Cardiac Safety Research Articles

Functionalizing Sgc8-Paclitaxel Conjugates with F-Base Modifications: Targeted Drug Delivery with Optimized Cardiac Safety.

Recent advancements in cancer treatment have improved patient prognoses, but chemotherapy induced cardiotoxicity remains a prevalent concern. This study explores the potential of F-base-modified aptamers for targeted drug delivery, focusing on their impact on cardiotoxicity. From the phosphoramidite, F-base-functionalized Sgc8-F23 was prepared in an automated and programmable way, which was further reacted with paclitaxel (PTX) to give the F-base- modified aptamer Sgc8-paclitaxel conjugates (Sgc8-F23-PTX) efficiently. The conjugate exhibited prolonged circulation time and enhanced efficacy as a precision anticancer drug delivery system. Echocardiographic assessments revealed no exacerbation of cardiac dysfunction after myocardial infarction (MI) and no pathological changes or increased apoptosis in non-infarcted cardiac regions. Autophagy pathway analysis showed no discernible differences in Sgc8-F23-PTX-treated cardiomyocytes compared with controls, in contrast to the increased autophagy with nanoparticle albumin-bound-paclitaxel (Nab-PTX). Similarly, apoptosis analysis showed no significant differences. Moreover, Sgc8-F23-PTX exhibited no inhibitory effect on hERG, hNav1.5, or hCav1.2 channels. These findings suggest the safety and efficacy of F-base-modified Sgc8 aptamers for targeted drug delivery with potential clinical applications. Further research is warranted for clinical translation and exploration of other drug carriers.

Differential Expression of Circulating miRNAs and Carfilzomib-Related Cardiovascular Adverse Events in Patients with Multiple Myeloma.

This study investigates the association between circulating microRNA (miRNA) expression and cardiovascular adverse events (CVAE) in multiple myeloma (MM) patients treated with a carfilzomib (CFZ)-based regimen. A cohort of 60 MM patients from the Prospective Observation of Cardiac Safety with Proteasome Inhibitor (PROTECT) study was analyzed. Among these, 31 patients (51.6%) developed CVAE post-CFZ treatment. The Taqman OpenArray Human microRNA panels were used for miRNA profiling. We identified 13 differentially expressed miRNAs at baseline, with higher expressions of miR-125a-5p, miR-15a-5p, miR-18a-3p, and miR-152-3p and lower expression of miR-140-3p in patients who later developed CVAE compared to those free of CVAE, adjusting for age, gender, race, and higher B-type natriuretic peptide levels. We also identified three miRNAs, including miR-150-5p, that were differentially expressed in patients with and without CVAE post-treatment. Additionally, five miRNAs responded differently to CFZ treatment in CVAE vs. non-CVAE patients, including significantly elevated post-treatment expression of miR-140-3p and lower expressions of miR-598, miR-152, miR-21, and miR-323a in CVAE patients. Pathway enrichment analysis highlighted the involvement of these miRNAs in cardiovascular diseases and vascular processes. These findings suggest that specific miRNAs could serve as predictive biomarkers for CVAE and provide insights into the underlying mechanisms of CFZ-CVAE. Further investigation is warranted before these findings can be applied in clinical settings.

Cardiac adverse events associated with lacosamide: a disproportionality analysis of the FAERS database

Lacosamide was the first approved third-generation antiepileptic drug. However, real-world data regarding its adverse cardiac reactions in large samples still need to be completed. We evaluated the cardiac safety profile of lacosamide using the Food and Drug Administration Adverse Event Reporting System (FAERS). We performed disproportionality analysis computing reporting odds ratio (ROR) as a quantitative metric to assess the signal of lacosamide-related cardiac adverse events (AEs) from 2013 Q1 to 2022 Q4. The signal was considered significant when the lower limit of the 95% confidence interval (CI) of the ROR exceeded 1, and ≥ 5 AEs were reported. Serious and nonserious cases were compared by statistical analysis, and signals were further prioritized using a rating scale. A total of 812 cardiac AEs associated with lacosamide were identified, and 92 signals were detected, of which 17 AEs were significantly associated signals. The median time-to-onset (TTO) for moderate priority signals was 10 days, whereas for weak priority signals, it was 54 days. Notably, all cardiac AEs exhibited an early failing pattern, indicating the risk gradually decreasing. Based on the comprehensive analysis of the FAERS database and prioritization of cardiac AE signals, our research enhances the awareness among healthcare professionals regarding cardiac AEs associated with lacosamide.

MultiCBlo: Enhancing predictions of compound-induced inhibition of cardiac ion channels with advanced multimodal learning

Predicting compound-induced inhibition of cardiac ion channels is crucial and challenging, significantly impacting cardiac drug efficacy and safety assessments. Despite the development of various computational methods for compound-induced inhibition prediction in cardiac ion channels, their performance remains limited. Most methods struggle to fuse multi-source data, relying solely on specific dataset training, leading to poor accuracy and generalization. We introduce MultiCBlo, a model that fuses multimodal information through a progressive learning approach, designed to predict compound-induced inhibition of cardiac ion channels with high accuracy. MultiCBlo employs progressive multimodal information fusion technology to integrate the compound's SMILES sequence, graph structure, and fingerprint, enhancing its representation. This is the first application of progressive multimodal learning for predicting compound-induced inhibition of cardiac ion channels, to our knowledge. The objective of this study was to predict the compound-induced inhibition of three major cardiac ion channels: hERG, Cav1.2, and Nav1.5. The results indicate that MultiCBlo significantly outperforms current models in predicting compound-induced inhibition of cardiac ion channels. We hope that MultiCBlo will facilitate cardiac drug development and reduce compound toxicity risks. Code and data are accessible at: https://github.com/taowang11/MultiCBlo. The online prediction platform is freely accessible at: https://huggingface.co/spaces/wtttt/PCICB.

Cardiovascular safety of pimitespib in patients with advanced solid tumors: An open-label, nonrandomized, phase 1 study.

Pimitespib (TAS-116), a first-in-class, oral, selective heat-shock protein 90 inhibitor, is approved as fourth-line treatment for gastrointestinal stromal tumors in Japan. This phase 1 study evaluated the cardiac safety of pimitespib. In this open-label, nonrandomized, multicenter study, Japanese patients (aged ≥20 years) with refractory, advanced solid tumors received placebo on day -1, then pimitespib 160 mg daily on days 1-5 of the cardiac safety evaluation period. Electrocardiograms were conducted at baseline, and on days -2, -1, 1, and 5; and blood samples were collected on days 1 and 5. Patients then received once-daily pimitespib for 5 days every 3 weeks. The primary end point was the time-matched difference in QT interval corrected for heart rate using the Fridericia correction (QTcF) between pimitespib and placebo. Pharmacokinetics, safety, and preliminary efficacy were also assessed. Of the 22 patients in the cardiac safety-evaluable population, no clinically relevant QTc prolongation was observed; the upper bound of the one-sided 95% confidence interval for the time-matched difference in change from baseline in QTcF was <20 msec at all time points on days 1 and 5. Pimitespib pharmacokinetic parameters were consistent with previous data, and the time-matched difference in change from baseline in QTcF showed no marked increase as plasma concentrations increased. The safety profile was acceptable; 40% of patients experienced grade 3 or greater adverse drug reactions, mostly diarrhea (20%). The median progression-free survival was 3.1 months. In Japanese patients with refractory, advanced solid tumors, pimitespib was not associated with clinically relevant QTc prolongation, and there were no cardiovascular safety concerns. Pimitespib is a new anticancer drug that is being used to treat cancer in the stomach or intestines (gastrointestinal stromal tumors). This study demonstrated that pimitespib had no marked effect on heart rhythm or negative effects on the heart or blood vessels and had promising anticancer effects in Japanese patients with advanced solid tumors who were unable to tolerate or benefit from standard treatment.

Cardiac safety of ribociclib evaluated with 24-hour rhythm Holter electrocardiogram

ObjectiveWe aimed to evaluate cardiac safety profile of ribociclib with 24-h rhythm Holter ECG.Material and methodForty-two female metastatic breast cancer patients were included in the study. Rhythm Holter ECG was performed before starting treatment with ribociclib and after 3 months of the treatment initiation.ResultsThe mean age of the patients was 56.36 ± 12.73. 52.4% (n = 22) of the patients were using ribociclib in combination with fulvestrant and 47.6% (n = 20) with aromatase inhibitors. None of the patients developed cardiotoxicity. When the rhythm Holter results before and in third month of the treatment were compared, there was no statistically significant difference.ConclusionThis is the first study evaluating effects of ribociclib treatment on cardiac rhythm with Holter ECG. The findings suggested ribociclib has a low risk of causing early cardiotoxicity.

Deconvoluting and derisking QRS complex widening to improve cardiac safety profile of novel plasmepsin X antimalarials.

Quinoline-related antimalarial drugs have been associated with cardiotoxicity risk, in particular QT prolongation and QRS complex widening. In collaboration with Medicines for Malaria Venture, we discovered novel plasmepsin X (PMX) inhibitors for malaria treatment. The first lead compounds tested in anesthetized guinea pigs (GPs) induced profound QRS widening, although exhibiting weak inhibition of NaV1.5-mediated currents in standard patch clamp assays. To understand the mechanism(s) underlying QRS widening to identify further compounds devoid of such liability, we established a set of in vitro models including CaV1.2, NaV1.5 rate-dependence, and NaV1.8 patch clamp assays, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), and Langendorff-perfused isolated GP hearts. Six compounds were tested in all models including anesthetized GP, and 8 additional compounds were tested in vitro only. All compounds tested in anesthetized GP and isolated hearts showed a similar cardiovascular profile, consisting of QRS widening, bradycardia, negative inotropy, hypotension, and for some, QT prolongation. However, a left shift of the concentration-response curves was noted from in vitro to in vivo GP data. When comparing in vitro models, there was a good consistency between decrease in sodium spike amplitude in hiPSC-CM and QRS widening in isolated hearts. Patch clamp assay results showed that the QRS widening observed with PMX inhibitors is likely multifactorial, primarily due to NaV1.8 and NaV1.5 rate-dependent sodium blockade and/or calcium channel-mediated mechanisms. In conclusion, early de-risking of QRS widening using a set of different in vitro assays allowed to identify novel PMX inhibitors with improved cardiac safety profile.

Machine learning and deep learning approaches for enhanced prediction of hERG blockade: a comprehensive QSAR modeling study

ABSTRACT Background Cardiotoxicity is a major cause of drug withdrawal. The hERG channel, regulating ion flow, is pivotal for heart and nervous system function. Its blockade is a concern in drug development. Predicting hERG blockade is essential for identifying cardiac safety issues. Various QSAR models exist, but their performance varies. Ongoing improvements show promise, necessitating continued efforts to enhance accuracy using emerging deep learning algorithms in predicting potential hERG blockade. Study design and method Using a large training dataset, six individual QSAR models were developed. Additionally, three ensemble models were constructed. All models were evaluated using 10-fold cross-validations and two external datasets. Results The 10-fold cross-validations resulted in Mathews correlation coefficient (MCC) values from 0.682 to 0.730, surpassing the best-reported model on the same dataset (0.689). External validations yielded MCC values from 0.520 to 0.715 for the first dataset, exceeding those of previously reported models (0–0.599). For the second dataset, MCC values fell between 0.025 and 0.215, aligning with those of reported models (0.112–0.220). Conclusions The developed models can assist the pharmaceutical industry and regulatory agencies in predicting hERG blockage activity, thereby enhancing safety assessments and reducing the risk of adverse cardiac events associated with new drug candidates.

Cardiac safety in full-face phenol-croton oil peels: A 22-year retrospective study

Cardiac safety in full-face phenol-croton oil peels: A 22-year retrospective study

Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint destruction due to synovial hypertrophy and the infiltration of inflammatory cells. Despite substantial progress in RA treatment, challenges persist, including suboptimal treatment responses and adverse effects associated with current therapies. This study investigates the anti-rheumatic capabilities of the newly identified multi-protein kinase inhibitor, KMU-11342, aiming to develop innovative agents targeting RA. In this study, we synthesized the novel multi-protein kinase inhibitor KMU-11342, based on indolin-2-one. We assessed its cardiac electrophysiological safety using the Langendorff system in rat hearts and evaluated its toxicity in zebrafish in vivo. Additionally, we examined the anti-rheumatic effects of KMU-11342 on human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), THP-1 cells, and osteoclastogenesis in RAW264.7 cells. KMU-11342 demonstrated the ability to inhibit LPS-induced chemokine inhibition and the upregulation of pro-inflammatory cytokines, cyclooxygenase-2, inducible nitric oxide synthase, p-IKKα/β, p-NF-κB p65, and the nuclear translocation of NF-κB p65 in RA-FLS. It effectively suppressed the upregulation of NLR family pyrin domain containing 3 (NLRP3) and caspase-1 cleavage. Furthermore, KMU-11342 hindered the activation of osteoclast differentiation factors such as RANKL-induced TRAP, cathepsin K, NFATc-1, and c-Fos in RAW264.7 cells. KMU-11342 mitigates LPS-mediated inflammatory responses in THP-1 cells by inhibiting the activation of NLRP3 inflammasome. Notably, KMU-11342 exhibited minimal cytotoxicity in vivo and electrophysiological cardiotoxicity ex vivo. Consequently, KMU-11342 holds promise for development as a therapeutic agent in RA treatment.

Evaluating cardiac lead safety using observational, real-world data: EP PASSION proof-of-concept study

BackgroundTraditional post-approval study (PAS) designs have been accepted by regulatory authorities to fulfill postmarketing requirements for cardiac leads, but they have several limitations. ObjectiveWe conducted a proof-of-concept study of alternative methods that use real-world data (RWD) to evaluate lead safety in large populations of patients. MethodsAbbott patient device databases were linked with Medicare Fee-For-Service (FFS) claims to identify lead complications in patients implanted with Abbott Optisure lead. A 1:1 comparison between the PAS method and RWD method of detecting mechanical lead–related complication events was conducted in 444 PAS participants who were enrolled in Medicare FFS. Agreement between methods was evaluated by McNemar test and Cohen κ. Survival free from complications at 3 years was compared between the PAS and RWD cohorts with an equivalence acceptance criterion of ±2.5%. ResultsThere were 1171 PAS patients and 5804 Medicare FFS patients who received an Optisure lead between August 27, 2014, and June 14, 2016. Patients were observed through December 31, 2018. Complete agreement was found between PAS-reported and claims-detected complications (McNemar P value = 1; Cohen κ = 1). Survival free from complications at 3 years by the RWD method was 98.4% (95% confidence limit, 98.0%–98.7%), which was within the acceptable range of the PAS 98.4% (95% confidence limit, 97.6%–99.0%). ConclusionThese results show a close agreement between RWD-detected and PAS-reported lead complication rates, which highlights the potential benefits of RWD-based methods to enhance the generation of clinical evidence for lead safety.

Concentration-QTc and cardiac safety analysis of single and multiple zavegepant nasal spray doses in healthy participants to support approval.

Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.

Evolving Cardiac Safety in Drug Discovery: Time for Immunology Integration.

Evolving Cardiac Safety in Drug Discovery: Time for Immunology Integration.

Lower dose radiotherapy did not alter cardiac function and was not pro-arrhythmic: results of the small prospective HALO trial

Abstract Background Stereotactic arrhythmia radiotherapy (STAR) is a highly promising bail-out treatment for patients with therapy-refractory ventricular tachycardia (VT). Despite precise, noninvasive targeting of the pro-arrhythmic area, surrounding healthy cardiac tissue inadvertently receives low-dose radiation. There is a historical notion that collateral cardiac damage from radiation of extra-cardiac structures can cause heart failure and arrhythmias. In the HALO trial, where non-small cell lung cancer (NSCLC) patients treated with stereotactic ablative radiotherapy (SABR) received relatively low-dose radiotherapy to the heart, detailed cardiac safety after radiotherapy was therefore evaluated. Objective The aim of this study was to prospectively evaluate cardiac function after collateral radiotherapy on the heart in patients with NSCLC treated with SABR. Methods The HALO trial was a prospective observational trial evaluating cardiac adverse effects in patients treated with SABR for early stage NSCLC. Patients with a tumour within 3cm of the pericardium were eligible to participate. The mean radiotherapy dose per segment was calculated by semi-automated angulation and segmentation using an in-house developed tool. The heart was segmented according to the AHA 17-segment model. Patients underwent cardiac magnetic resonance imaging (CMR) pre-treatment, 3 and 12 months after treatment. CMR strain-analysis was conducted by two independent observers using cvi42 software. Longitudinal, radial and circumferential strain were measured both globally and segmentally and evaluated for dose-dependent effects. Results Ten patients were included in this study. Two patients dropped out before first follow-up and were not included in this analysis. Median age was 66 years (range 58-81) and four were male (50%). Median distance between the tumour and pericardium was 0.46cm (range 0.00-2.80). Patients were treated with 8 fractions of 7.0-7.5 Gy (n=6), 5 fractions of 11.0 Gy (n=1) or 3 fractions of 18.0 Gy (n=1). Median global cardiac radiotherapy dose was 6.7 Gy (range 0.1-17.9). Pre-treatment, median left ventricular ejection fraction as measured on CMR was 65% (range 40-75), global longitudinal strain was -15% (-20 - -9), global circumferential strain was -17% (-26 - -9) and global radial strain was 28% (11-60). These did not significantly change comparing 3 months and 12 months after treatment with pre-treatment. As can be appreciated from Table 1, there were no dose-dependent effects on segmental longitudinal, radial and circumferential strain both 3 months or 12 months after SABR. There were no ventricular arrhythmias observed during follow-up. Conclusion In this small study, collateral radiotherapy in patients with NSCLC treated with SABR did not significantly alter cardiac function as measured on CMR, and no relevant pro-arrhythmic effects were observed during short term follow-up. Extending the research into a larger dataset is warranted.

Cardiac Safety of Ozanimod Use, a Novel Sphingosine-1-Phosphate Receptor Ligand, in COVID-19 Patients Requiring Oxygen: Secondary Analysis of the COZI Randomized Clinical Trial

BackgroundOzanimod is a novel immune modulator that could be useful in viral pulmonary infections by reducing lung inflammation. It is an S1P receptor ligand known to induce bradycardia and more serious adverse cardiac effects, such as atrioventricular block and QT interval prolongation. We present a substudy of the COVID-19 Ozanimod Intervention (COZI) trial in which ozanimod was administered in acute pulmonary infection patients, to assess cardiac safety. MethodsIn this pilot randomized open-label trial, COVID-19 patients requiring oxygen support were randomized into 2 groups: standard-of-care + ozanimod (OZA) vs standard-of-care alone (SOC). All patients were monitored with a 14-day electrocardiogram monitor (CardioSTAT, Icentia, Quebec, QC) during their hospitalization. We evaluated the cardiac effects of ozanimod on heart rate (HR), PR interval length, and QT interval duration. ResultsA total of 42 patients were analyzed: 23 in the SOC group and 19 in the OZA group. Mean hourly HR over the first 10 days of treatment decreased in the OZA group, compared with that in the SOC group (P < 0.0001). The maximum decrease in HR occurred on day 3. The maximum decrease in HR occurred on day 3, without a significant difference between groups: 49 beats per minute (interquartile range, 42-59) in the OZA group, and 54 beats per minute (48–60) in the SOC group, P = 0.45. No high-degree atrioventricular block was recorded. QT and PR interval median values were within the normal range in both groups, without a significant difference. ConclusionsThe maximal reduction in HR occurred 3 days after the onset of ozanimod treatment in patients hospitalized for COVID-19, but it did not remain significant over the 10-day treatment period. No relevant cardiac adverse event was observed.

Abstract PO3-01-02: Real world outcomes of neoadjuvant therapy with Trastuzumab and Pertuzumab associated with carboplatin and docetaxel (TCHP) in HER2+ early breast cancer patients unfit for anthracyclines: a retrospective cohort comparative study

Abstract Backgound Neoadjuvant chemotherapy (CT) with anti-HER2 blockade using trastuzumab (H) and pertuzumab (P) is a standard of care for patients (pts) with HER2-positive early-stage Breast Cancer (eBC). Historically, taxanes (T) and anthracyclines (A) have been the mainstays of (neo)adjuvant CT in this setting, but the added benefit of A in the era of anti-HER2 therapy has been questioned. This study aimed to assess the effectiveness, cardiac safety, and cost-effectiveness of an anthracycline-free regimen (TCHP) in a real-world population of pts deemed unfit for A, compared to pts treated with the standard regimen of doxorubicin and cyclophosphamide plus dual-blockade associated with docetaxel (AC-DHP) at a single Portuguese Comprehensive Cancer Center. Methods This retrospective cohort study included a consecutive series of female eBC HER2+ pts who initiated primary treatment with TCHP between July 2018 and August 2022. The primary endpoint was pathological complete response (pCR), and secondary endpoints were cardiac safety and disease-free survival (DFS). The outcomes were compared with a historical database of eBC HER2+ pts who started primary treatment with AC-DHP between August 2015 and May 2021. Clinical data was collected from medical and administrative records. Descriptive statistics were used to describe categorical and continuous variables, and the Kaplan-Meier method was used for DFS analysis. Costs analysis employed the micro-costing technique, considering individual medical direct costs from diagnosis until surgery. Multivariate logistic regression models were used for effectiveness analysis and the gamma general model for costs analysis. The incremental cost-effectiveness ratio (ICER) was calculated using the pCR rate as a measure of effectiveness. Results A total of 233 and 23 pts were included in the TCHP and AC-DHP groups respectively. Reasons for choosing the anthracycline-free regimen in the TCHP group were primarily age-related frailty (52%), medical comorbidities (26%), and previous exposure to anthracyclines (22%). The TCHP pts were older (median age 71 years, range [45-77] vs. 47 years [24-70]) and had lower baseline Left Ventricular Ejection Fractions (LVEF) (median 65% [51-80] vs. 60% [56-73]), with a higher proportion of hormone receptor (HR) negative pts (78.3% vs. 33.0%). Clinical stages were balanced between groups, but the TCHP group had a higher nodal involvement (N+) (73.9% vs. 61.8%). The pCR rates were higher in the TCHP group (65.2% vs. 46.1%, HR 0.98 [95% CI 0.36 - 2.70]). Subgroup analysis by HR status showed comparable pCR rates: 77.1% vs. 74.1% in HR- pts and 40% vs. 39.7% in HR+ pts. Cardiac safety analysis indicated a median decrease in LVEF of 9% in both the TCHP and AC-DHP groups, with 43.5% of TCHP pts experiencing a decline of 10% or more, and 13.0% dropping below 50%. In comparison, these figures were 44.2% and 3.9%, respectively, in the AC-DHP group. At the end of the follow-up, only one patient in the TCHP group with a LVEF &amp;lt; 50% persisted with mild symptoms of chronic heart failure. The median follow-up time for DFS events, starting from surgery, was 31.1 months in the TCHP group and 45.7 months in the AC-DHP group, with 1-year DFS rates of 91.3% and 100%, respectively. The ICER analysis indicated that TCHP was cost-effective, as the incremental cost for achieving an additional pCR in similar subgroups can be outweighed by later cost savings, mainly due to further adjuvant treatment with trastuzumab instead of TDM-1. Conclusions In a real-world population of HER2+ eBC patients unfit for anthracyclines, the TCHP regimen demonstrated a higher overall pCR rate compared to a historical control treated with the AC-DHP regimen, along with an acceptable cardiac safety profile. These results support the broader use of the TCHP regimen in HER2+ eBC pts, as recommended by current NCCN guidelines. However, larger studies involving similar populations are needed to provide higher levels of evidence. Citation Format: Ricardo Pinto, Rita Calisto, Patrícia Redondo, Ana Silva, Pedro Castro, Rute Fernandes, Raquel Teixeira, Diana Mata, Ana Ferreira, Maria Bento, Cláudia Vieira. Real world outcomes of neoadjuvant therapy with Trastuzumab and Pertuzumab associated with carboplatin and docetaxel (TCHP) in HER2+ early breast cancer patients unfit for anthracyclines: a retrospective cohort comparative study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-01-02.

Abstract PO2-01-07: Real-world efficacy of dual HER2-blockade in combination with anthracycline-containing and anthracycline-free neoadjuvant treatment in early breast cancer (BC)

Abstract BACKGROUND: Neoadjuvant therapy with antiHER-2 blockade is the standard of care for HER-2 positive early BC. The objective of this treatment is tumor downstaging to increase resectability and pathological complete response (pCR), a reliable surrogate endpoint for survival. Adding Trastuzumab (T) to chemotherapy resulted in an improvement in pCR, however, resistance to this agent is common and the incorporation of Pertuzumab (P) to the neoadjuvant scene demonstrated an increase in pCR in the Peony (39.3% vs 21.8%) and Neosphere trials (45.8% vs 29%). Across all studies, pCR is even higher in patients (pts) with negative hormonal receptor (HR) status (50%-63%) (3, 4). Tryphaena and Berenice found low rates of cardiotoxicity with T-P combination. Recently, TRAIN-2 data showed that anthracyclines and platinum have a similar pCR (67% vs 68%), but febrile neutropenia and cardiotoxicity is higher in the anthracycline group, concluding that omitting this therapy might be a preferred approach in the presence of dual HER2 blockade. Our study investigated the pCR benefit of dual HER2 blockade with anthracyclines and platinum in HER2 positive early BC. METHODS: We conducted a retrospective, unicenter, observational study of pts, treated with neoadjuvant T-P plus chemotherapy, in HER-2 positive early BC, between April 2015 and December 2022 at University Hospital A Coruña (Spain). The primary endpoint was total pCR in breast and axila (tpCR: ypT0/is ypN0). Secondary endpoints were: association between clinicopatological characteristics and pCR; and between cardiotoxicity and treatment pattern. Statistical analyses were conducted with Statistical Package for the Social Science (SPSS). RESULTS: During the study period, from April 2015 to May 2022, 154 pts were enrrolled. The median age was 51,3 years [range 26 – 799 years], all patients were female. Infiltrating ductal carcinoma was present in 92.2% pts, and 5.8% were inflammatory BC. At diagnosis, 11.7%, 61.7% and 26.6% had stages I, II and III, respectively, and 51.3% revealed axillary node involvement. Among observed cases, 94 (61%) were positive HR; 68 (45%) had histological grade 2 and 83 (53.9%) histological grade 3 tumors; and 151 pts (99.3%) presented a ki-67 level &amp;gt;20%. HER2 by immunohistochemistry (IHC) resulted in 3+ for 133 pts (86.9%) and in 2+ for 20 pts (13.1%), all of them with positive result by in situ hybridation (ISH). P-T were mostly combined with anthracyclines (64.9%). tpCR rate was 50.6%, and it was not significantly different according chemotherapy approach. tpCR was significantly higher among HR negative tumours (73.3%) compared with HR positive (36.2%) (p= 0.001), and in HER2 positive 3+ (55.6%) compared with HER2 positive 2+ (15%) tumours (p= 0.001). Achievement of tpCR was not significantly associated with tumor size, stage, histological grade and ki-67 level. Breast pCR was higher than tpCR (54.2%). 13 pts (8.4%) presented recurrence disease, in 76.9% of cases was a metastatic relapse. Cardiotoxicity was low during all stages of treatment and was not significantly associated with chemotherapy pattern. CONCLUSIONS: Neoadjuvant T-P plus chemotherapy with either anthracyclines or platinum therapy, demonstrated same efficacy and cardiac safety in our real-world study. pCR rates are lower in positive HR and HER2 positive 2+, needing more investigation with combination strategies including hormonotherapy, Our results are similar to data from randomized trials and other real-world efficacy studies, but we need more follow-up to identify late cardiotoxicity by anthracyclines and recurrences in positive HR tumors. Citation Format: Beatriz Alonso de Castro, Cristina Reboredo, Lourdes Calvo, Maria-Eva Perez-Lopez, Martin Igor Gomez Randulfe Rodriguez, Sofia silva diaz, Iria Parajo Vazquez, Silvia Antolin Novoa. Real-world efficacy of dual HER2-blockade in combination with anthracycline-containing and anthracycline-free neoadjuvant treatment in early breast cancer (BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-07.

Should You Run a Dedicated TQT Study? Sponsor and Regulatory Considerations on Substitution Pathways to Assess QT Liability.

Cardiac safety regulatory guidance for drug development has undergone several monumental shifts over the past decade as technological advancements, analysis models and study best practices have transformed this landscape. Once, clinical proarrhythmic risk assessment of a new chemical entity (NCE) was nearly exclusively evaluated in a dedicated thorough QT (TQT) study. However, since the introduction of the International Council for Harmonisation (ICH) E14/S7B Q&A 5.1 and 6.1 TQT substitutions, drug developers are offered an alternative pathway to evaluate proarrhythmic risk during an ascending dose study in healthy volunteers or during a powered patient study, respectively. In addition, the findings as well as the manner in which nonclinical studies are conducted (i.e., utilizing best practices) can dictate the need for a positive control in the clinical study and/or affect the labeling outcome. Drug sponsors are now faced with the option of pursuing a dedicated TQT study or requesting a TQT substitution. Potential factors influencing the choice of pathway include the NCE mechanism of action, pharmacokinetic properties, and safety profile, as well as business considerations. This tutorial will highlight the regulatory framework for integrated arrhythmia risk prediction models to outline drug safety, delineate potential reasons why a TQT substitution request may be rejected and discuss when a standalone TQT is recommended.

Collaborative science in action: A 20 year perspective from the Health and Environmental Sciences Institute (HESI) Cardiac Safety Committee

The Health and Environmental Sciences Institute (HESI) is a nonprofit organization dedicated to resolving global health challenges through collaborative scientific efforts across academia, regulatory authorities and the private sector. Collaborative science across non-clinical disciplines offers an important keystone to accelerate the development of safer and more effective medicines. HESI works to address complex challenges by leveraging diverse subject-matter expertise across sectors offering access to resources, data and shared knowledge. In 2008, the HESI Cardiac Safety Committee (CSC) was established to improve public health by reducing unanticipated cardiovascular (CV)-related adverse effects from pharmaceuticals or chemicals. The committee continues to significantly impact the field of CV safety by bringing together experts from across sectors to address challenges of detecting and predicting adverse cardiac outcomes. Committee members have collaborated on the organization, management and publication of prospective studies, retrospective analyses, workshops, and symposia resulting in 38 peer reviewed manuscripts. Without this collaboration these manuscripts would not have been published. Through their work, the CSC is actively addressing challenges and opportunities in detecting potential cardiac failure modes using in vivo, in vitro and in silico models, with the aim of facilitating drug development and improving study design. By examining past successes and future prospects of the CSC, this manuscript sheds light on how the consortium's multifaceted approach not only addresses current challenges in detecting potential cardiac failure modes but also paves the way for enhanced drug development and study design methodologies. Further, exploring future opportunities and challenges will focus on improving the translational predictability of nonclinical evaluations and reducing reliance on animal research in CV safety assessments.

Expert Survey on Managing Safety Events in Sleep Laboratory

Objectives: An increasing number of studies have highlighted the impact of sleep on physical and mental health and a corresponding rise in public interest; numbers of polysomnography (PSG) examinations have correspondingly increased. However, research and recommendations concerning safety events that may occur during PSG are lacking. This study aimed to investigate the current status of safety events in sleep laboratories in Korea and gather expert opinions on this matter. Methods: We conducted a web-based survey of Korean sleep experts to explore their opinions on safety events in sleep laboratories. Results: All Korean sleep experts who participated in this study agreed on the need for guidelines concerning safety events that can occur during PSG. Through this survey, they provided insights into the cardiac and pulmonary safety events that may arise during PSG. Conclusions: This study can assist sleep physicians in managing safety events in sleep laboratories currently, and in the future, it may contribute to the development of guidelines for handling safety events during PSG.