Citations

Abstract Background: Kinases from the SRC family of kinases (SFK) are predominantly inactive in non-cancerous cells and have been shown to be highly activated in tumor tissue. The role of SFKs in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development has been extensively described. NXP900 is a novel, selective SFK inhibitor with low nanomolar potency against YES1 (0.47nM) and SRC (2.4nM). NXP900 has a unique binding mode of action (MOA), whereby it locks its target into its native “closed” conformation (type 1.5 inhibitor), resulting in inhibition of both the kinase and the scaffolding functions of the target kinase. This MOA differentiates NXP900 from other multi-kinase inhibitors, that, among other kinases, also inhibit the kinase activity of SFK targets. These multi-kinase inhibitors lock their targets in the active “open” conformation (type 1 inhibitors), and in the case of SFK targets, while this results in inhibition of the kinase activity, it also promotes the association of SFK with pro-cancer signaling partners. In addition, NXP900 is very selective, with minimal inhibitory activity against kinases outside the SFK. Methods: Study NXP900-101 (NCT05873686) is a first-in-human, Phase 1, dose escalation and expansion clinical trial of NXP900 in patients with advanced solid tumors. The primary objective of the study is to identify a dosing regimen with an acceptable safety profile and clinically relevant pharmacokinetics and pharmacodynamics (PK/PD) for additional clinical investigations. The key safety endpoints are estimation of the incidence and intensity of adverse events and identification of the highest tolerable dose. To characterize the PK/PD profile of NXP900, serial blood samples were collected after single and multiple doses of NXP900. Results: In 26 patients with advanced solid tumors treated with 20-200 mg/day NXP900, the median age was 61 years (range: 35-88), 65% were male and the median number of prior lines of anti-cancer therapy, including surgery, was 5. The most common treatment emergent adverse events (total incidence >20%) were largely reported as Grade 1-2 and included fatigue (42%, Grade 1-2: 91%), diarrhea (35%, Grade 1-2: 89%), nausea (31%, Grade 1-2: 100%), and dyspnea (23%, Grade 1-2: 67%). NXP900 exposure was dose proportional across the evaluated range (20-200 mg); following a single 200 mg oral dose, NXP900 demonstrated rapid absorption with median peak plasma concentration and terminal half-life of approximately 3 and 12 hours, respectively. Multiple dosing (20-200 mg daily) resulted in moderate drug accumulation. PD analysis showed that NXP900 potently inhibited the phosphorylation of SRC across a range of clinically relevant doses in peripheral blood mononuclear cells. Conclusions: In its first-in-human clinical trial in patients with advanced solid tumors NXP900 was biologically active with an acceptable safety profile, supporting its continued clinical development. Citation Format: Gerald Falchook, Jordi Rodon Ahnert, Shivaani Kummar, Hani M. Babikar, Stefan Symeonides, Mitesh J. Borad, Jason Henry, J. Mark Sloan, Justin L. Hay, Megan Sardone, Udai Banerji. First in human phase 1 trial of the SRC family kinase inhibitor NXP900 in patients with advanced solid tumors [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 CT153.

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.

Background: Although it is well established that the type of organism can be a risk factor for failure in patients with periprosthetic joint infection (PJI), no study to date has examined the impact of the number of positive cultures on treatment outcomes in patients undergoing 2-stage exchange. The purpose of this multicenter study was to determine the prognostic utility of multiple positive cultures at resection as a predictor of failure following reimplantation. Methods: This retrospective multicenter study identified 437 patients with chronic knee PJI who had undergone 2-stage exchange arthroplasty with a minimum of 1 year of follow-up following reimplantation. PJI was defined with use of the 2013 Musculoskeletal Infection Society (MSIS) criteria. Patients with culture-negative PJI were excluded (n = 138). Treatment failure was defined as either any reoperation for infection or PJI-related mortality. Multivariable regression controlling for risk factors for failure after a 2-stage arthroplasty was performed to determine whether ≥2 positive intraoperative cultures at resection can predict outcomes following reimplantation when compared with a single positive culture. Results: Two hundred and ninety-nine patients were included. At a mean follow-up of 6.2 ± 2.6 years, 48 patients (16.1%) experienced failure. Patients who had a failure were more likely to have had a longer interstage interval (p = 0.038) and were also more likely to have had ≥2 positive cultures at the time of resection arthroplasty (95.8% versus 75.3%; p = 0.001). On regression analysis, ≥2 positive cultures at resection was the only variable that was identified as a risk factor for failure following reimplantation in both the univariate (odds ratio [OR], 7.55 [95% CI, 2.24 to 47.0]; p = 0.006) and multivariable models (OR, 8.12 [95% CI, 2.31 to 51.9]; p = 0.005). Conclusions: This is the first study to examine the impact of the number of positive cultures on outcomes in patients with PJI. We found that the presence of ≥2 positive cultures at resection was an indicator of a poor prognosis and resulted in a greater than eightfold increase in the risk of treatment failure in patients undergoing a 2-stage exchange. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

ABSTRACT Background Although Percutaneous Coronary Intervention (PCI) is the cornerstone treatment acute myocardial infarction (AMI), its use in the elderly, specifically nonagenarians patients, is not well studied. This study sought to compare the outcomes and complications of nonagenarian patients who experienced AMI between those who underwent PCI and those who underwent medical treatment only. Methods We evaluated 301,440 nonagenarian (ages 90−99) patients who presented to the hospital with AMI who were listed in the National Inpatient Sample from 2016 to 2021. AMI was defined according to the ICD‐10 Diagnostic Codes. Multivariable logistic regression analysis was used to examine the association of PCI with primary outcomes of mortality and secondary outcomes. The temporal trend of both the incidence of PCI in nonagenarian patients as well as the mortality rate between 2016 and 2021 were expressed as percentages over time. Results Of the total ( n = 301,440) nonagenarian patients with AMI, 33,035 patients underwent PCI while 268,406 did not undergo PCI and rather, just utilized optimized medical therapy (OMT). Of these, 3290 (9.96%) died in the PCI group, and 43580 (16.24%) died in the OMT group. All of the secondary outcomes were significantly different between the PCI and OMT groups. Comparing the two groups, the PCI group was associated with decreased mortality (OR 0.63 [95% CI, 0.58−0.69]; p < 0.001), acute heart failure (OR 0.88 [95% CI, 0.82−0.95] p < 0.001), and AKI (OR 0.75 [95% CI, 0.70−0.79]; p < 0.001), and increased cardiogenic shock (OR 3.06 [95% CI, 2.77−3.38]. The temporal of PCI in nonagenarian patients showed an increase in frequency from about 8.3 in 2016 to about 13.7% in 2021. Furthermore, comparing the mortality between the PCI and OMT groups showed a significant difference with a decreased mortality in the PCI group. Conclusions Nonagenarian patients experiencing AMI who underwent PCI is associated with a significant mortality decrease compared to those who underwent OMT only. The PCI group was also associated with a significant decrease in multiple secondary complications including acute heart failure, AKI, acute stroke, and an increase in cardiogenic shock. Temporally, we have seen an increase in PCI being used in nonagenarian patients over the interval.

ABSTRACTAlthough recent studies have demonstrated the efficacy of chimeric antigen receptor T‐cell (CAR‐T) therapy in relapsed large B‐cell lymphoma (LBCL) with MYC rearrangement (R‐MYC), the data comparing CAR‐T to autologous hematopoietic cell transplant (auto‐HCT) in such patients who achieve a complete or partial response (CR/PR) after salvage therapies are limited. We compared the clinical outcomes of patients with R‐MYC LBCL (including double and triple hit lymphomas) who underwent CAR‐T or auto‐HCT after achieving a CR/PR with salvage therapies using the Center for International Blood & Marrow Transplant Research registry. Among the 252 patients (auto‐HCT = 98, CAR‐T = 154), relative to auto‐HCT, CAR‐T was associated with significantly lower overall survival (OS) (Hazard Ratio [HR] 2.09, 95% CI 1.38–3.15, p < 0.001) on multivariate analysis. There were no differences in progression‐free survival (PFS) (HR 1.21, 95% CI 0.81–1.8 p = 0.36), risk of relapse (HR 1.1, 95% CI 0.71–1.69 p = 0.68), nonrelapse mortality (NRM) (HR 1.74, 95% CI 0.64–4.7 p = 0.28) while the post‐relapse survival was longer in auto‐HCT relative to CAR‐T (HR 1.93, 95% CI 1.21–3.06 p = 0.01). On propensity score matched analysis accounting for differences in characteristics across the two cohorts, we detected no significant differences in OS (HR 1.72, 95% CI 0.92–3.21 p = 0.09), PFS (HR 1.04, 95% CI 0.64–1.68 p = 0.88), NRM (HR 1.22, 95% CI 0.35–4.2 p = 0.76), relapse (HR = 0.93, 95% CI 0.54–1.6 p = 0.8) and post‐relapse survival (HR 2.25, 95% CI 0.98–5.17, p = 0.06). These data, although retrospective, support consideration for auto‐HCT in patients with R‐MYC LBCL who achieve a CR/PR after salvage therapies, particularly in regions with no or limited access to CAR‐T.

Abstract Background: Prior research on the associations of p16, COX-2, and Ki67 immunopositivity in ductal carcinoma in situ (DCIS) tissue with the risk of subsequent ipsilateral invasive breast cancer (IBC) is limited. Methods: In a case–control study nested in a cohort of women diagnosed with DCIS, immunostaining for p16, COX-2, and Ki67 was performed on DCIS tissue from those who developed subsequent ipsilateral IBC (cases; n = 146) and on matched subjects who did not develop IBC (controls; n = 273). Conditional logistic regression was used to estimate ORs and 95% confidence intervals for the associations between immunopositivity for p16, COX-2, and Ki67 and the risk of subsequent ipsilateral IBC. Results: There was no association between p16, COX-2, and Ki67 immunopositivity, examined either individually or in combination, and a risk of ipsilateral IBC. Compared with all other groups, the multivariable OR (95% confidence interval) for women who were triple positive for the three markers was 1.16 (0.38–3.54). Conclusions: p16, COX-2, and Ki67 immunopositivity was not associated with altered risk of ipsilateral IBC in women with DCIS. Impact: p16, COX-2, and Ki67 may not be prognostic for ipsilateral IBC in women with DCIS.

Myocardial Bridging (MB) is typically a benign congenital coronary anomaly. MB can infrequently result in complications such as myocardial ischemia, arrhythmias, and sudden cardiac death. Recent studies suggest an underlying genetic component for MB involving DES, FBN1, SCN2B, or NOTCH1. The role of percutaneous coronary intervention (PCI) in managing MB, compared to optimal medical therapy (OMT), remains uncertain. Our study used the National Inpatient Sample (NIS) Database to identify patients aged 18 or older with myocardial bridging who were managed with PCI versus medical therapy. We compared the outcomes between both groups including in-hospital mortality, the trend of management of MB and other in-hospital outcomes or complications. Our results showed no statistically significant difference between both subgroups when comparing in-hospital mortality and secondary outcomes of cardiac arrest and the development of an acute kidney injury (AKI). Patients with myocardial bridging treated with PCI had a higher risk of developing cardiogenic shock, requiring LVAD, and requiring the use of intra-aortic balloon pump (IABP) compared to the medical therapy subgroup. Our study suggests the decision to perform PCI in myocardial bridging patients should be individualized such as in patients with refractory symptoms despite medical therapy or those with known high-risk features.

Abstract Purpose/Background Clozapine was approved in the United States (US) using 1989 regulations and knowledge. After 30 years, many sections of the US package insert (PI) are outdated. Methods We comprehensively reviewed the literature to propose PI updates. We present the information in 2 articles. In Part I, we focus on basic pharmacology based on 407 relevant articles. Part II focuses on clinical aspects and pharmacovigilance. Findings/Results Based on more recent expectations of Food and Drug Administration regulations, we reviewed clozapine basic pharmacology including the following: 1) clearance, 2) pharmacokinetics and pharmacodynamics, and 3) monitoring tools. We identified 9 major problems in the basic pharmacological sections of the PI including the following: 1) in vivo studies indicate that clozapine is dependent on CYP1A2 for its metabolism, 2) the minor role of CYP2D6 in clozapine metabolism requires removing the PI recommendation to lower clozapine doses in CYP2D6 poor metabolizers, 3) in nontoxic concentrations CYP3A4 has a minor role in clozapine metabolism and potent CYP3A4 inhibitors lack clinically relevant effects, 4) several drug-drug interactions need to be updated based on recent literature, 5) systemic inflammation may decrease clozapine metabolism and increase the risk of clozapine intoxication, 6) obesity may decrease clozapine metabolism, 7) patients of Asian and Indigenous American ancestry need lower clozapine doses, 8) personalized titration and c-reactive protein monitoring should be considered until prospective studies are available, and 9) the half-life section needs to be modified to acknowledge that single dosing at night is frequent in the US. Implications/Conclusions An improvement in the US clozapine PI may lead to improvement in PIs worldwide.

Abstract Purpose/Background This is the second part of a 2-part article that proposes improving the United States (US) clozapine package insert. Part II focuses on fatal outcomes and the 5 boxed warnings, 4 specifically for clozapine: severe neutropenia, seizure, orthostatic hypotension and myocarditis, and 1 for all antipsychotics (elderly with dementia). Methods US reports to the World Health Organization's global pharmacovigilance database were analyzed from clozapine's introduction to January 15, 2023. Findings/Results The US was the top reporter worldwide for clozapine with 56,003 reports and 9587 associated fatal outcomes. The 4 clozapine boxed warnings were associated with 534 fatal outcomes (218 with severe neutropenia, 131 with seizures, 125 with orthostasis, 36 with myocarditis, 24 with cardiomyopathy, and 0 with mitral valve prolapse). With no boxed warnings, pneumonia was associated with 674 fatal outcomes and increased white blood cell count (a sign of infection) with 596 fatal outcomes. After considering overlaps, pneumonia and increases in white blood cell count explained 900 fatalities, or 9.4% of 9587 fatal outcomes. The Food and Drug Administration continues to focus on severe neutropenia which was associated with only 218 or 2.3% of fatal outcomes, whereas 97.7% of fatal outcomes reported in US clozapine-treated patients had another cause. Implications/Conclusions To help prevent future deaths in clozapine-treated patients, the clozapine package insert should focus on fatal outcomes during infections. Part II offers detailed solutions regarding current boxed warnings and lack of a warning for pneumonia and other infections. The Supplementary Material includes letters of support from 124 non-US clozapine experts from 44 countries/regions who support Parts I and II.