Citations

ABSTRACT Background Obesity is an important risk factor associated with atrial fibrillation (AF). The impact of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) on recurrent AF among patients undergoing catheter ablation is not well described. Objective This study aimed to evaluate the effect of GLP‐1 RA on the recurrence of AF among obese patients after catheter ablation. Methods Utilizing the TriNetX research network, we identified patients aged over 18 with obesity (BMI ≥ 30) who underwent AF ablation from January 1, 2015, to December 1, 2022, using Current Procedural Terminology codes. Patients were categorized based on their baseline GLP‐1 RA use. Through propensity‐score matching, each cohort comprised 1558 patients. The primary outcome encompassed a composite of cardioversion, initiation of new antiarrhythmic drug (AAD) therapy, or redo AF ablation. Additional outcomes during the 12‐month follow‐up included AF readmission, heart failure readmissions, readmissions due to ischemic stroke, and mortality, with a separate analysis done for patients with BMI > 40. Results GLP‐1 RA use in patients with obesity undergoing AF ablation was linked to a significantly reduced risk of cardioversion, new AAD therapy, and the need for redo AF ablation (hazard ratio [HR] 0.72 [0.65–0.80]; p < 0.001). At 12 months, individuals on GLP‐1 agonists exhibited a lower likelihood of mortality (HR 0.61 [0.40–0.93]; p < 0.001). Although all other secondary outcomes were lower in the GLP‐1 RA group, there was no significant difference in ischemic stroke between the groups. These results were consistent among patients with BMI > 40, although apart from ischemic stroke, there was no difference in mortality between the two groups. Conclusion The utilization of GLP‐1 RA in individuals with obesity is linked to a decreased likelihood of arrhythmia recurrence following AF ablation, leading to a reduced requirement for cardioversion, AAD therapy, or redo AF ablation.

Abstract Purpose: Recent advances have seen the development of targeted therapeutics against the receptor tyrosine kinase (RTK)/RAS/MAPK pathway, which, when aberrantly activated, drives the malignant transformation of many cancer indications. However, the efficacy of inhibitors targeting single molecules is dampened by pathway feedback activation and acquired drug resistance. We seek to evaluate the application of JAB-3312 (sitneprotafib), a potent inhibitor of SHP2, in RTK/RAS/MAPK pathway–targeted combination therapies. Furthermore, SHP2 plays a vital role in PD-1–mediated immunosuppression. The rational combination of JAB-3312 with PD-1 blocking therapies is also explored. Experimental Design: Biochemical and cellular assays were applied to evaluate the potency of JAB-3312 in SHP2 inhibition. Tumor cell lines and cell line– and patient-derived xenografts were used to test different combinations of JAB-3312 with KRASG12C, MEK, EGFR, and PD-1 inhibitors. Results: JAB-3312 produced potent in vitro inhibition of SHP2 activity and downstream ERK phosphorylation, with IC50 values of 1.44 nmol/L and 0.68 to 4.84 nmol/L, respectively. When used in combination, JAB-3312 significantly increased the antitumor activity of the KRASG12C inhibitor glecirasib in naïve and resistant models. The combination of JAB-3312 with MEK inhibitors significantly delayed RTK signaling reactivation and enhanced tumor growth inhibition in KRAS-mutated cancer models. The JAB-3312–osimertinib combination exhibited great efficacy in osimertinib-resistant non–small cell lung cancer models. Additionally, JAB-3312 enhanced the efficacy of PD-1 blockade therapies by promoting an antitumor microenvironment. Representative cases of patients who responded to the combination therapies from two ongoing clinical trials (NCT05288205 and NCT04720976) were reported. Conclusions: JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockade therapies is a promising strategy that warrants further clinical investigation.

Abstract Aims Catheter ablation is commonly performed in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) for management of ventricular arrhythmias (VAs). The impact of catheter ablation on cardiac function is unknown. The aim is to assess the impact of catheter ablation for VAs on cardiac function in patients with ARVC. Methods and results This retrospective study included consecutive patients with ARVC who underwent catheter ablation for VAs. Cardiac and valvular functions were assessed on pre- and post-procedure cardiac imaging. The severities of tricuspid regurgitation, pulmonic regurgitation, right ventricular (RV) enlargement, and RV systolic dysfunction was graded as absent (=0), mild (=1), mild-moderate (=2), moderate (=3), moderate-severe (=4), or severe (=5). Thirty-four patients were included. Median age at the time of ablation was 49 [inter-quartile range (IQR), 23] years, and 10 (29%) patients were female. After a median follow-up of 1 (IQR, 0) day, 11 (34%) patients had worsening RV function, and 4 (12%) patients had worsening left ventricular ejection fraction (LVEF) &gt;5%. Five (15%) patients required inotropic support. After a median follow-up of 6.5 (IQR, 6.4) months, 20 (59%) patients had repeat transthoracic echocardiograms. Among patients with worsening RV function post-ablation, one-sixth (17%) had improvement in the RV function at follow-up. In contrast, among patients who had an acute drop in LVEF post-ablation, two-thirds (67%) had improvement at follow-up. Conclusion Right ventricular dysfunction following catheter ablation in patients with ARVC is common, affecting one-third of patients. Patients undergoing catheter ablation of VAs should be counselled on the potential negative impact of ablation on cardiac function.

ABSTRACT Background Incident atrial functional mitral regurgitation (AFMR) is associated with mortality. Transcatheter edge‐to‐edge repair (TEER) has shown effectiveness in improving MR and symptoms in AFMR, but previous studies lacked comparison to conservative management. We aimed to study the association of AFMR severity and mitral TEER with symptoms, heart failure hospitalizations (HFH) and all‐cause mortality in moderate/severe AFMR. Methods Consecutive adults with moderate/severe AFMR managed conservatively or with TEER 2010−2023 were identified retrospectively. To ensure similar technique in evaluation in the two groups, variables were obtained from the closest transthoracic echocardiogram before TEER in the TEER group. In addition to multivariable analysis, the association of TEER (vs. conservative management) with HFH and mortality was assessed using propensity‐score matched analyses; the propensity score was based on age, sex, EuroSCORE II, effective regurgitant orifice area, integrative MR severity, and NYHA class III/IV (vs. I/II). Results Among 230 patients with moderate/severe AFMR [mean age 77; 56% females], 46 were managed with TEER. Severe (vs. moderate) AFMR was independently associated with baseline NYHA class III/IV (multivariable OR 2.18 [95% CI 1.13−4.26]) and HFH [multivariable HR 2.75 (95% CI 1.25−6.03)] but not mortality ( p = 0.26). TEER improved MR to ≤ moderate in 93% but was not associated with lower HFH or death rates versus conservative management on multivariable or matched analysis. However, 1‐year NYHA improved more with TEER versus conservative management in patients with baseline NYHA class III/IV (62% vs. 27%, p = 0.03). Rhythm control was associated with improved survival (HR 0.38 [0.15−0.98]). Conclusions AFMR severity was associated with symptoms and HFH but not mortality. MR severity and NYHA class improved with TEER, but the association of TEER with HF hospitalizations or death remains unproven. Randomized studies are needed to evaluate the potential role of TEER and rhythm control on outcomes in AFMR.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract Clonal hematopoiesis (CH) of indeterminate potential (CHIP), driven by somatic mutations in leukemia-associated genes, confers increased risk of hematologic malignancies, cardiovascular disease, and all-cause mortality. In blood of healthy individuals, small CH clones can expand over time to reach 2% variant allele frequency (VAF), the current threshold for CHIP. Nevertheless, reliable detection of low-VAF CHIP mutations is challenging, often relying on deep targeted sequencing. Here, we present UNISOM, a streamlined workflow for enhancing CHIP detection from whole-genome and whole-exome sequencing data that are underpowered, especially for low VAFs. UNISOM utilizes a meta-caller for variant detection, in couple with machine learning models which classify variants into CHIP, germline, and artifact. In whole-exome sequencing data, UNISOM recovered nearly 80% of the CHIP mutations identified via deep targeted sequencing in the same cohort. Applied to whole-genome sequencing data from Mayo Clinic Biobank, it recapitulated the patterns previously established in much larger cohorts, including the most frequently mutated CHIP genes and predominant mutation types and signatures, as well as strong associations of CHIP with age and smoking status. Notably, 30% of the identified CHIP mutations had &lt; 5% VAFs, demonstrating its high sensitivity toward small mutant clones. This workflow is applicable to CHIP screening in population genomic studies. The UNISOM pipeline is freely available at https://github.com/shulanmayo/UNISOM and https://ngdc.cncb.ac.cn/biocode/tool/7816.

Abstract Background: Savo is an oral, potent and highly selective MET-TKI. In the Phase 2 SAVANNAH study (NCT03778229), savo + osi had a high rate of durable responses in pts with EGFRm advanced NSCLC and high MET OverExp and/or Amp levels. Early clearance of plasma EGFRm may predict outcomes. We report an exploratory analysis of plasma EGFRm clearance and its association with MET tissue biomarker status, ORR and PFS. Methods: Pts with EGFRm advanced NSCLC and MET OverExp and/or Amp with PD on 1L+ osi received savo 300 mg QD, 300 mg BID or 600 mg QD + osi 80 mg QD. MET OverExp/Amp was centrally confirmed (by IHC [Roche], 3+ intensity in ≥50% of tumor cells [MET IHC3+/≥50%]; by FISH [Abbott Molecular], MET gene copy number ≥5 or MET:CEP7 ratio ≥2 [FISH5+], or at higher thresholds of MET IHC3+/≥90% or FISH10+). Baseline (BL) and Wk 3 plasma EGFRm (Ex19del/L858R) were analyzed by ddPCR (Biodesix) as an estimate of tumor burden. MET Amp was not monitored in ctDNA due to low detection sensitivity. Clearance was defined as undetected EGFRm ctDNA at Wk 3, when detected at BL. PFS was investigator-assessed (RECIST 1.1). DCO: Aug 23, 2024. Results: Of 344 pts with evaluable BL ctDNA, 259 (75%) had detected EGFRm ctDNA. Of these, 225 had evaluable ctDNA at Wk 3 (82 [36%] had EGFRm clearance at Wk 3). Confirmed ORR was higher in pts with EGFRm Wk 3 clearance (56/82; 68%) vs non-clearance (38/143; 27%). PFS was longer in pts with vs without EGFRm clearance at Wk 3 (Table). Across all pts evaluable for ctDNA at Wk 3, clearance rates were higher in pts with vs without high MET (69/162 [43%] vs 13/63 [21%]; odds ratio [95% CI] 0.35 [0.16, 0.72]). Similar results were seen in the savo 300 mg QD + osi subgroup. Conclusions: In SAVANNAH, among pts with detected EGFRm ctDNA at BL, clearance at Wk 3 was associated with improved ORR and PFS. Plasma EGFRm clearance at Wk 3 is enriched in pts with MET IHC3+/≥90% or FISH10+ status, consistent with improved efficacy in this biomarker subgroup. Citation Format: Jonathan W. Riess, Filippo de Marinis, Benjamin Levy, Tae Min Kim, Laura Bonanno, Quincy Chu, Marcello Tiseo, Adrian Sacher, Silvia Novello, Christina Baik, Lyudmila Bazhenova, Jacques Cadranel, Giulio Metro, Cheng-Ta Yang, Tsung-Ying Yang, Gee-Chen Chang, Konstantinos Leventakos, Lorenzo Livi, James Chih-Hsin Yang, Lecia V. Sequist, John Argue, Wanning Xu, Aleksandra Markovets, Ryan Hartmaier, Myung-Ju Ahn. SAVANNAH: Clearance of plasma EGFRm in patients with EGFRm MET-overexpressed (OverExp) and/or -amplified (Amp) NSCLC post-osimertinib (osi) treated with savolitinib (savo) + osi [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB416.

Abstract Background: Effective treatments (Tx) are needed for MTAP-del cancers (10-15% of all cancers). BMS-986504 (formerly MRTX1719) is a potential first-in-class MTA-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor that selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP-del but not MTAP-wild-type cells. In the first-in-human phase 1/2 CA240-0007 study, BMS-986504 was well tolerated and showed clinical activity in heavily pretreated pts across multiple advanced solid tumors with homozygous MTAP-del. Here, we report results of exploratory PD analyses of PRMT5 inhibition with BMS-986504 in CA240-0007. Methods: Pts with advanced, unresectable or metastatic solid tumors with homozygous MTAP-del received BMS-986504 (50 to 800 mg) in 3-wk cycles. Symmetric dimethylarginine (SDMA) and intron retention are known PD BMs of PRMT5 inhibition. Therefore, PD effects of BMS-986504 were assessed via changes in plasma and tumor SDMA levels (mass spec and IHC), intron retention, and gene expression (RNASeq) based on samples collected at baseline (BL) and cycle 2 day 1 (C2D1). Additional analyses correlating efficacy outcomes with PD results and select mutations at BL were performed in clinically evaluable pts as of 19-SEP-24. Results: Robust PD modulation of the PRMT5 pathway was observed with BMS-986504. Among pts with matched samples (n = 63), median plasma SDMA levels were reduced by 56% from BL (122.6 ng/mL) to C2D1 (53.8 ng/mL). There were dose-dependent reductions in median plasma SDMA with the greatest reductions at 400 mg QD (59.7% [n = 20]), 400 mg BID (61.9% [n = 9]) and 600 mg QD (59.1% [n = 14]). These PD effects were corroborated in the tumor. Median tumor SDMA levels decreased from an HScore of 285 at BL to 0 at C2D1. Consistent with the SDMA decreases, increased intron retention was observed in 9/11 pts with matched samples. BMS-986504 led to downregulation of several gene pathways including DNA repair and mitotic spindle formation, and MYC and E2F targets, as assessed by RNASeq. There was no significant change in expression of MAT2A, PRMT5, or other PRMT genes, suggesting a lack of compensation for PRMT5 inhibition through these genes. Responses were observed with BMS-986504 across EGFR, KRAS, and TP53 mutation subgroups. Additional correlative analyses among BMs and efficacy outcomes will be presented. Conclusions: BMS-986504 demonstrated robust PD effects across multiple doses and solid tumors which is consistent with the proposed mechanism of action. There was a trend of increasing plasma SDMA reduction across doses, with the greatest reductions observed at 400 mg QD and above. Together these results support further investigation of BMS-986504 at 400 mg QD and higher doses as a potential first-in-class synthetic lethal Tx option in pts with advanced solid tumors with MTAP-del. Citation Format: Jordi Rodón, Tyler Simpson, Ben George, Pasi A. Jänne, Kathryn C. Arbour, Konstantinos Leventakos, Kyriakos P. Papadopoulos, Melissa L. Johnson, Alexander I. Spira, Cesar A. Perez, Hani M. Babiker, Richard Zuniga, Candace L. Haddox, Tapsi Kumar, Yidi Qin, Wen-Chi Chou, Peter Olson, Kenna Anderes, Alice Wozniak, Curtis Chin, Ming Lei, Jason T. Henry. Pharmacodynamic (PD) and exploratory biomarker (BM) analysis of the PRMT5 inhibitor BMS-986504 in patients (pts) with advanced solid tumors with homozygous MTAP deletion (MTAP-del) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT079.

Abstract Recent studies have described the tumor microenvironment and the key transcription factors in untreated small cell lung cancer (SCLC), but less is known about the salient features in recurrent SCLC (rSCLC). This information could provide valuable insight about the effectiveness of second and later line therapies. In this study, we compared transcriptome profiles (by RNA-seq) of rSCLC against untreated primaries (pSCLC). rSCLC samples (n=23) were obtained from frozen biopsies in patients enrolled in our MC1923 (NCT04607954) phase 2 clinical trial whose disease progressed after chemoimmunotherapy. The pSCLC group (n=73) included publicly available data from fresh frozen primary tumors after surgical resections. Normalized expression data were used in immune deconvolution and gene set enrichment analysis (GSEA) in molecular signature database. Additional GSEA included gene sets describing ASCL1 (A), NEUROD1 (N), ASCL1 and NEUROD1 (AN), and POU2F3 (P) transcription factor activities which are used for subtyping of SCLC. Immune deconvolutions by multiple software algorithms suggested depletion of immune infiltrates in rSCLC compared with pSCLC including dendritic cells, B cells, CD8+ T cells, and M1 macrophages. Furthermore, we found decreased chemotaxis and increased apoptosis of dendritic cells, reduced TNF signaling, and reduced lymphocyte co-stimulation in rSCLC by GSEA. Additionally, in comparisons with pSCLC, rSCLC tumors had significantly lower enrichment scores for POU2F3 activity, representing the SCLC-P subtype (p &lt; 0.007). Importantly, the SCLC-P was recently reported to be more immune inflamed than the other A, N, and AN subtypes. Altogether, our analyses provide strong evidence that the tumor microenvironment of rSCLC is significantly more immunosuppressed and with reduced immune cell infiltrates compared to pSCLC. Developing therapeutic strategies aimed at “warming” the tumor microenvironment and enhancing anti-tumor immune activity in ongoing multimodal therapies of recurrent SCLC will likely provide significant benefits to patients. Citation Format: Farhad Kosari, Mohamed Ali, Sarah H. Johnson, Alex Adjei, Julian R. Molina, Aaron S. Mansfield, Anastasios Dimou, Kaushal Parikh, Mohamed Shanshal, Katherine E. Smith, Ailsa G. Luce, Anna J. Schwecke, Janet Lensing, Ying-Chun Lo, John C. Cheville, George Vasmatzis, Konstantinos Leventakos. Small cell lung cancer (SCLC) at recurrence has a “colder” tumor microenvironment than primary SCLC according to gene expression profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6614.

Abstract Deletions in 9p21 are common across multiple cancer types including NSCLC. Notably, 9p21 deletions have been implicated in an immune-excluded tumor immune phenotype and worse outcomes following ICIs. Whether this effect is due to CDKN2A loss, collateral loss of MTAP, or loss of type I interferon genes (IFNK, IFNA) has not been fully adjudicated. The Tempus Database (Tempus AI, Inc., Chicago, IL) was queried for de-identified records of patients with NSCLC and DNA (Tempus xT) and RNA (Tempus xR) molecular profiling. CDKN2A/MTAP deleted samples were defined as those containing biallelic loss of CDKN2A/B and MTAP. As IFNK is not included in the DNA sequencing bait set, IFNK status was defined as low in any sample with expression ≤ the first quartile of IFNK expression from samples with intact CDKN2A/B and MTAP. Samples with tumor purity &lt; 40% or mixed loss of CDKN2A/B and MTAP were excluded. Association analysis of CDKN2A/MTAP/IFNK status with other genomic events and clinical outcomes was performed. N=16, 947 patients were included in the overall analysis, of whom n=1, 991 had CDKN2A/B/MTAP deletion (11.7%, CMdel). Significantly more CMdelpatients had low IFNK expression compared to CDKN2A/B/MTAP intact (CMwt) patients (n=14, 956); of CMdel(n=1300), 65.3% had high IFNK expression (IFNKhi) and 34.7% had low IFNK expression (IFNKlo). Among CMdelpatients, IFNKhisamples were enriched in never smokers compared to IFNKlopatients (24% vs 18%, p=0.002). CMdel was enriched in samples with EGFR and ALK driver alterations, and depleted in samples with KRAS or TP53 alterations. In both CMdeland CMwtcontexts, KRAS, EGFR, and ALK alterations associated with IFNKhiexpression, whereas TP53, NFE2L2, STK11, KEAP1, SMARCA4, and KMT2D associated with IFNKloexpression. IFNKhiexpression within CMdelpatients was associated with an increase in the estimated proportion of immune cell subpopulations, including CD8 T cells and macrophages (M1 and M2), and a decrease in neutrophils and NK cells. In metastatic/unresectable stage III patients with recorded ICI-containing 1L therapies (n=1, 795), patients with CMdeland IFNKlotrended toward higher rates of progressive disease (PD) (37%), whereas CMdel/IFNKhihad comparable rates of PD to CMwtl/IFNKhiand CMwtl/IFNKlo(28%, 27%, 30%, respectively). CMdel/IFNKlopatients treated with non-ICI/TKI therapies (mostly consisting of chemotherapy) had a non-significant trend toward increased rate of PD (63%). CMdelassociates with driver alterations in EGFR and ALK, along with worse ICI and chemotherapy outcomes in the context of IFNKlobut not IFNKhi expression. Further work to disentangle the impact of immune infiltrate and the co-mutation landscape will help clarify the underlying associated biology. Citation Format: Natalie Vokes, Jessica L. Symons, Brooke Rhead, Pooja A. Shah, Santiago Trevino, Konstantinos Levantakos, Stamatina Fragkogianni, Calvin Chao, Jordi A. Rodon. Low interferon expression coupled with 9p21 loss in non-small cell lung cancer (NSCLC) patients associated with distinct somatic landscape, altered immune population, and poorer response to immune checkpoint inhibitor (ICI) therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6620.