 high and low cohorts (about 48 points), which slightly improved during the study for TTF1 high (3.5±23.7) and slightly worsened for TTF1 low cohort (-0.7±22.5). Substantial improvements were observed for both cohorts in emotional functioning scale at certain study time points (TTF1 high: up to 9.1±25.7, TTF1 low: up to 6.6±17.0). A relatively high mean score was observed for cognitive function scale for both cohorts at baseline (TTF1 high: 70.1±30.2; TTF1 low: 72.5±21.4). Pts in the TTF1 low vs. high cohort showed more pronounced worsening of cognitive function. Median TDD was numerically longer (about one month) for TTF1 high (5,3 mo) compared to TTF1 low cohort (3,9 mo). The probability to maintain QoL after six months was similar between the two cohorts. Conclusions: QoL showed similar global and HR-QoL scores with only slight changes during the study. Median TDD was numerically longer for high TTF1 pts, but similar after six months between pts still on 2 nd line Nal/IRI/5-FU regardless of duration of TTF in 1 st -line. Clinical trial information: NCT03468335 .

Adagrasib (Ada) + cetuximab (Cetux) for <i>KRAS</i> ^G12C -mutated metastatic colorectal cancer (mCRC): Longer follow-up analysis from KRYSTAL-1.

131 Background: KRAS G12C mutations occur in 3%–4% of CRC cases and are associated with poor prognosis. In the phase 1/2 KRYSTAL-1 study (NCT03785249), at a median follow-up of 11.9 months (mo), Ada (irreversible inhibitor of KRAS G12C ) in combination with Cetux (anti-EGFR antibody) demonstrated promising clinical activity (objective response rate [ORR] of 34% per blinded independent central review [BICR] and 43% per investigator [INV]) and was well tolerated in patients (pts) with previously treated KRAS G12C -mutated mCRC. Based on these findings, Ada + Cetux was granted accelerated approval in the United States for these pts. Here, we present longer-term follow-up analyses from this study. Methods: Adults with previously treated KRAS G12C -mutated mCRC and ECOG performance status of 0 or 1 were treated with Ada (600 mg BID) in combination with Cetux (400 mg/m 2 followed by 250 mg/m 2 QW or 500 mg/m 2 Q2W) until disease progression, unacceptable toxicity, withdrawal of consent, or death, in separate phase 1 and phase 2 cohorts. Primary endpoints were safety (phase 1) and ORR per BICR (phase 2). Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (phase 2). Results: A total of 94 pts received Ada + Cetux. The median number of prior lines of systemic therapy was 3 (range, 1–9); 23 pts (24%) had received ≥ 4 prior lines of systemic therapy. The most frequent sites of metastases at baseline were the lung (71%) and liver (64%). At a median follow-up of 20.4 mo, ORR per INV was 43% (95% CI 32–53) and all were partial responses; median DOR was 5.9 (95% CI 5.5–7.6) mo. Disease control rate per INV was 86% (95% CI 78–92). Median PFS per INV was 6.9 (95% CI 5.9–7.4) mo; 6- and 12-mo PFS rates were 61% and 19%, respectively. Median OS was 16.0 (95% CI 13.3–18.8) mo; 6- and 12-mo OS rates were 88% and 66%, respectively. Any-grade treatment-related adverse events (TRAEs) were reported in 100% of pts, 28% of which were grade 3/4. TRAEs led to discontinuation in 10% of pts. Efficacy analyses by BICR, subgroup analyses, and additional safety results will be presented. Conclusions: In heavily pretreated pts with KRAS G12C -mutated mCRC, Ada + Cetux continued to demonstrate clinically meaningful activity and tolerable safety with longer follow-up. These updated results are consistent with those from the primary analysis and constitute the longest duration of follow-up for dual KRAS G12C /EGFR blockade in this setting. Efficacy of second-line Ada + Cetux vs chemotherapy in KRAS G12C -mutated mCRC is being investigated in the phase 3 KRYSTAL-10 study (NCT04793958). Clinical trial information: NCT03785249 .

Integrating pharmacogenetic testing in the management of gastrointestinal cancers.

113 Background: Gastrointestinal cancers are among the most prevalent malignancies, often treated with chemotherapeutic agents whose efficacy and toxicity can be influenced by genetic variations. Pharmacogenetic testing for key metabolic genes, including DPYD, UGT1A1, and G6PD, can guide personalized treatment approaches. Methods: We analyzed samples from 3,519 individuals for genotyping using semiconductor-based Next-Generation Sequencing (NGS) technology. High-quality genomic DNA was extracted and subjected to target enrichment via high multiplex PCR amplification using an NGS panel targeting variants of key metabolic genes, including DPYD, G6PD, and UGT1A1. Results: For the DPYD gene, 96% of patients were normal metabolizers. However, 4% intermediate and 0.17% individuals had poor metabolizer status. Poor metabolizers possess homozygous non-functional alleles, leading to complete dihydropyrimidine dehydrogenase (DPD) deficiency and increased toxicity risk with fluoropyrimidine drugs like 5-fluorouracil (5-FU), Capecitabine, and Tegafur. Patients with certain homozygous or compound heterozygous variants in the DPYD gene are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to fluorouracil. 5-FU is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete absence of DPD activity. Intermediate metabolizers exhibit approximately 50% reduced DPD activity, necessitating a 50% reduction in starting doses followed by careful titration based on toxicity. UGT1A1 analysis revealed 46% normal, 42% intermediate, and 12% poor metabolizers, affecting Irinotecan metabolism and toxicity risks. Poor metabolizers show decreased UGT1A1 activity, resulting in reduced clearance of Irinotecan and increased risk of dose-limiting toxicities. These patients are also at higher risk for neutropenia, diarrhea, and asthenia, requiring starting dose adjustments. Additionally, they may experience elevated hyperbilirubinemia with treatments like Regorafenib. Recognizing G6PD deficiency in GI cancers can prevent serious complications and ensure safer treatment options. G6PD testing indicated that 98% were homozygous wildtype, 2% heterozygous, and 0.31% homozygous/hemizygous deficient. Patients with homozygous/hemizygous deficient genotype may be at increased risk for drug-induced hemolysis, particularly when treated with Dabrafenib. Conclusions: These findings highlight the therapeutic significance of incorporating genetic testing into clinical practice to tailor treatments, enhance drug efficacy, and minimize side effects in GI cancer management. By integrating pharmacogenetic insights, the safety and effectiveness of therapies can be significantly improved, ultimately leading to better patient care in GI oncology.

Phase 2 randomized study evaluating safety, efficacy, and optimal dose of ABBV-400 in combination with fluorouracil, folinic acid, and bevacizumab in previously treated patients with metastatic colorectal cancer.

TPS308 Background: Colorectal cancer (CRC) is the third most common cancer. In the metastatic (m) setting, the 5-year relative overall survival is approximately 15%. Conventional treatment comprises fluorouracil (5-FU)–based chemotherapy. Recently, targeted therapies have been studied for specific molecular subtypes. c-Met overexpression frequently occurs in a variety of tumors, including CRC. ABBV-400 is a c-Met–directed antibody-drug conjugate composed of the monoclonal antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor payload. Preliminary data from the first-in-human study of ABBV-400 in patients with advanced solid tumors indicate encouraging efficacy of ABBV-400 monotherapy in patients with third-line or later mCRC. This phase 2 randomized study evaluates the safety, efficacy, and optimal dose of ABBV-400 in combination with 5-FU, folinic acid (FA), and bevacizumab (bev) in patients with mCRC with progression after first line (1L) treatment. Methods: Global, open-label, phase 2 randomized controlled study (NCT06107413). Eligible patients (≥18 years) have confirmed unresectable mCRC and measurable disease per RECIST v1.1, are microsatellite stable or mismatch repair proficient, BRAF V600E wild type, and have progression after 1L combination chemotherapy ± an anti-vascular endothelial growth factor or anti-epidermal growth factor receptor antibody. Primary objectives are (a) optimize ABBV-400 dose in combination with 5-FU, FA, and bev; (b) evaluate the efficacy of the combination, using objective response and progression-free survival as dual primary endpoints; (c) evaluate the safety and tolerability of the combination. Approximately 206 patients planned for enrollment in 2 stages: safety lead-in dose escalation (stage 1; n=30) and dose optimization (stage 2; n=176). In stage 1, patients receive escalating doses of ABBV-400 either every 2 weeks (Q2W; 0.8–2.4 mg/kg) or every 4 weeks (Q4W; 1.6–3.0 mg/kg) in combination with Q2W 5-FU (2400 mg/m 2 infusion), FA (200 mg/m 2 ), and bev (5 mg/kg) in 28-day cycles. Dose escalation of ABBV-400 uses a Bayesian optimal interval design, with target toxicity rate of 30%. Dose-limiting toxicities (DLT) are assessed during cycle 1, with ≥6 DLT evaluable patients required to declare a dose safe for the dose-optimization stage. In stage 2, patients are randomized to up to 4 ABBV-400 dose cohorts (2 with Q2W and 2 with Q4W ABBV-400 schedule; all in combination with Q2W 5-FU, FA, and bev) and a comparator cohort (irinotecan [180 mg/m 2 ] + 5-FU [400 mg/m 2 bolus and 2400 mg/m 2 infusion] + FA [200 mg/m 2 ] + bev [5 mg/kg]; all Q2W). Patients are treated until progression, unacceptable toxicity, or other discontinuation criteria are met. Enrollment was initiated in November 2023, with 3 patients enrolled as of January 4, 2024. Clinical trial information: NCT06107413 .

Unconventional in-plane field-like spin–orbit torques induced by rare-earth Dy interface in Py/Dy/Pt tri-layers

Spin transport across an interface in energy-efficient spintronic devices, especially for spin–orbit torque applications, has sparked interest in the spintronics community. Here, we employ a rare-earth metal spacer Dy to modify the interface of a Py-based heterostructure, with the aim of modulating the spin dynamics of the system and thereby controlling the spin–orbit torques. As the thickness of Dy increases, it is found that the saturation magnetization of Py/Dy decreases and eventually reaches a plateau, suggesting the induced magnetic moment of Dy that aligns opposite to the Fe and Ni moments. Such a self-assembled antiferromagnetic interface can be destroyed by the insertion of a Cu layer between Py and Dy. Utilizing this interface effect, an additional spin dissipation is observed by enhancement of spin dynamic damping, which has achieved a high spin mixing conductance at the interface of Py/Dy according to spin pumping theory. Utilizing the Py/Dy interface, an unconventional in-plane field-like torque spin–orbit torque (SOT) in a Py/Dy/Pt structure is achieved, while the field-like SOT efficiency experiences a notable enhancement in the Py/Dy/Pt system. By optimizing the interface between the Dy layer and Pt, it is possible to further enhance the performance and efficiency of the devices, thereby promoting the development of spintronic devices. This discovery has significant implications for the future design of low-power spintronic devices.

DNMT3b-mediated CpA methylation facilitates REST binding and gene silencing and exacerbates hippocampal demyelination in diabetic mice