First-line Therapy Research Articles

Optimizing resources: low-dose nivolumab combinations in the management of relapsed/refractory Hodgkin lymphoma.

Up to one-third of patients with classical Hodgkin lymphoma (cHL) are not responsive to first-line therapy or eventually relapse. Immune checkpoint inhibitors (ICIs) have been successfully employed to treat relapsed/refractory cHL (r/r cHL) but place patients at risk of financial toxicity. Early-phase trials and observational data suggest that low doses of ICIs may achieve similar results to those obtained with high doses. In this study, we report a single-center experience using low-dose nivolumab (LD-Nivo) in different combinations for r/r cHL, including monotherapy, LD-Nivo plus brentuximab vedotin (BV), and LD-Nivo plus chemotherapy. The primary outcome was to assess the efficacy of LD-nivo in patients with r/r cHL. We included 23 consecutive patients (median age 27years; 57% female). LD-Nivo was prescribed in 40, 100, and 140mg fixed doses Q2W. Survival analysis was performed employing the Kaplan-Meier method. 73% of patients achieved an overall response, 43% complete response, and 30% partial response. One-year overall survival was 94.4% (95% CI, 0.84-1), and the 1-year progression-free survival was 89.4% (95% CI, 0.77-1). OS and PFS were similar accross combinations. The median dose of nivolumab was 0.78mg/kg (range, 0.62-1.11), and the median number of cycles until a response was documented was 6 (range, 2-9). During follow-up, 18 patients received transplantation (11 autologous, 6 allogeneic). No statistically significant differences in survival or response were detected between nivolumab combinations or doses. Adverse events were observed in 61% of the patients, with none grade 3-4. LD-Nivo demonstrated promising results in relapsed/refractory HL, highlighting its potential as a cost-effective treatment option. Further research is needed to validate these findings and guide clinical practice.

Rituximab as a first-line therapy in children with new-onset idiopathic nephrotic syndrome

Abstract Background Idiopathic nephrotic syndrome (INS) in children, commonly treated with steroids, poses challenges due to associated side effects. Rituximab, known for its efficacy in reducing relapse frequency in difficult-to-treat cases, emerges a potential first-line therapy for pediatric new-onset INS. Method This is a single-center, retrospective, observational study to evaluate the efficacy and safety of rituximab as a first-line therapy for pediatric INS. The complete treatment strategy was weekly injections at a dose of 375 mg/m2 for 4 doses. Children with new-onset INS who received rituximab as a first-line monotherapy from 1 January 2022 to 31 December 2023 were included and followed until 31 May 2024. Results Seventeen patients (median age at diagnosis: 4.8 years) were included. Twelve patients achieved complete remission within a median time of 19 days. Over a follow-up period ranging from 41 to 112 weeks, eleven patients maintained remission even after B-cell reconstitution, with one patient experiencing a relapse at 85 weeks. Three patients, who presented with hematuria, hypocomplementemia, or renal injury at initial diagnosis, exhibited resistance to rituximab. No severe adverse events were noted. Conclusion Rituximab, as a first-line therapy, may be an effective and safe option for inducing and maintaining remission in newly diagnosed INS.

Clinical Relevance of Intensive Laboratory Monitoring With Standard Venetoclax Ramp-Up for Chronic Lymphocytic Leukemia: A Real-World Experience

PURPOSE Venetoclax is the standard of care for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) but requires intensive monitoring for optimal safety. Clinical relevance of intensive monitoring in practice is unknown, especially for patients with low or intermediate risk for tumor lysis syndrome (TLS). PATIENTS AND METHODS A retrospective review was conducted to determine clinical significance of monitoring for TLS during standard ramp-up for patients with CLL/SLL. Patients receiving abbreviated ramp-up, clinical trials, or concurrent Bruton tyrosine kinase inhibitors were excluded. The primary end point was TLS incidence, with secondary end points describing associated clinical interventions. RESULTS Fifty-five patients met study criteria. The majority of patients received venetoclax as first-line therapy (58%), with anti-CD20 antibody therapy (82%), and were at low risk of TLS (75%). No clinical TLS events occurred, whereas laboratory TLS occurred in only 1.8% of patients. No patients required antihyperuricemic therapy, and few interventions for hyperphosphatemia or hypocalcemia (3.6% of patients) were required. Additional intravenous fluids were uncommonly required (1.8% of patients), and no unplanned hospitalizations were required. CONCLUSION These findings support efforts to reduce intensive monitoring requirements during venetoclax ramp-up for patients with CLL, potentially increasing accessibility of venetoclax.

Clinical significance of visual cardiac 18F-FDG uptake in advanced non-small cell lung cancer

BackgroundTwo-deoxy-2-[fluorine-18]-fluoro-d-glucose (18F-FDG) positron emission tomography (PET) is useful for detecting malignant lesions; however, the clinical significance of cardiac 18F-FDG uptake in patients with cancer remains unclear. This preliminary study explored the relationship between cardiac 18F-FDG uptake and advanced diseases such as cancer cachexia in non-small cell lung cancer (NSCLC).MethodsForty-three patients with advanced NSCLC who underwent 18F-FDG PET and complained of weight loss before the first-line systemic therapy were retrospectively included in this study. Visual assessment using a 5-point scale based on 18F-FDG uptake was performed; a cut-off score of 3 was determined, a low score was 1, 2, or 3, and a high score was 4 or 5).ResultsHigh and low visual cardiac 18F-FDG uptakes were observed in 27 (62.8%) and 16 (37.2%) patients, respectively. Of the 43 patients, 17 (39.5%) definitely had cachexia, and 26 (60.5%) did not. A low visual score and standardized uptake valuemax for cardiac 18F-FDG uptake were significantly associated with high metabolic tumor activity (p = 0.009, and p = 0.009, respectively) and a high neutrophil-to-lymphocyte ratio (p = 0.016, and p = 0.047, respectively), whereas a low visual score for cardiac 18F-FDG uptake and high metabolic tumor activity were significantly associated with cachexia (p = 0.004). The amount of cardiac 18F-FDG accumulation depicted a close relationship with body mass index, low weight loss, and inflammation. The combination of cachexia and low visual cardiac 18F-FDG uptake was identified as a significant predictor for poor overall survival (OS) (p = 0.034).ConclusionDecreased visual cardiac 18F-FDG uptake was associated with poor nutritional status and OS, and cachexia in patients with advanced NSCLC.

Factors associated with poor asthma control in children: A prediction model.

Inhaled corticosteroids (ICS) are the first-line therapy for pediatric asthma. However, very few studies have developed simple tools for predicting treatment outcomes in pediatric asthma. This study aimed to construct a predictive model for poor asthma control in children after 6 months of ICS therapy. This retrospective study included children with asthma, aged 6-15 years, who received ICS with complete follow-up for 6 months. The potential factors associated with poor asthma control were also assessed. Poor control was considered if the child had partial or uncontrolled symptoms according to the Global Initiative for Asthma guidelines. Among the 165 eligible children, 33 (20%) had poor symptom control. The factors associated with poor control were a history of more than four exacerbations in the 12 months before ICS treatment (odds ratio [OR], 3.39 [1.06, 10.83]), the presence of moderate to severe allergic rhinitis symptoms at the 6-month follow-up visit (OR, 21.93 [2.97, 162.05]), and poor adherence to asthma medications (OR, 4.16 [1.32, 13.12]). By incorporating these factors, a model for predicting poorly controlled asthma was constructed and converted into a nomogram with a total score of 200, with prediction risk ranging from 0 to 100%. The area under the receiver operating characteristic curve of the developed model was 0.737, indicating a moderate performance level. We developed a predictive tool for poor asthma control. The model has a good discriminatory ability and is simple to use, which could facilitate the individualized management of children with asthma.

Catheter Ablation or Antiarrhythmic Drugs for Ventricular Tachycardia.

Patients with ventricular tachycardia and ischemic cardiomyopathy are at high risk for adverse outcomes. Catheter ablation is commonly used when antiarrhythmic drugs do not suppress ventricular tachycardia. Whether catheter ablation is more effective than antiarrhythmic drugs as a first-line therapy in patients with ventricular tachycardia is uncertain. In an international trial, we randomly assigned in a 1:1 ratio patients with previous myocardial infarction and clinically significant ventricular tachycardia (defined as ventricular tachycardia storm, receipt of appropriate implantable cardioverter-defibrillator [ICD] shock or antitachycardia pacing, or sustained ventricular tachycardia terminated by emergency treatment) to receive antiarrhythmic drug therapy or to undergo catheter ablation. All the patients had an ICD. Catheter ablation was performed within 14 days after randomization; sotalol or amiodarone was administered as antiarrhythmic drug therapy according to prespecified criteria. The primary end point was a composite of death from any cause during follow-up or, more than 14 days after randomization, ventricular tachycardia storm, appropriate ICD shock, or sustained ventricular tachycardia treated by medical intervention. A total of 416 patients were followed for a median of 4.3 years. A primary end-point event occurred in 103 of 203 patients (50.7%) assigned to catheter ablation and in 129 of 213 (60.6%) assigned to drug therapy (hazard ratio, 0.75; 95% confidence interval, 0.58 to 0.97; P = 0.03). Among patients in the catheter ablation group, adverse events within 30 days after the procedure included death in 2 patients (1.0%) and nonfatal adverse events in 23 patients (11.3%). Among the patients assigned to drug therapy, adverse events that were attributed to antiarrhythmic drug treatment included death from pulmonary toxic effects in 1 patient (0.5%) and nonfatal adverse events in 46 patients (21.6%). Among patients with ischemic cardiomyopathy and ventricular tachycardia, an initial strategy of catheter ablation led to a lower risk of a composite primary end-point event than antiarrhythmic drug therapy. (Funded by the Canadian Institutes of Health Research and others; VANISH2 ClinicalTrials.gov number, NCT02830360.).

Efficiency and safety of Buzhong Tiaogan granule for treating the colorectal cancer patients with liver metastasis: study protocol for a multicenter randomized controlled trial.

To evaluate the clinical efficacy and safety of Buzhong Tiaogan granule (BTG) in treatment of colorectal cancer patients with liver metastasis and provide high-level evidence for clinical practice. This is a prospective, randomized, controlled, multi-center controlled trial. A total of 210 patients diagnosed with spleen deficiency and liver depression, as well as colorectal cancer liver metastasis (CRLM) of the stasis and toxin interception type, will be enrolled in the study. The participants will be randomly allocated into two groups: a treatment group that will receive BTG plus conventional first-line anti-tumor therapy and a control group that will receive conventional first-line anti-tumor therapy alone. The primary outcomes are progression-free survival (PFS) and quality of life scores. The secondary outcomes are as follows: (a) overall survival (OS); (b) objective response rate (ORR); (c) liver-specific progression-free survival; (d) disease control rate (DCR); (e) traditional Chinese medicine (TCM) syndrome score; (f) Piper Fatigue Scale, and (g) Karnofsky Performance Status (KPS) score. Safety evaluations will be conducted throughout the study period. The results of this trial will provide scientific and objective data necessary for the evaluation of the efficacy and safety of BTG for colorectal cancer patients with liver metastasis. The trial was registered at ClinicalTrials.gov (ChiCTR2400084861) on May 27, 2024.

Contemporary treatment of metastatic clear cell renal cell carcinoma

Renal cell carcinoma is one of the mostcommon malignant tumors in Germany with an increasing incidence. Drug therapy is indicated in relapsed or metastatic disease. The article is based on the content of the recent guidelines and aselective literature search. Combination therapies based on acheckpoint inhibitor are the current standard in first-line treatment of metastatic renal cell carcinoma. The median overall survival could thus be extended to > 50months. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score is used for risk classification. When selecting asuitable combination therapy, it is important to consider the advantages and disadvantages for each individual patient. There is currently no standard for follow-up therapies. So far, combination therapies have not shown any significant advantage in second-line treatment. It is recommended to switch to asubstance that has not yet been used. Currently, one purely immuno-oncology combination and four combinations of one immune checkpoint inhibitor and one tyrosine kinase inhibitor (TKI) are approved for first-line therapy in Germany. The added value of further intensification of therapy, in particular through triple combinations or further combination therapy in the second line, has not yet been proven.

The distinctive pharmacokinetic profile of rezafungin, a long-acting echinocandin developed in the era of modern pharmacometrics.

Echinocandin drugs are the current first-line therapy for fungal infections caused by Candida spp. Most patients require once-daily intravenous (IV) administration in a hospital or outpatient setting for treatment, which may negatively impact their quality of life and stress healthcare resources. Similar to other echinocandins, the novel FDA-, EMA-, and Medical and Healthcare Products Regulatory Agency-approved echinocandin, rezafungin (CD101), exhibited strong antifungal activity against several fungal pathogens and a low drug-drug interaction liability, which are important for medically complex patients. A pharmacometric-based approach has been adopted throughout the development of rezafungin, which contrasts with older echinocandins where dosing regimens were largely derived empirically, and only recently based on pharmacometric guidance. This state-of-the-art approach used model-based simulations incorporating pre-clinical and clinical data as it became available to optimize the dosing regimen for rezafungin. The enhanced stability of the molecular structure and the safety profile of rezafungin allow for the administration of once-weekly IV doses, compared to the daily dosing requirement for other echinocandin drugs, with this distinctive pharmacokinetic profile of rezafungin resulting in a front-loaded dosing regimen with high exposures early in therapy for enhanced fungal killing. The long shelf-life of rezafungin makes this echinocandin more flexible in terms of storage and manufacturing. Demonstrated across clinical development, rezafungin may provide patients with next-generation first-line antifungal treatment for the treatment of candidaemia and invasive candidiasis.

Toripalimab Plus Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Lung Cancer

Patients with extensive-stage small cell lung cancer (ES-SCLC) have poor prognoses and unmet medical needs. To evaluate the efficacy and safety of toripalimab plus etoposide and platinum-based chemotherapy (EP) vs placebo plus EP as a first-line treatment for patients with ES-SCLC. This multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (EXTENTORCH study) enrolled patients from September 26, 2019, to May 20, 2021, and was conducted at 49 sites in China. Eligible patients had histologically or cytologically confirmed ES-SCLC without previous systemic antitumor therapy for ES-SCLC. Data were analyzed between May 6, 2023, and June 1, 2024. Patients were randomized (1:1) to receive toripalimab, 240 mg, or placebo plus EP every 3 weeks for up to 4 to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxic effects, or up to 2 years of treatment. The primary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing results identified correlative biomarkers for clinical efficacy. Among 595 screened patients, 442 eligible patients were randomized (median [range] age, 63 [30-77] years; 366 [82.8%] male); 223 patients were randomized to toripalimab plus EP, and 219 to placebo plus EP. By April 20, 2023, the median (range) survival follow-up was 13.7 (0.0-42.7) months. Compared with placebo, toripalimab improved investigator-assessed PFS (hazard ratio [HR], 0.67 [95% CI, 0.54-0.82]; P < .001), and significantly reduced the risk of death (HR, 0.80 [95% CI, 0.65-0.98]; P = .03). The median OS was 14.6 (95% CI, 12.9-16.6) months in the toripalimab group vs 13.3 (95% CI, 11.8-14.4) months in the placebo group. Whole-exome sequencing results from 300 patients identified low intratumor heterogeneity, HLA-A11+ HLA-B62- haplotype, wild-type KMT2D and COL4A4, or sequence variations in CTNNA2 or SCN4A correlated with favorable PFS and OS in the toripalimab group. No new safety signals were observed. Grade 3 or higher treatment-emergent adverse event incidence was similar between the toripalimab and placebo safety set groups (199 of 222 patients [89.6%] vs 193 of 216 patients [89.4%], respectively). In this phase 3 randomized clinical trial, adding toripalimab to first-line chemotherapy demonstrated significant improvements in PFS and OS for patients with ES-SCLC. The treatment exhibited an acceptable safety profile, supporting this combination regimen as a new treatment option for patients with ES-SCLC. ClinicalTrials.gov Identifier: NCT04012606.

Abstract A009: Increasing the Sensitivity to sorafenib of Resistant Hepatocellular Carcinoma Cells with Bovine Lactoferrin through Ferroptosis

Abstract Hepatocellular carcinoma (HCC) remains one of the most lethal cancers worldwide, with a high mortality rate largely due to late-stage diagnosis and the limited efficacy of current therapeutic options. Sorafenib is one of the first-line therapies for advanced HCC. However, its effectiveness is often compromised by the development of drug resistance, significantly limiting its long-term therapeutic potential. This limitation has driven extensive research into alternative therapeutic strategies that can target this resistance, thereby improving the clinical outcomes of patients. Bovine Lf (bLf), which is functionally similar to human Lf (hLf), is safe for human use and has demonstrated anticancer properties, including synergistic effects with chemotherapy. In our study, we explored the role of bovine lactoferrin (bLf) as a potential agent to increase the sensitivity of sorafenib-resistant HCC cells. We developed sorafenib-resistant HCC cell lines through repeated exposure to the drug, with IC50 calculations confirming their increased drug tolerance. These resistant cells were subsequently treated with a combination of sorafenib and bLf. This combination significantly reduced cell viability, with a sorafenib IC50 below the level of the parental sensitive cell line. RNA-seq data revealed significant changes in gene expression profiles, highlighting the differential expression of both mRNAs and long noncoding RNAs (lncRNAs) among resistant, nonresistant, and resistant bLf-treated cells. Further insights were gained through gene set enrichment analysis (GSEA), which identified ferroptosis as a critical pathway significantly enriched in resistant cells treated with bLf and sorafenib vs sorafenib treatment only. Among the differentially expressed lncRNAs, LINC02015 was the most upregulated in resistant cells, and the most downregulated in resistant cells treated with bLf and sorafenib. This lncRNA has emerged as a potentially influencing ferroptosis in other pathologies. Notably, LINC02015 was found to be correlated with HMOX1, a gene with established roles in oxidative stress and iron metabolism. Based on these findings, we conducted a more focused analysis of the ATF3/HMOX1/GPX4 axis, a signaling pathway previously implicated in the regulation of ferroptosis and cellular responses to oxidative stress. Our data suggest that this axis could play a role in modulating lactoferrin-induced ferroptosis in the context of sorafenib resistance. In conclusion, our study provides compelling evidence that bovine lactoferrin (bLf) has the potential to serve as a novel therapeutic agent for overcoming sorafenib resistance in hepatocellular carcinoma by inducing ferroptosis. By potentially targeting the LINC02015/ATF3/HMOX1/GPX4 axis, bLf not only enhances the efficacy of sorafenib but also opens new avenues for the development of combinatory treatment strategies aimed at improving outcomes for HCC patients. Citation Format: Hury V Hernandez-Galdamez, Mireya De la Garza, Karla Rubio, Ivonne Ramirez-Diaz, Josue Guzman-Linares, Theresa Azcarraga Acosta, Guillermo Barreto, stefan günther, Teresita del niño Jesus Flores-Tellez, Mario A Aguilar-Chaparro, Pablo Muriel de la torre, Magda Reyes-López, Saul Villa-Treviño, Carolina Piña-Vazquez. Increasing the Sensitivity to sorafenib of Resistant Hepatocellular Carcinoma Cells with Bovine Lactoferrin through Ferroptosis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A009.

Abstract B036: Pathway repression in progression on osimertinib therapy in NSCLC via a comprehensive genomic and epigenomic circulating tumor DNA (ctDNA) assay

Abstract Background: Osimertinib is currently the most common precision therapy for patients with non- small cell lung cancer (NSCLC) with EGFR mutations. While it prolongs progression-free survival, resistance eventually develops in many, leading to disease progression. Somatic NGS has identified resistance mutations in the EGFR pathway and other oncogenes, but these account for only 40-45% of cases, suggesting non-genetic factors, such as epigenetic changes, may be involved. This study investigates the epigenetic landscape at diagnosis and progression on first- line osimertinib, focusing on cases with and without canonical resistance mutations. Methods: We defined two cohorts from GuardantINFORM, a clinico-genomics database, restricting to only patients with a test on the Guardant Infinity platform, a comprehensive blood-based NGS assay, that analyzes DNA sequence variants and performs extensive methylation profiling (∼15Mb) in &amp;gt;20,000 differentially methylated regions (DMRs) assessed for sample-specific methylation patterns. (A) Diagnosis Cohort: Comprised of 34 NSCLC patients with blood samples collected within six days prior to the initiation of first-line osimertinib therapy. (B) Progression Cohort: Comprised of 36 patients who were on first-line osimertinib therapy, with blood samples collected within 60 days of discontinuation. The progression cohort was further stratified based on the presence or absence of known resistance mutations identified through somatic variant analysis by Guardant360. Gene set enrichment analysis was conducted on these methylation profiles using the Reactome database to define pathway-level differences between the cohorts. Results: Pathway enrichment analysis in the diagnosis and progression cohorts found expected biological processes in NSCLC such as extracellular matrix organization, G- protein coupled receptor (GPCR) signaling, and FGFR pathways. Additionally, the progression cohort lacking canonical resistance mutations (n=23) exhibited unique enrichment in two specific pathways: Glucose-dependent Insulinotropic Polypeptide and Physiological Factors. These pathways include genes such as GATA4, which has been implicated in the epithelial- mesenchymal transition (EMT)—a process associated with transforming to a small cell phenotype, a known mechanism of resistance to EGFR inhibition, including osimertinib. Conclusion: This study demonstrates the utility of epigenetic profiling via liquid biopsies in uncovering non-genetic mechanisms underlying osimertinib resistance in advanced NSCLC. Identification of unique epigenetic pathways in progressing patients without canonical resistance mutations highlights the potential for discovering novel biomarkers of resistance. Further investigation into these findings may advance our understanding of resistance mechanisms across various cancer therapies, particularly for patients without identified genomic resistance, and inform clinical decision-making and trial design. Citation Format: Aaron Hardin, Leslie Bucheit, Amar Das, Craig Eagel, Helmy Eltoukhy. Pathway repression in progression on osimertinib therapy in NSCLC via a comprehensive genomic and epigenomic circulating tumor DNA (ctDNA) assay [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B036.

OGC SO19 - Management and outcomes for Barrett’s oesophagus with dysplasia in a tertiary centre

Abstract Background Barrett’s oesophagus is a premalignant condition. Development of high-grade dysplasia (HGD) formerly was an indication for oesophagectomy, but endoscopic treatment (ET) is now recommended as first-line therapy: radiofrequency ablation (RFA) or endoscopic mucosal resection (EMR). Oesophagectomy is only considered for cases where ET was unsuccessful. Previous review of our institution’s outcomes between 2014 and 2017 showed a 54% complete EMR excision rate and 20% salvage oesophagectomy (n=25). Since then, RFA has been utilised in our institution. We aimed to review our recent data to assess current outcomes. Method Retrospective analysis was performed of patients identified via registration at the Hull University Hospital Trust oesophagogastric MDT between March 2017 and December 2023. Inclusion criteria was confirmed histology of HGD on 2 occasions by 2 specialist pathologists, 6 weeks apart. EMR was performed for focal oesophageal lesions and non-nodular segments were treated by RFA. Patients were included once they had at least one surveillance endoscopy and 6 months had passed following treatment. Patients who were either unfit for ET and managed medically (n=6), and those who were subsequently proven to have more advanced disease and treated surgically (n=4) were excluded. Results 35 patients were identified: 20 underwent EMR, 15 RFA. 55% of EMR patients had successful excision, 9 required additional RFA for residual low-grade dysplasia (LGD). 66% RFA patients had successful ablation. 3 patients required further EMR for residual LGD. Overall 82% had successful ET with no HGD on surveillance. 5 patients had persistent HGD and 1 T1b disease: 4 underwent oesophagectomy, 2 managed oncologically. Barrett’s tended towards being longer in patients where ET failed to eradicate HGD (median 6cm vs 3cm MWU p=0.07). No patient in the series died because of disease-related pathology. 1 patient developed stricture post-RFA requiring dilatation. Conclusion ET for HGD is effective with a high rate of successful treatment. It can be used as a single or dual modality. Salvage oesophagectomy rates are lower than previously reported (8% vs 20%) and complications are low (3% stricture rate). Longer segment Barrett’s may be less likely be responsive to ET, although not reaching significance in our series. ET should continue to be offered as the first-line treatment for oesophageal HGD.

Abstract B044: Fragmentomic features of cell-free DNA predict late-stage melanoma treatment benefit and survival

Abstract The levels of circulating tumour DNA (ctDNA) in cancer patients are associated with response and survival outcomes. Analysis of ctDNA generally requires knowledge of tumour mutations or the application of expensive next generation targeted sequencing. Here we utilize a cutting-edge approach, combining cell-free DNA molecules (cfDNA) fragmentomics and machine learning, to infer the presence of ctDNA to predict response and survival to immune checkpoint inhibitors in stage III unresectable and IV melanoma patients. Genome libraries were constructed from cfDNA derived from 48 (discovery cohort) and 96 (validation cohort) stage III unresectable and IV melanoma patients prior to the commencement of immune-checkpoint inhibitors. The discovery cohort included any-line therapy, patients had a median age of 66, 69% were male, 33% were BRAF V600 mutant, and 88% had an ECOG of 0-1. The validation cohort included first-line therapy, patients had a median age of 69, 59% were male, 22% were BRAF V600 mutant, and 89% had an ECOG of 0-1. Genome libraries were subjected to shallow whole genome sequencing (8x) and the following metrics were calculated: tumour content prediction, aneuploidy levels, various proportions of fragments ranging from 20 bp to 320 bp, the proportion of mitochondrial DNA, and the amplitude of 10 bp size oscillations between 75-150 bp, and the Shannon diversity of trinucleotide motifs at each end of the read. Non-penalized logistic modelling was used to predict clinical benefit, and the resulting logistic model was transformed into a “white-box” model. The white-box model was applied to the cohorts and used to test progression-free and overall survival. The removal of reads with inserts &amp;lt;90 and &amp;gt;150 bp greatly improved chromosome aneuploidy detection from 19% to 31%. Logistic modelling of the fragmentomic features of cfDNA yielded an AUROC of 0.83 for prediction of clinical benefit in the discovery cohort. A cutoff was set for the fragmentomic model score and used to stratify groups for survival analysis. Patients with a low score showed significantly worse progression- free (mPFS 931 vs 286 days, HR 3.4, 95% CI 1.55-7.46, p&amp;lt;0.002) and overall (mOS NR vs 363 days, HR 8.1, 95% CI 2.7-24.3, p&amp;lt;0.001) survival. These results were replicated in the validation cohort with an AUROC of 0.78 for prediction of clinical benefit and significant associations with progression-free (mPFS 1986 vs 926 days, HR 2.33 95% CI 1.27-3.92, p=0.005) and overall (mOS NR vs 1238 days, HR 4.51 95% CI 1.7-11.96, p=0.002) survival. Fragmentomic features of plasma cfDNA enable the prediction of clinical benefit, progression-free, and overall survival in stage IV melanoma patients treated with immune-checkpoint inhibitors. Citation Format: Aaron B Beasley, Leslie Calapre, Ashleigh Stewart, Anna L Reid, Russell Diefenbach, Wei Yen Chan, Rebecca Auzins, Luisa Pinnel, Sanjeev Adhikari, Muhammad A Khattak, Peter Lau, Tarek M Meniawy, Jenny H Lee, Lydia Warburton, Michael Millward, Alexander M Menzies, Richard A Scolyer, Georgina V Long, Helen Rizos, Elin S Gray. Fragmentomic features of cell-free DNA predict late-stage melanoma treatment benefit and survival [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B044.

Demographics and Immunotherapy Efficacy for Advanced Hepatocellular carcinoma: A Systematic Review and Meta-Analysis of Phase III Clinical Trials

Introduction: Immune checkpoint inhibitors (ICIs) are fundamental in treating advanced hepatocellular carcinoma (HCC). Considering previous reports implied varied responses among patient subgroups, such as patients with different hepatitis etiologies, we planned this meta-analysis to identify specific populations that might derive greater survival benefits from ICIs as a first-line treatment. Methods: We conducted a comprehensive search in PubMed and the Cochrane Library for phase III clinical trials comparing ICIs and multikinase inhibitors (MKIs) as first-line therapies for advanced HCC. We extracted and synthesized hazard ratios (HRs) for overall survival (OS) across different patient subgroups mainly using the random effect model. Results: Our analysis included nine phase III trials involving ICIs, either alone or in combination with other treatments, compared with MKIs. The synthesized HRs for patients with hepatitis B virus, hepatitis C virus, and nonviral etiologies were 0.74, 0.77, and 0.86, respectively, showing no significant differences (p = 0.13). Such finding remained when we only analyzed clinical trials with positive results. HRs consistently favored ICIs across various demographics such as age, sex, geographic region, performance status, alpha-fetoprotein levels, and disease stage or extent. Notably, patients with extrahepatic spread showed a trend towards better outcomes (HR 0.73) compared to those without (HR 0.85, p = 0.07). Conclusion: The efficacy of ICIs as a first-line treatment for advanced HCC was consistent across diverse patient subgroups, regardless of hepatitis etiology or other demographic factors. These findings do not support using these characteristics to determine the use of ICI therapy in advanced HCC.

Abstract 4118762: Large-scale multinational trends in the use of cardioprotective antihyperglycemic agents as first-line therapy in patients with type 2 diabetes and cardiovascular disease: a LEGEND-T2DM study

Background: US guidelines for type 2 diabetes (T2DM) recommend metformin as first-line anti-hyperglycemic therapy (AHT), but prioritizing the use of AHTs that reduce cardiovascular disease (CVD) risk – GLP1-RAs and SGLT2is – is increasingly suggested for people with CVD. We examine the multinational use patterns of GLP1-RAs, SGLT2is, DPP4is, and sulfonylureas (SUs) as first-line therapies for patients with CVD. Methods: In 10 US and 6 non-US databases between 2016 and 2021 mapped to a common data model [A], we measured yearly initiation of GLP1-RAs, SGLT2is, DPP4is, and SUs as first-line AHTs in patients with T2DM with and without CVD [B]. We also compared the initiation of the drug classes as second-line after metformin. We calculated the annual rate of change in proportional initiation of each drug class as first-line AHT and assessed differences in trends as group x time interactions in linear mixed models. Results: Across all data sources, 3.3 million patients with T2DM used GLP1-RAs, SGLT2is, DPP4is, or SUs as first-line AHTs, and 3.9m initiated these drug classes as second-line AHT after metformin. Within the first-line cohort, 1.4m (41%) had established CVD compared with 1.2m (31%) in the second-line cohort. For GLP1-RAs and SGLT2is, the annual rate of their relative use as first-line agents increased among patients with T2DM with CVD (GLP1RAs: ranging 1.3-5.4% in US [C] and 0.3-0.8% in non-US [D], SGLT2is: 2.1-12.9% in US [E] and 8.1-10.6% in non-US databases [F]). There was a larger relative increase in the use of SGLT2i and a smaller increase in GLP1RA use in CVD vs non-CVD cohorts (P interaction &lt;.001). While there was a larger increase in GLP1RAs uptake in the US cohorts, SGLT2i use increased more in non-US cohorts ([C-F], P interaction &lt;.001 for all, except .01 for SGLT2i). Of note, across cohorts, the uptake of GLP1RA and SGLT2i as first-line was higher than second-line use among those with CVD (P interaction &lt;.001). In contrast, DPP4i and SU use as first-line was lower than GLP1RA and SGLT2is and decreased over time (P&lt;.001). Conclusions: In a large-scale multinational, federated cohort of patients with T2DM, the use of cardioprotective agents increased as first-line AHT, with variation in SGLT2i and GLP1RAs uptake across study cohorts.

A Proposal for a Simple Subclassification of Advanced Hepatocellular Carcinoma in Systemic Treatment.

This study focused on the presence or absence of vascular invasion and extrahepatic metastasis in hepatocellular carcinoma (HCC) and examined their impact on systemic treatment outcomes. We retrospectively analyzed 362 patients with unresectable HCC who received first-line systemic therapy. The prognostic evaluation was based on the presence of vascular invasion and extrahepatic metastasis at the time of treatment initiation. Patients with vascular invasion or extrahepatic metastasis (advanced group) had significantly worse outcomes than those without these features (intermediate group), with median survival times of 434 and 658 days, respectively. Further subdivision of the advanced group into three categories-patients with only extrahepatic metastasis (m group, n = 77), patients with only vascular invasion (v group, n = 78), and patients with both vascular invasion and extrahepatic metastasis (vm group, n = 52)-revealed that the m group had significantly better outcomes than those in the other two groups, with median survival times of 649, 323, and 187 days, respectively. A comparison of the clinical backgrounds among the three groups demonstrated that the m group had significantly better liver function at the time of treatment initiation than that in the other two groups. Multivariable analysis, including performance status, Child-Pugh score, and the use of immune checkpoint inhibitors as first-line therapy, identified the m group as an independent and significant prognostic factor (hazard ratio, 0.50). Unresectable HCC with extrahepatic metastasis and no vascular invasion represents a novel staging category for systemic treatment.

Overview of diabetes agents in cardiovascular disease: it takes an orchestra to play Tchaikovsky in symphony

Purpose of review The aim of this review was to discuss the use and concerns of diabetes agents, clinical targets, and key aspects to be considered in the management of patients with type 2 diabetes mellitus (T2DM), and at high risk or established cardiovascular disease (CVD). Recent findings The recent European and American guidelines recommended SGLT2 inhibitors and GLP-1 receptor agonists as the preferred first-line diabetes agents in patients with T2DM and CVD. This is a paradigm shift from using metformin as first-line therapy. Amid their widespread use, however, there are also concerns about their side effects. With the rapidly growing diabetes regimens available, questions arise about how best to approach the management of patients with T2DM and CVD. Summary To reduce CVD morbidity and mortality in patients with T2DM and at high or very high risk for CVD, the two key diabetes agents SGLT2i and/or GLP1-based therapies should be offered. Although lacking cardiovascular benefit, other diabetes agents remain necessary for many patients with T2DM for their glucocentric effects; Metformin and pioglitazone are useful in severe insulin resistance, while insulin therapy is often necessary in advanced diabetes; GLP1-RA is cautioned in patients with active gastrointestinal and mental health conditions, while DPP4 inhibitor is likely a well tolerated option in a challenging psychosocial setting. Other important aspects that should be considered include obesity, chronic kidney disease, women's cardiovascular health, and psychosocial factors.

Genomic alterations associated with early-stage disease and early recurrence in patients with colorectal cancer.

The molecular characterization of early-stage (1-3) colorectal cancer (CRC) remains incomplete, as opposed to metastatic disease, where comprehensive genomic profiling (CGP) is routinely performed. This study aimed to characterize the genomics of stages 1-3 versus IV CRC, and the genomics of patients recurring within 1 year of diagnosis. Patients from a de-identified CRC clinico-genomic database who received Foundation Medicine testing (FoundationOne/FoundationOne CDx) during routine clinical care at approximately 280 US cancer clinics between March 2014 and June 2023 were included. Genomic alterations (GA) were compared by Fisher's exact test. A total of 4702 patients were included; 1902 with stages 1-3 and 2800 with stage 4 disease. Among patients with stages 1-3 disease, 546 recurred within 1 year. Patients staged 1-3 had higher prevalence of microsatellite instability (MSI-H, 11.4% vs 4.5%, P < .001), tumor mutational burden (TMB) ≥ 10 Mut/Mb (14.6% vs 6.8%, P < .001), GA in RNF43 (11.2% vs 5.7%, P < .001), MSH6 (3.9% vs 1.7%, P < .001), MLH1 (2.3% vs 0.7%, P < .001), and MSH2 (1.5% vs 0.6%, P < .01) compared to those with stage 4 disease. Patients who recurred within 1 year had higher prevalence of MSI-H (13.2% vs 4.4%, P < .001), TMB ≥ 10 Mut/Mb (16.2% vs 6.9%, P < .001), BRAF V600E (17.2% vs 7.9%, P < .003), GA in RNF43 (13.7% vs 5.3%, P < .001), MSH6 (4.2% vs 1.6%, P = .035), and BRCA1/2 (6.2% vs 3.0%, P = .030). On recurrence, more patients received targeted therapy when CGP was performed before versus after first-line therapy (43% vs 19%, P < .001). Early-stage CRC patients can have distinct genomic profiles and CGP in this population can help expand access to targeted therapies.

First-line triplet therapy for advanced-stage PIK3CA-mutant HR+ breast cancer improves outcomes.

First-line triplet therapy for advanced-stage PIK3CA-mutant HR+ breast cancer improves outcomes.