Browse Articles

Phase II study of neoadjuvant FLOT and chemoradiation for trimodality therapy of esophageal/GEJ adenocarcinoma.

466 Background: Recent data support use of perioperative FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) chemotherapy over pre-operative chemoradiation (CRT) for patients with resectable esophageal/GEJ adenocarcinoma with limited studies evaluating combined FLOT/CRT. This prospective phase II study (NCT04028167) evaluated a neoadjuvant approach of FLOT followed by CRT for resectable esophageal/GEJ adenocarcinoma (EAC). Methods: Operable patients with cT1-2 N1-2 or cT3-4N any4 Nany non-metastatic EAC were eligible. Neoadjuvant treatment consisted of FLOT x 3 cycles followed by restaging PET and chemoradiation (41.4 Gy / 23 fractions to the primary site and regional lymphatics with weekly carboplatin/paclitaxel). Adjuvant nivolumab for non-pathologic complete response (pCR) was permitted. The primary endpoint was pCR rate among patients receiving the study regimen and undergoing resection, with secondary endpoints including disease free survival (DFS), overall survival (OS), toxicity, and correlative studies. DFS/OS was measured using the Kaplan Meier (KM) method. Interim results are presented after a planned safety analysis. Results: Since 4/2020, 23 patients with median age of 62 (range 40-73) have enrolled. cT3-4 and cN+ disease was present in 20/23 (87%) and 16/23 (70%) of patients, respectively. FLOT was completed by 21/23 patients (reasons for discontinuation included allergic reaction and G5 sepsis/endocarditis). All 21 patients initiating chemoradiation completed planned treatment and 17/21 underwent resection (2 refused surgery after achieving cCR, 1 died of cardiac arrest, 1 patient is awaiting surgery). A pCR was observed in 5/17 resected patients (29%), with pCR or near pCR observed in 9/17 (53%). The complete response rate (pCR + cCR for patients refusing surgery) was 7/19 (37%). Adjuvant nivolumab was administered in 9 patients. The median follow-up among all patients was 20 months with 2-year DFS and OS estimates of 61% and 73%. The regimen was tolerated with G3+ hematologic, G3+ gastrointestinal, and G3+ other toxicity observed in 39%, 13%, and 22% of patients, respectively. Conclusions: In a locoregionally advanced population, neoadjuvant sequential FLOT followed by CRT was well tolerated with encouraging DFS/OS and a high rate of complete response compared to prior studies. This hybrid platform may enhance both locoregional and distant control and is of interest for expanded evaluation. Clinical trial information: NCT04028167 .

Lipid nanoparticle ferries therapeutic mRNA to the placenta

Predicting carbon dioxide emissions using deep learning and Ninja metaheuristic optimization algorithm

Deafness-associated mitochondrial 12S rRNA mutation reshapes mitochondrial and cellular homeostasis

Correlation of mesothelin (MSLN) expression measured by RNA sequencing (RNASeq) and immunohistochemistry (IHC) in MSLN-expressing tumors.

766 Background: BASECAMP-1 (NCT04981119) is a pre-screening study to identify patients with tumor-associated human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH) for interventional studies, such as EVEREST-2 (NCT06051695), a phase 1/2 study of logic-gated chimeric antigen receptor T-cell (CAR T) therapy for MSLN-expressing cancers. MSLN is a cell surface protein expressed in several cancer types, including mesothelioma (MESO), colorectal (CRC), non-small cell lung (NSCLC), ovarian (OVCA), and pancreatic (PANC) cancer, which can be associated with poor prognosis (1). Longitudinal clinical, genomic, and biomarker data were collected from patients enrolled in BASECAMP-1, providing a large dataset for translational discovery and propensity scoring. The aim of this analysis was to determine whether MSLN expression measured by RNAseq and IHC are correlated among patients with solid tumors. Methods: In BASECAMP-1, tumor tissue from patients with germline heterozygous HLA-A*02 is tested for HLA-A*02 LOH using an investigational next generation sequencing device codeveloped with Tempus Labs (Lozac'hmeur, et al. NPJ Precis Oncol. 2024) that detects somatic alterations, including HLA LOH, and generates RNAseq data (eg, MSLN expression). Gene-level transcripts per million read (TPM) values were determined and the log2 TPM +1 was displayed in a scatter plot (the mean and standard deviation [SD] are provided in the Table). Patients with HLA-A*02 LOH also submit tissue for IHC testing for exploratory biomarkers (eg, MSLN expression using anti-MSLN clone 5B2). Statistical significance was determined with ANOVA or t-tests. Results: As of June 1, 2024, 314 patients had been screened for BASECAMP-1 and had RNAseq results; 34 patients also had MSLN IHC results. MSLN expression by RNAseq was consistently higher in patients with PANC or OVCA vs CRC or NSCLC ( P <0.001). MSLN expression by RNAseq and IHC were correlated overall ( P <0.001), particularly among patients with PANC and OVCA. Among the 8 patients with OVCA or PANC who were IHC+ for MSLN, only 1 had an RNAseq value below 6 log2 TPM+1; this patient had mesonephric-like ovarian adenocarcinoma, which may account for the low value. The one MESO sample with both RNAseq and IHC available was IHC+ and had a high RNAseq value. Conclusions: This analysis demonstrated high correlation between RNAseq and IHC MSLN expression in tumor tissue. 1. Faust, et al. Cancers. 2022. Clinical trial information: NCT04981119 . MSLN expression by RNASeq by tumor type and IHC status. Tumor Overall (N=314) IHC data available (n=34) MSLN Positive MSLN Negative n Mean TPM a (SD) n Mean TPM a (SD) n Mean TPM a (SD) All 314 5.1 (2.3) 20 6.0 (2.1) 14 2.3 (1.7) adNSCLC 33 3.8 (2.4) 2 4.7 (1.7) 7 1.5 (1.3) sqNSCLC 4 3.1 (1.8) 0 0 MESO 4 4.5 (4.2) 1 5.7 0 CRC 148 4.4 (2.0) 8 5.1 (2.1) 7 3.1 (1.6) PANC 100 6.1 (1.8) 3 7.8 (0.6) 0 OVCA 25 7.2 (2.1) 5 6.6 (2.8) 0 a MSLN log2 transcripts per million+1. ad, adenocarcinoma; sq, squamous.

Identification of candidate biomarkers for gastric cancer by bioinformatics analysis of pooled microarray gene expression datasets in Gene Expression Omnibus.

467 Background: Gastric cancer (GC) remains one of the most prevalent malignant diseases worldwide. The high mortality rate is largely due to the limited treatment options and the challenges in diagnosing the cancer at an early stage. Understanding the genetic differences driving the proliferation of GC is crucial for advancing diagnostic methods and developing targeted treatments. This study aims to identify biomarkers involved in the pathogenesis of GC through integrated bioinformatics analysis. Methods: Extracted from the Geo Expression Omnibus, three DataSets (GSE118916, GSE79973, and GSE13861) were analyzed for differentially expressed genes (DEGs) using the R statistical language. The three data sets were then compared for common DEGs, which would serve as the focus of this study. These DEGs were functionally analyzed for pathways by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein–protein interaction (PPI) network was constructed to screen out candidate genes. Results: The results revealed that 123 DEGs of the three datasets containing 26 upregulated genes and 97 downregulated genes were ascertained in our study. The GO and KEGG enrichment analysis results showed that the functions of DEGs were mainly involved in the retinol metabolic process, xenobiotic metabolic process, collagen type I trimer, potassium: proton exchanging ATPase complex, benzaldehyde dehydrogenase (NAD+) activity, alcohol dehydrogenase (NADP+) activity, Collecting duct acid secretion, and Tyrosine metabolism. Through the PPI analysis network, the core genes with the highest degree of 7 nodes were selected: COL1A1, COL1A2, COL11A1, THBS2, ATP4A, COL10A1, and CXCL8. Conclusions: The 7 genes identified in this study may play a vital regulatory role in the occurrence and development of GC and may also be potential therapeutic targets. Further mechanistic studies of the pathogenesis and treatment of GC may be able to identify new targets using these shared pathways. These findings could contribute to a better understanding of the origins of gastric cancer and facilitate the development of early interventions. The bioinformatics analysis conducted in this study offers new insights and directions for further research on gastric cancer.

A real-world prospective analysis of the relationship between nanoliposomal irinotecan and fluorouracil with folinic acid and neutropenia in patients with pancreatic cancer (NAPOLEON-2 study, NN-2401).

762 Background: Nanoliposomal irinotecan and fluorouracil with folinic acid (NFF) is a standard regimen after gemcitabine-based chemotherapy (CTx) for unresectable or recurrent pancreatic cancer (urPC) patients. Neutropenia caused by systemic CTx has been reported to be a prognostic marker in several cancers, however, the relationship between neutropenia and efficacy of NFF in urPC patients is unknown. Therefore, we initiated a prospective observational study to investigate whether neutropenia can be a prognostic marker in the real-world (NN-2401), followed by a retrospective one (NN-2301). Methods: We collected the data of urPC patients treated with NFF who had received at least one previous CTx in 17 hospitals in Japan from June 2021 to October 2023. The primary endpoint was overall survival (OS). Secondary endpoints included the progression-free survival (PFS) and overall response rate (ORR). To analyze them, we divided urPC patients into three groups by the grade of the most severe neutropenia during NFF (Cutoff A, grade 0 vs 1-4; Cutoff B, grade 0-1 vs 2-4; Cutoff C, grade 0-2 vs 3-4). Besides that, we compared OS among the following three groups receiving NFF ≥4 cycles in Cutoff C; one showed neutropenia with NFF reduction after the 4th cycle (Cutoff C High-Late), another showed neutropenia with NFF reduction in the 2nd or 3rd cycle (Cutoff C High-Early), and the other did grade 0-2 neutropenia (Cutoff C Low). Results: Among the 150 patients, the number of patients with the most severe neutropenia of grade 0, 1, 2, 3, or 4 was 79, 7, 23, 34, and 7, respectively. The median OS of severe neutropenia group in Cutoff A, B, or C was 9.8, 9.8, and 10.6 months, respectively. Both OS and PFS were significantly better in all severe neutropenia groups; hazard ratio [HR] of OS for Cutoff A, B, or C was 0.58, 0.54, and 0.60, respectively; HR of PFS was 0.61, 0.56, and 0.56, respectively. Only Cutoff C showed a significant difference with an odds ratio of 3.06 (95% confidence interval [CI], 1.06-8.80; p=0.04) in ORR. Multivariate Cox regression analysis showed significant difference of OS in all Cutoffs; adjusted HR was 0.58 for Cutoff A, 0.53 for Cutoff B, and 0.52 for Cutoff C. Logistic regression analysis showed a significant difference in ORR of Cutoff C with an odds ratio of 4.02 (95%CI, 1.29-12.6; p=0.02). In addition, the numbers of patients were 73, 14, and 19 in Cutoff C Low, High-Late, and High-Early, respectively. The median OS of Cutoff C High-Late was significantly better than that of Cutoff C High-Early or Cutoff C Low (15.0 vs 10.4 or 9.1 months, p<0.05). Conclusions: In NFF treatment, neutropenia showed the usefulness as a prognostic marker for both OS and PFS, and also a predictive one for tumor response in urPC patients. The results are similar to our previous data, so we conclude that neutropenia can be a useful biomarker of NFF. Clinical trial information: UMIN000043939 .

NRG-GI007: Secondary endpoints of safety assessment and clinical complete response (cCR) of chemoradiation with endoscopically injected oncolytic virus OBP-301 in medically inoperable esophageal cancer.

435 Background: Definitive chemoradiation (CRT) is a standard-of-care for patients (Pts) with medically inoperable esophageal cancer (EC). The NRG/RTOG 0436 study of cisplatin/paclitaxel and RT (+/- cetuximab) as definitive therapy showed that 58% of control arm Pts have locally persistent disease. OBP-301 is a conditionally-restricted, replication-competent adenovirus derived from human adenovirus type 5 that adds a human Telomerase Reverse Transcriptase gene promoter, replicating only in tumor cells to cause lysis.It may cause immunogenic cell death, enhance RT increasing radiosensitization by blocking DNA repair and improve local control. Methods: In NRG-GI007, a phase 1 study (NCT04391049), OBP-301 was added to weekly carboplatin/paclitaxel and RT (50.4 Gy/28 fxs) for medically inoperable EC Pts with pathologically proven adenocarcinoma or squamous cell carcinoma (SCC) of the esophagus or Siewert Type I/II gastroesophageal junction. Pts receive 1-2mL of intratumoral OBP-301 1×10 12 virus particles/ml via endoscopy 3 days prior to and then at days 12 and 26 of CRT. The primary endpoint was protocol-defined dose-limiting toxicity, already reported. Secondary endpoints reported here are treatment-related (definitely or probably related to any protocol treatment) AEs - all and grade 4+ non-hematologic, and cCR in the primary tumor, defined as negative EGD/biopsy 6-8 weeks post-CRT. Per the protocol design, no statistical testing is done for these endpoints. Results: Initially, 6 evaluable (eligible and started protocol treatment) Pts were enrolled from June 2020 to April 2023. As initial dose level was deemed safe, an additional 9 Pts were enrolled from August 2023 to July 2024, totaling 15 evaluable Pts for secondary endpoints. Median age was 74 years, 9 Pts (60%) with ECOG PS 1. 11 Pts (73%) had adenocarcinoma and 4 had SCC; 11 Pts had N+ disease. 14 Pts (93%) received all planned OBP-301 injections and received 50.4 Gy RT. The most common treatment-related grade 3/4 AEs were decreased neutrophil (6 Pts; 40%) and lymphocyte counts (5 Pts; 33%), expected with CRT. No grade ≥3 OBP-301-related non-hematologic AEs were reported. 2 Pts died prior to restaging neitherdefinitely or probably related to OBP-301: 1 Pt developed grade 5 respiratory failure 6 weeks after CRT (suspected RT pneumonitis), while a 2 nd Pt had an unrecognized tumor invasion of the bronchus at baseline, which worsened during week 3 of CRT, resulting in a grade 5 tracheo-esophageal fistula. 2 Pts have not yet reached time for restaging. All 11 Pts who have been restaged had a cCR, for a preliminary cCR rate of 100% (95% CI: 74.1%, 100%). Conclusions: OBP-301 + CRT is safe and the preliminary cCR rate compares favorably to the historical control from NRG/RTOG 0436. Updated safety and cCR data will be presented. A randomized study is being planned. Clinical trial information: NCT04391049 .

Robust machine learning based Intrusion detection system using simple statistical techniques in feature selection

Porphyromonas gingivalis gingipain potentially activates influenza A virus infectivity through proteolytic cleavage of viral hemagglutinin

Evaluation of event-free survival (EFS) as a surrogate for overall survival (OS) in patients with locally advanced esophageal carcinoma (LA EC) receiving definitive chemoradiotherapy (dCRT).

412 Background: Drug development in esophageal cancer is rapidly evolving, and identifying surrogates for patient outcomes to accelerate clinical drug development remains an important unmet medical need. Although early clinical endpoints such as EFS, disease free survival (DFS) are proven to be valid surrogates for overall survival (OS) in early esophageal (Ajani JA et al. 2022), gastric (Oba K et al. 2013; Wainberg ZA et al. 2023), and gastroesophageal junction tumors (Ronellenfitsch U. et al. 2013) after disease resection, there are no such surrogacy data evaluating patients who underwent non-operative management. Specifically, there has been no prior systemic evaluation of the predictive value of EFS as a surrogate for OS among LA EC patients treated with dCRT. This study evaluated the trial-level correlation between EFS and OS in unresectable LA EC patients receiving dCRT. Methods: A systematic literature review was conducted to identify randomized controlled trials (RCTs) of dCRT interventions in unresectable LA EC (search cutoff date: April 2023). Studies reporting EFS (or similar outcomes such as progression free survival (PFS), defined as time from randomization to local, regional, or distant recurrence, or death) and OS were included. EFS and OS hazard ratios (HRs) of each treatment comparison were extracted. Correlation between the log(HR) of EFS and OS was assessed using weighted linear regression (WLR). The coefficient of determination (R 2 ) was used to evaluate the strength of the correlation. A good surrogate was defined as an R 2 ≥ 0.65 (Ciani et al . 2017) or an R 2 ≥ 0.75 (Lassere et al . 2008). Leave-one-out cross-validations and sensitivity analyses were conducted to assess the robustness of the WLR model and correlation analyses, respectively. Results: The final analysis included 14 between-treatment comparisons from 11 RCTs (total number of patients = 2,812). We found a strong statistical correlation between EFS and OS, with an estimated slope coefficient of 0.91 ( p < 0.001) and R 2 of 0.80 (95% confidence interval [CI]: 0.38, 0.96). In the leave-one-out cross validation, 71.4% of observed OS HRs fell within the predicted 95% CIs. Sensitivity analyses showed R 2 of 0.75 among studies conducted in China and R 2 of 0.73 after including studies that did not report EFS definition. Conclusions: In a pooled analysis of 11 clinical trials corresponding to over 2800 patients, we observed a strong statistical correlation between EFS and OS outcomes. This analysis supports the utility of EFS as a valid surrogate of OS in patients with unresectable LA EC receiving dCRT.

A phase 2, multicenter, open-label study of AlloStim in-situ cancer vaccine immunotherapy as 3L therapy in MSS/pMMR metastatic colorectal cancer.

TPS317 Background: Neoantigen therapeutic cancer vaccines have had limited clinical benefit in metastatic tumor settings. Tumor immunoediting selects tumor clones over time that are non-immunogenic. In addition, the metastatic tumor microenvironment (TME) becomes profoundly immunosuppressive. Microsatellite stable (MSS) and mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) tumors do not accumulate mutations, resulting in low mutational burden (TMB) and a lack of neoantigen targets. Consequently, therapeutic vaccine approaches for mCRC have had difficulty in demonstrating clinical effectiveness. Novel approaches that boost the immune response in low TMB tumors may benefit mCRC patients. AlloStim is an allogeneic, non-genetically manipulated, living Th1-like cell immunotherapy. The Th1-like cells are ex-vivo differentiated and expanded from healthy blood donors and activated prior to infusion. These cells are designed to be rejected upon intradermal (ID) injection. Repeated ID injections elicit high titers of allo-specific Th1 memory cells in circulation. In allo-primed patients, intravenous (IV) infusion of AlloStim causes a rejection response that releases cytokines, such as IL-12, which non-specifically activate circulating memory T cells and NK cells. Activated host memory T-cells and NK cells extravasate and traffic to metastatic tumor sites. This creates the conditions for “in-situ vaccination”. Activated NK cells cause disruption of the cell membrane and release of chaperoned neoantigens into the tumor microenvironment, a process known as immunological cell death (ICD). The release of neoantigens into the microenvironment in the context of inflammation mediated by infiltrating Th1 memory cells creates conditions for in-situ vaccination. In situ vaccination represents an alternative immunotherapy approach in which a therapeutic cancer vaccine is generated in vivo without the need to previously identify and isolate tumor neoantigens. Methods: To investigate this novel in-situ vaccine mechanism, a phase 2, multicenter, single-arm clinical trial in 3L MSS/pMMR mCRC subjects that have been previously treated with oxaliplatin-containing and irinotecan-containing chemotherapy regimens, anti-EGFR (RAS wt and left-sided) and anti-VEGF was initiated. Patients were administered weekly AlloStim in three 28-day cycles consisting of 4 ID injections and a combination ID and IV infusion on the final week in each cycle to create self-amplifying waves of allo-specific and tumor-specific host immune cells in circulation which traffic to tumors upon IV infusion. The primary end-point is overall survival. 21 evaluable patients have been enrolled and are currently being followed for maturity of the survival data. Clinical trial information: NCT04444622 .

Seven-year efficacy and safety in a randomized phase III trial investigating duration of adjuvant oxaliplatin-based therapy (3 vs. 6 months) for patients with high-risk stage II colon cancer: ACHIEVE-2 trial.

169 Background: ACHIEVE-2 was conducted as one of four phase III trials for patients with high-risk stage II colon cancer (CC) investigating the duration of adjuvant (adj) oxaliplatin-based therapy in a prospective pooled analysis, IDEA collaboration. The results of the 7-year follow-up are presented here. Methods: From Feb 2014 to Jan 2017, 525 Asian patients with high-risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation, or vascular invasion) were randomly assigned to 3- or 6-month mFOLFOX6/CAPOX treatment after curative surgery. The cutoff date for the data was Jan 2024. Results: Of the 525 randomized patients, 11 were not treated. Among the 514 participants (255 in the 3-month arm; 259 in the 6-montharm), 432 (84%) received CAPOX and 184 (36%) presented with T4 as a high-risk factor for recurrence. The baseline characteristics of the patients in each arm were well balanced between the treatment arms and two therapy regimens. The 7-year disease-free survival (DFS) rates were 83.4% and 81.8% in the 3- and 6-month arms, respectively (hazard ratio [HR]= 1.00 [95% CI, 0.66-1.53]). The 7-year overall survival (OS) rates were 88.4% and 88.8% in the 3- and 6-month arms, respectively (HR= 1.16 [95% CI, 0.70-1.93]). With CAPOX, the HR for DFS and OS of the 3-month arm compared with the 6-month arm were 0.97 (95% CI, 0.61-1.52) and 1.09 (95% CI, 0.64-1.89), respectively. Multivariate analysis of the six high-risk factors for recurrence showed that T4 and inadequate nodal harvest were independent risk factors for both DFS and OS. The rates of any grade of peripheral sensory neuropathy (PSN) lasting up to 96 months in the 3- vs. 6-month arms were 7.9% vs. 25.0% ( P= 0.0189 ). With CAPOX, the incidence of PSN lasting up to 96 months in the 3- vs. 6-month arms were 9.4% vs. 27.5%. Conclusions: The incidence of long-lasting PSN was significantly lower at 3 months than at 6 months of therapy. Three months of CAPOX therapy may be appropriate for high-risk stage II CC, as shorter treatment did not worsen the outcome, even after a long follow-up. Clinical trial information: UMIN000013036 .

Impact of <i>UGT1A1*28</i> polymorphism on tolerability in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX in NAPOLI 3.

717 Background: SN-38, the active metabolite of irinotecan, is cleared by the liver enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and biliary excretion. UGT1A1*28 (genotype 7/7) homozygosity is associated with reduced activity of UGT1A1 and a recommendation for dose adjustment of non-liposomal irinotecan, a component of the FOLFIRINOX regimen. In this post-hoc analysis, we analyzed the impact of UGT1A1*28 homozygosity on the incidence and profile of treatment-emergent adverse events (TEAEs) among patients enrolled in NAPOLI 3 (NCT04083235). Methods: Patients (N = 770) with confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m 2 + oxaliplatin 60 mg/m 2 + leucovorin 400 mg/m 2 + 5-fluorouracil 2400 mg/m 2 (NALIRIFOX) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. UGT1A1*28 status was evaluated in all patients before enrollment. All patients, regardless of UGT1A1*28 status, received the full starting dose of liposomal irinotecan and followed the same dose reduction rules. This exploratory analysis of TEAEs by UGT1A1*28 status was descriptive; statistical analyses were not performed. Results: Overall, 83 patients (11.0%) were homozygous for UGT1A1*28 , among whom the incidence of TEAEs was similar to patients with non-homozygous status (Table). The most frequently reported TEAEs (≥ 40%) among the homozygous group (vs the overall NAPOLI 3 population) were diarrhea (59.0% vs 70.5%), nausea (56.4% vs 59.5%), vomiting (46.2% vs 39.7%) and anemia (41.0% vs 26.2%) in the NALIRIFOX arm and nausea (45.5% vs 42.7%), fatigue (45.5% vs 37.7%), diarrhea (45.5% vs 36.7%) and anemia (40.9% vs 40.4%) in the Gem+NabP arm. Conclusions: The incidence of TEAEs, including TEAEs leading to death, was similar between patients with homozygous and non-homozygous UGT1A1*28 status, in both treatment arms. The profile of TEAEs was consistent with that of the overall NAPOLI 3 population. UGT1A1*28 status did not substantially influence the safety profile or subsequent need for dose reductions of liposomal irinotecan in NAPOLI 3. Clinical trial information: NCT04083235 . UGT1A1*28 homozygous UGT1A1*28 non-homozygous TEAE, n (%) NALIRIFOX (n = 39) Gem+NabP (n = 44) NALIRIFOX (n = 328) Gem+NabP (n = 331) Any 39 (100.0) 44 (100.0) 327 (99.7) 328 (99.1) Related to any drug 39 (100.0) 41 (93.2) 310 (94.5) 308 (93.1) Grade ≥ 3 31 (79.5) 34 (77.3) 288 (87.8) 288 (87.0) Serious 24 (61.5) 24 (54.5) 176 (53.7) 168 (50.8) Leading to treatment discontinuation 15 (38.5) 10 (22.7) 103 (31.4) 100 (30.2) Leading to dose reduction of any drug 23 (59.0) 14 (31.8) 182 (55.5) 174 (52.6) Leading to interruption of any drug 1 (2.6) 1 (2.3) 15 (4.6) 3 (0.9) Leading to death 2 (5.1) 4 (9.1) 20 (6.1) 19 (5.7)

2024 FDA approvals

Synergistic effect of defocus incorporated multiple segment glasses and repeated low level red light therapy against myopia progression

Abstract Defocus incorporated multiple segment (DIMS) lenses and repeated low-level red-light (RLRL) are used to retard myopia progression. However, it is currently unknown if there is a synergistic effect of the two interventions. In the current study, 190 school-aged children with myopia (380 eyes) were studied for the change in axial length (AL) over nearly one year of follow-up. Of 380 eyes, 170 eyes wore DIMS lenses, 80 eyes had RLRL therapy, and 130 eyes had both interventions (DIMS_RLRL) for myopia control. AL changes were calculated at each follow-up visit by subtracting the baseline measurements and normalized to yearly changes in mm. AL changes as a primary outcome were analyzed in a generalized linear mixed model to compare effect sizes of myopia control among three interventions while adjusting for age, sex, baseline axial length, and follow-up length. Participants had a mean age of 9.84 ± 2.63 years old, mean AL of 24.49 ± 1.20 mm, mean SER of -2.90 ± 2.08 diopters, and mean follow-up time of 301 ± 91 days. By the end of the study, the adjusted mean yearly axial change with combination therapy was − 0.13 mm, -0.04 mm for the eyes with RLRL alone, and 0.16 mm for the eyes with DIMS lenses alone (p &lt; 0.0001). Combination therapy of DIMS and RLRL has significantly greater effect size in controlling myopia progression than either RLRL alone (p = 0.0009) or DIMS alone (p &lt; 0.0001).

Toxin protein LukS-PV targeting complement receptor C5aR1 inhibits cell proliferation in hepatocellular carcinoma via the HDAC7–Wnt/β-catenin axis

Trends in utilization of colorectal cancer screening modalities among patients with average risk in the United States from 2017 to 2023.

98 Background: Colorectal cancer (CRC) is the second leading cause of cancer mortality in the US. The national CRC screening rate (58%) is still below 80%, which is the goal set by the National Colorectal Cancer Roundtable. National guidelines recommend multiple strategies for CRC screening including colonoscopy, sigmoidoscopy, CT colonography, fecal occult blood test (FOBT), fecal immunochemical tests (FIT), or multi-target stool DNA (mt-sDNA) test. To provide updated insights regarding proportional utilization of different CRC screening strategies, we analyzed modality-specific CRC screening rates across demographic subgroups between 2017 and 2023. Methods: A retrospective review was conducted using a large national claims database that covers over 165 million lives and is representative of the US population for the study period from 2017 to 2023. Individuals were included if they were aged 45-75 years, at average CRC risk in the baseline period of 1 year before the index date and continuously enrolled in a health plan for at least 1 year after the index date. The index date was defined as date of the first claim for a CRC screening test. CRC screening uptake by modality and newly screened individuals each calendar year were examined among the entire eligible population and across demographic subgroups. Results: Overall rates of CRC screening were relatively stable across the study years (approximately 20%) with the lowest annual proportion of screen eligible patients in 2020 (16.6%) and highest in 2023 (24.4%). For CRC-screened individuals, colonoscopy was the most commonly used screening modality, increasing from 1,943,733 (53%) in 2017 to 2,319,695 (58.7%) in 2023. The mt-sDNA test use increased significantly from 87,769 (2.4%) in 2017 to 807,227 (20.4%) in 2023; while FIT/FOBT use declined from 1,611,730 (44%) in 2017 to 805,150 (20.4%) in 2023. Utilization of colonoscopy and mt-sDNA tests increased notably among the 45–49 age group starting in 2021, while FIT/FOBT use simultaneously declined in this age group. Observed trends were similar to the above findings across additional subgroups defined by gender, race/ethnicity, payer type, and geographic region. Conclusions: Data from this large study of national claims data provides updated results for overall and proportional utilization of guideline-endorsed CRC screening strategies. While colonoscopy usage remained stable , the use of the non-invasive mt-sDNA test has increased significantly as FIT/FOBT usage declined over time, reflecting growing interest in this noninvasive, home-based option.

Evaluating the clinical benefits of anti-cancer drugs approved by Food and Drug Administration for gastrointestinal neoplasms for the past two decades.

820 Background: The number of FDA-approved anticancer drugs have increased in recent years with a more use of surrogate endpoints. However, it is unclear whether the same trend applies to GI cancers. Therefore, we aimed to evaluate the trend in FDA-approved GI cancer drugs over the past two decades and the associated clinical benefit. Methods: The FDA’s online database was searched for drugs approved for GI cancers from 2006 until 2024. Primary and secondary endpoints along with trial characteristics were extracted. ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) was assessed by two blinded investigators with a third resolving disagreements. We divided the study into period A (01/2006-12/2014) and period B (01/2015-08/2024). Results: Since 2006, FDA approved 62 regimens for GI cancer based on 70 trials, mostly (n= 45;72.6%) in period B. Most trials (n=44) were phase III with only 26 phase II: 22 single arm, and 4 randomized. All the 22 single-arm phase II trials were approved in period B with two randomized phase II trials approved in each period. Approvals based on phase III trials dropped by 33.5% (from n=15 to n=29) between the two periods. Half (n=34) of the approvals were based on overall survival (OS) benefit, while the use of objective response rate (ORR) as an endpoint has increased from 11.8% (n=2) in period A to 45.3% (n=24) in period B. Quality of life (QoL) was assessed only in 27% of the studies and found benefit only in 22.7%. The mean gain in OS was similar across both periods; 2.3 months [1.2-4.7]. Out of the 19 accelerated approvals, 17 were in period B, of which 23% (4/17) were based on secondary endpoint, 18% (3/17) were withdrawn, and 59% (10/17) received full approval. Substantial clinical benefit (ESMO score 4-5) was seen in 11.8% of the trials in period A and 19.6% in period B, with 17.4% overall from 2006-2024. Conclusions: Despite rising FDA approvals for GI cancer drugs since 2006, only 17.4% demonstrated substantial clinical benefit based on ESMO-MCBS. Recent approvals rely more on single-arm phase II studies and ORR, often without OS or QoL benefit. These trends underscore the need for more rigorous clinical trials that prioritize meaningful endpoint to ensure that new therapies provide real clinical value to the patient.

Utility of computed tomography (CT) –based staging of mismatch repair deficient (dMMR) colon cancer.

45 Background: dMMR tumors are characterized by rapid primary tumor growth with reduced likelihood for nodal and distant metastases compared to MMR proficient (pMMR) tumors. Neoadjuvant immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy for localized colon cancer with high pathologic complete response rates and low relapse rates. This raises the question if surgical treatment could be avoided with accurate radiographic staging while avoiding overtreatment of early stage tumors. This study assesses the utility of radiographic staging by CT for dMMR tumors compared to pathologic staging. Methods: Patients with stage I-III colon cancer treated with upfront surgical resection were retrospectively reviewed from a single institution from 2012 to 2023 in two cohorts: 1) dMMR colon cancer and 2) pMMR colon cancer limited to similar sample size as matched controls. Clinical stage was determined based on CT scans prior to surgical resection by 2 independent radiologists blinded to pathologic stage, and the results were correlated to pathologic stage. Clinical characteristics were extracted from the electronic medical record. Statistical analysis was performed using SPSS. Results: We identified 80 patients with dMMR colon cancer and 66 with pMMR tumors. CT clinical tumor staging was discordant from pathologic staging for 68% of dMMR tumors and 61% for pMMR tumors. For T4 dMMR tumors, CT had a 74% sensitivity and 44% specificity. T4 tumors were understaged by radiology to less than T4 for 56% of cases. For dMMR nodal staging, CT had 89% sensitivity and 50% specificity (Table 1). For pathologic node positive tumors, 14% were understaged by radiologist CT read to node negative. For pathologic node negative tumors, 50% of tumors were overstaged to node positive by radiologist CT read. There was poor inter-rater reliability for both T stage and N stage for dMMR and pMMR tumors. The weakest agreement between radiologists was for T stage (dMMR kappa = 0.246, mMMR kappa = 0.145). Conclusions: Radiologic clinical staging of dMMR and pMMR colon cancer does not correlate well with pathologic staging. There were high rates of understaging by CT evaluation for patients who may be candidates for neoadjuvant treatment (T4, N+). Furthermore, there was poor inter-rater reliability between radiologists, indicating that CT staging alone may not be sufficient. Additional diagnostic modalities for nodal detection may be necessary to accurately clinically stage patients before neoadjuvant ICIs in patients with locally advanced disease. Comparing utility of pMMR versus dMMR tumors for T4 and node positive disease. pMMR (n = 66) dMMR (n = 80) T4 versus T3 or less Sensitivity (%) 92 74 Specificity (%) 51 47 PPV (%) 80 77 NPV (%) 82 63 Node positive versus node negative Sensitivity (%) 60 50 Specificity (%) 75 89 PPV (%) 81 89 NPV (%) 53 50 Abbreviations: PPV = positive predictive value; NPV = negative predictive value.