Discontinuation Rates Research Articles

Finerenone and left ventricular hypertrophy in chronic kidney disease and type 2 diabetes.

Left ventricular hypertrophy (LVH) has been associated with an increased risk of cardiovascular (CV) disease and linked to increased morbidity and mortality. In patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), hypertension is common, and patients with these co-morbidities additionally have a high prevalence of LVH. This analysis of the prespecified pooled FIDELITY analysis comprising the randomized, double-blind, placebo-controlled, multicentre FIDELIO-DKD and FIGARO-DKD phase III studies aimed to explore the CV and kidney effects of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in patients with CKD and T2D stratified by a diagnosis of LVH at baseline. A diagnosis of LVH in the FIDELITY patient population was determined at baseline using investigator-reported electrocardiogram (ECG) findings. The two efficacy outcomes, assessed by baseline LVH, were the composite CV outcome of time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure (HHF), and a composite kidney outcome of time to onset of kidney failure, a sustained decrease in estimated glomerular filtration rate (eGFR)≥57% from baseline over ≥4weeks, or kidney-related death. Safety outcomes by baseline LVH were reported as treatment-emergent adverse events. At baseline out of 13026 patients in FIDELITY, 96.5% had hypertension and 9.6% had investigator-reported LVH. The relative risk reduction for the composite CV and kidney outcomes with finerenone versus placebo was lower in the LVH subgroup; however, the treatment effect of finerenone was not modified by baseline LVH for either outcome (Pinteraction=0.1075 for composite CV outcome and Pinteraction=0.1782 for composite kidney outcome). Analysis of the composite CV outcome components showed a greater reduction in the risk of HHF versus placebo for patients with baseline LVH compared with those without (Pinteraction=0.0024). Overall safety events were comparable between the LVH subgroups and treatment arms. Treatment-emergent hyperkalaemia was observed more frequently with finerenone versus placebo, but discontinuation rates were low in both treatment arms and between LVH subgroups. In conclusion, the overall CV and kidney benefits of finerenone versus placebo were not modified by the presence of LVH at baseline, with overall safety findings being similar between LVH subgroups. A greater benefit was observed for HHF in patients with versus without LVH, suggesting that LVH may be a predictor of the treatment effect of finerenone on HHF.

A multicenter retrospective study to assess feasibility, safety and efficacy of first-line carboplatin-paclitaxel versus carboplatin monotherapy in a frail, elderly epithelial ovarian cancer population

ObjectiveUnderrepresentation of elderly ovarian cancer patients in clinical trials has led to lack of clarity regarding optimal first-line chemotherapy in this cohort. The Elderly Women with Ovarian Cancer (EWOC)-1 trial...

Clinical outcomes of first-line combination therapy with immune checkpoint inhibitor for metastatic non-clear cell renal cell carcinoma: a multi-institutional retrospective study in Japan.

In metastatic clear cell renal cell carcinoma (ccRCC), recent studies have shown promising efficacy of immune checkpoint inhibitor (ICI) combination therapy. However, there are insufficient evidences about clinical efficacy and safety of ICI combination therapy in metastatic non-ccRCC (nccRCC). We retrospectively investigated 44 patients treated with nivolumab plus ipilimumab (ICI + ICI group) or anti-PD-1/PD-L1 inhibitor plus tyrosine kinase inhibitors (TKI) (ICI + TKI group), and assessed clinical efficacy in both groups. Of all patients, overall response rate and disease control rate for ICI combination treatments were 36.3% and 75%, respectively. The median progression-free survival (PFS) and overall survival (OS) was 8.8 and 23.9months, respectively. Multivariate analysis revealed that the presence of liver metastasis significantly affected worse PFS and OS (p = 0.035 and p = 0.049). Importantly, PFS and OS seemed similar in ICI + ICI group and ICI + TKI group (p = 0.778 and p = 0.559). Although the discontinuation rate of the combination therapy due to adverse effects in patients aged ≥ 75years was significantly higher compared to that in patients aged < 75years (45% versus 12%, p = 0.017), there were no significant differences in PFS and OS between two groups (p = 0.290 and p = 0.257, respectively). This study confirms clinical benefit of ICI combination therapy for metastatic nccRCC patients in real-world settings. Furthermore, the effectiveness of combination therapy was comparable between patients aged < 75 and those ≥75years with respect to clinical prognosis.

High-Dose Furmonertinib in Patients With EGFR-Mutated NSCLC and Leptomeningeal Metastases: A Prospective Real-World Study

IntroductionLeptomeningeal metastasis (LM) is one of the most severe complications of NSCLC. Furmonertinib is a pan-EGFR tyrosine kinase inhibitor (TKI) with a high rate of brain penetration and a wide therapeutic window. Here, we evaluated the efficacy and safety of high-dose furmonertinib in patients with EGFR-mutated NSCLC and LM. MethodsThis prospective real-world study included patients with EGFR-mutated NSCLC and LM treated with a high-dose furmonertinib (240 mg once daily) as a monotherapy or in combination with other treatments. The primary end point was overall survival, and the secondary end points included time to treatment discontinuation and clinical response rate. Additional efficacy evaluations included changes in brain magnetic resonance imaging by the response assessment in neuro-oncology–LM radiologic criteria. We also introduced next-generation sequencing–based assays to evaluate genomic and epigenomic features of cell-free DNA (cfDNA) in patients’ cerebrospinal fluid (CSF) samples and to analyze their associations with patient outcomes. ResultsWe enrolled 48 patients, of whom 35 (72.9%) had received third-generation EGFR TKIs. The median overall survival was 8.43 months (95% confidence interval: 5.48–11.39 mo), while the median time to treatment discontinuation was 8.27 months (95% confidence interval: 5.40–11.14 mo), and the clinical response rate was 75%. The LM objective response rate and disease control rate assessed with response assessment in neuro-oncology-LM radiologic criteria were 50.0% and 92.1%, respectively. The adverse event profiles were consistent with previous reports of furmonertinib. Briefly, 22 (45.8%) had adverse events possibly related to furmonertinib and 3 (6.3%) had a grade 3-elevated aminotransaminase or nausea or leucopenia, leading to a dose reduction to 160 mg daily. Furthermore, methylation analysis of cfDNA in CSF revealed that there was a considerable correlation between the changes of aberrant methylated fragments from lung cancer cells and the response of the patients. Meanwhile, the copy number burden scores derived from the low-pass whole genome sequencing assay may offer another objective and effective method for the diagnosis and evaluation of treatment efficacy in LM. ConclusionsIn the real world, the high-dose furmonertinib-based treatment may potentially have clinical efficacy and tolerable safety in patients of EGFR-mutated NSCLC with LM, even in patients previously treated with other third-generation EGFR TKIs. Methylation and copy number burden analysis of cfDNA in CSF may be considered objective indicators for the diagnosis of LM and evaluation of treatment response.

Impact of the Early Phase of the COVID-19 Pandemic on the Quality of Care for Colorectal and Anal Cancers at Comprehensive Cancer Centers on Two Continents.

The early phase of the COVID-19 pandemic affected cancer care globally. Evaluating the impact of the pandemic on the quality of cancer care delivery is crucial for understanding how changes in care delivery may influence outcomes. Our study compared care delivered during the early phase of the pandemic with the same period in the previous year at two institutions across continents (Princess Margaret Cancer Center [PM] in Canada and A.C. Camargo Cancer Center [AC] in Brazil). Patients newly diagnosed with colorectal or anal cancer between February and December 2019 and the same period in 2020 were analyzed. Sociodemographic and clinical characteristics and performance of individual indicators within and between centers and between the peri-COVID-19 and control cohorts were tested using Cohen's h test to assess the standardized differences between the two groups. Among 925 patients, distinct effects of the early COVID-19 pandemic on oncology services were observed. AC experienced a 50% reduction in patient consultations (98 v 197) versus a 12.5% reduction at PM (294 v 336). Similarly, AC experienced a higher proportion of stage IV disease presentations (42.9% v 29.9%; P = .015) and an increase in treatment delay (61.9% v 9.7%; P < .001) compared with prepandemic. At PM, a 10% increase in treatment interruption (32.4% v 22.3%; P < .001) and a higher rate of discontinuation of radiotherapy (9.4% v 1.1%; P < .001) were observed during the pandemic. Postsurgical readmission rates increased in both AC (20.9% v 2.6%; P < .001) and PM (10.5% v 3.6%; P < .01). The early phase of the COVID-19 pandemic affected the quality of care delivery for colorectal and anal cancers at both centers. However, the magnitude of this impact was greater in Brazil.

404. REAL-WORLD TREATMENT PATTERN OF EOSINOPHILIC ESOPHAGITIS IN JAPAN

Abstract Background Eosinophilic esophagitis (EoE) is characterized by eosinophilic infiltration in the esophageal epithelium that causes esophageal dysfunction-related symptoms. The treatment for EoE includes acid suppressants (proton pump inhibitors (PPIs) or potassium competitive acid blocker (P-CAB)), topical corticosteroid (TCS), and diet therapy. In addition, biologics (i.e. dupilumab) have been recently approved for EoE in the US. However, the appropriate initial and maintenance therapy for EoE have not been established yet. Therefore, the aim of the study was to investigate the treatment pattern of EoE and its association with fibrostenosis in Japan. Methods We investigated prescription pattern for EoE analyzing an employer-based health insurance claim database from 2005 to 2022. EoE cases were identified based on the International Classification of Diseases-tenth Revision code, K20.0. The initial treatment of interest for EoE included PPIs, P-CAB, and TCS (swallowed inhaled CS). The initial treatment for EoE was defined as these drugs prescribed within two months from the index date of EoE diagnosis. The discontinuation rates of initial PPIs or P-CAB were analyzed using Kaplan-Meier method. The discontinuation of treatment was defined as no treatment following within 90 days from the prescription of the previous treatment. Results Overall, 984 EoE patients (45 years old [38-52], male 747 [75.9%]) were ultimately analyzed. Most of the initial treatment for EoE was acid suppressants (PPIs [323 54.9%], P-CAB [241, 41%]), followed by TCS (13, 2.2%) and combination therapy of PPIs or P-CAB and TCS (11, 1.9%). PPIs or P-CAB discontinued in approximately 50% and 70% of the cases at approximately 150 days and 720 days respectively from the start of the initial therapy. The switching to the second-line therapy from the initial PPIs or P-CAB rarely happened. During the observation period, no EoE patients developed esophageal stenosis. Conclusion PPIs or P-CAB were most prescribed as the initial treatment for EoE in Japan. In addition, more than half of EoE patients discontinued such initial therapy within 2 years without fibrostenotic complication. These findings indicate that EoE that can respond to initial acid suppressants therapy does not necessarily require the maintenance therapy to prevent esophageal fibrostenosis.

Cost-effectiveness analysis comparing single-pill combination of perindopril/amlodipine/indapamide to the free equivalent combination in patients with hypertension from an Italian national health system perspective

ABSTRACT Objective To evaluate the cost-effectiveness of a single-pill combination (SPC) of perindopril/amlodipine/indapamide versus its free equivalent combination (FEC) in adults with hypertension in Italy. Methods A Markov model was developed to perform a cost-utility analysis with a lifetime horizon and an Italian healthcare payer’s perspective. In the model, the additional effect of the SPC on blood pressure level compared with the FEC was translated into a decreased risk of cardiovascular events and CKD, which was modeled via Framingham risk algorithms. Difference in persistence rates of SPC and FEC were modeled via discontinuation rates. Results A perindopril/amlodipine/indapamide SPC is associated with lower cost and better health outcomes compared to its FEC. Over a lifetime horizon, it is associated with a 0.050 QALY gain and cost savings of €376, resulting from lower cardiovascular event rates. In the alternative scenario, where different approach for modeling impact of adherence was considered, incremental gain of 0.069 QALY and savings of €1,004 were observed. Results were robust to sensitivity and scenario analyses, indicating that use of this SPC is a cost-effective strategy. Conclusions The findings indicate that a perindopril/amlodipine/indapamide SPC is a cost-saving treatment option for hypertension in Italy, compared to its FEC.

Heart failure treatment in the last years of life: A nationwide study of 364 000 individuals.

In patients with heart failure, treatment patterns in the last years of life have not been assessed at large scale. We aimed to assess whether heart failure treatment patterns up to 5 years prior to death changed over time. In a cohort study covering the whole Swedish population, we assessed all heart failure patients who died between 1 July 2007 and 31 December 2020 for evidence-based treatments. The proportion on the respective treatment at the time of death was examined by year of death using binomial regression. Looking back in time, treatment discontinuation rates were estimated using Poisson regression on time-split data. Combining these models, the proportion on each medication was estimated up to 5 years prior to death. A total of 364 480 patients died with heart failure during the study period. Half were women, and the median (interquartile range) age at death was 86 (79-90). The use of all heart failure treatments decreased gradually closer to death, but the discontinuation rate of beta blockers decreased over time, resulting in an increasing proportion of patients on treatment at the time of death. In patients with heart failure, a changing pattern of medical treatment during the last years of life was observed, most notably with an increasing use of beta blockers. This may in part be due to a changing pattern of comorbidities over time, with an increase in e.g. hypertension and atrial fibrillation, but a decline in ischaemic heart disease.

Factors associated with cause-specific discontinuation of long-term anti-tumor necrosis factor agent use in patients with ankylosing spondylitis: a retrospective cohort study

ObjectTo investigate the factors associated with cause-specific discontinuation of long-term anti-tumor necrosis factor (TNF) agent use in patients with ankylosing spondylitis (AS).MethodsAS patients who initiated first-line anti-TNF treatment between 2004 and 2018 and continued treatment for at least two years were enrolled in the study. Enrolled patients were observed until the last visit, discontinuation of treatment, or September 2022. Reasons for discontinuation of the first-line anti-TNF agent were categorized into the following: (1) clinical remission, (2) loss of efficacy, (3) adverse events, and (4) other reasons including loss to follow-up, cost, or reimbursement issues. A cumulative incidence function curve was used to visualize the cumulative failure rates over time for each specific reason. Univariable and multivariable cause-specific hazard models were utilized to identify factors associated with cause-specific discontinuation of the first-line anti-TNF agent.ResultsA total of 429 AS patients was included in the study, with 121 treated with adalimumab (ADA), 176 with etanercept (ETN), 89 with infliximab (INF), and 43 with golimumab (GLM). The median overall survival on the first-line anti-TNF agent was 10.6 (7.9–14.5) years. Among the patients, 103 (24.0%) discontinued treatment, with 36 (34.9%) due to inefficacy, 31 (30.1%) due to clinical remission, 15 (14.6%) due to adverse events, and 21 (20.4%) due to other reasons. Patients treated with ETN had a lower risk of discontinuation due to clinical remission compared to those receiving ADA (hazard ratio [HR] 0.45 [0.21–0.99], P = 0.048). Higher baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; HR 1.31 [1.04–1.65], P = 0.023) and INF use were linked to a higher risk of treatment discontinuation for inefficacy compared to ADA use (HR 4.53 [1.45–14.16], P = 0.009). Older age was related to an increased risk of discontinuation due to infection-related adverse events (HR 1.07 [1.02–1.12], P = 0.005), and current smoking was a risk factor for discontinuation due to other reasons (HR 6.22 [1.82–21.28], P = 0.004).ConclusionAS patients on their first anti-TNF treatment for at least two years demonstrated a favorable long-term treatment retention rate, with a 24.0% discontinuation rate over a 10.6-year overall survival period. The predictors for discontinuation varied by causes, underscoring the complexity of treatment response and the importance of personalized approaches to treatment management.

Inpatient Use of Guideline-Directed Medical Therapy During HeartFailure Hospitalizations Among Community-Based Health Systems.

Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains underused. Acute heart failure (HF) hospitalization represents a critical opportunity for rapid initiation of evidence-based medications. However, data on GDMT use at discharge are mostly derived from national quality improvement registries. This study aimed to describe contemporary GDMT use patterns across HF hospitalizations at community-based health systems. The authors identified HF hospitalizations from 2016 to 2022 in a U.S. database aggregating deidentified electronic health record data from more than 30 health systems. In-hospital and discharge rates of GDMT use were reported for eligible HFrEF patients. Factors associated with inpatient GDMT use and predischarge discontinuation were evaluated with the use of multivariable models. A total of 20,387 HF hospitalizations among 13,729 HFrEF patients were identified. Renin-angiotensin system inhibitors, beta-blockers, and mineralocorticoid receptor antagonists were administered during 70%, 86%, and 37% of eligible hospitalizations, respectively. Angiotensin receptor-neprilysin inhibitors and sodium-glucose cotransporter 2 inhibitors were used in 17% and 8% of eligible hospitalizations, respectively. Discharge GDMT rates were low. Triple/quadruple therapy was administered in 26% of hospitalizations, falling to 14% on discharge. Predischarge GDMT discontinuations were associated with inpatient hypotension, hyperkalemia, and worsening renal function, but 43%-57% had no medical contraindications. In adjusted analyses, use of 3 or more GDMT classes was associated with fewer 90-day all-cause deaths and HF readmissions compared with less comprehensive GDMT. Inpatient GDMT use in a national analysis of HF hospitalizations was lower than reported in quality improvement registries. High discontinuation rates emphasize an unmet need for inpatient and postdischarge strategies to optimize GDMT use.

Real-world evidence on efficacy and toxicity of targeted therapy in older melanoma patients treated in a tertiary-hospital setting.

Melanoma is the deadliest form of skin cancer. The median age at diagnosis is 66. While most patients are treated with immunotherapy, the use of targeted therapy is a valid alternative for patients whose tumors harbor a BRAF or c-KIT driver mutation. These agents, while effective, come with a variety of side effects which limit their use, especially in older patients. We sought to assess the efficacy and toxicity of these agents in older melanoma patients. Melanoma patients over 65 treated with BRAF/MEK or c-KIT inhibitors were retrospectively identified, and their data were analyzed for treatment efficacy and toxicity. All data were compared using the Chi-square test for categorical comparisons and the Kruskal-Wallis method for median comparisons. One hundred and sixteen patients were identified. One hundred and six patients were treated with BRAF/MEK inhibitors. The assessed response rate (RR) was 83% and was comparable across different subgroups, including advanced line patients and those with a more aggressive disease. The median progression free survival (PFS) was 7.9 months, and the median overall survival (OS) was 15.7 months. Twenty-seven percent experienced grade 3-4 toxicity leading to a 24% treatment discontinuation rate. Another 10 patients were treated with the c-KIT inhibitor imatinib, for whom the assessed RR was 55%. The median PFS was 4.3 months, and the median OS was 22.6 months. Forty percent needed dose reductions, yet none had to stop treatment due to adverse effects. The use of targeted therapy in older patients is effective yet challenging due to toxicity. Deploying mitigation strategies can help maximizing their usefulness.

Transthyretin amyloid cardiomyopathy: Literature review and red-flag symptom clusters for each cardiology specialty.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is a progressive and infiltrative cardiac disorder that may cause fatal consequences if left untreated. The estimated survival time from diagnosis is approximately 3-6years. Because of the non-specificity of initial symptom manifestation and insufficient awareness among treating physicians, approximately one-third of patients with ATTRwt-CM are initially misdiagnosed with other cardiac diseases. Although heart failure (HF) is the most common initial manifestation of ATTRwt-CM, observed in nearly 70% of affected patients, patients may also present with other cardiologic symptoms, such as atrial fibrillation (AF) and aortic stenosis (AS). This non-specific and diverse nature of the initial ATTRwt-CM presentation indicates that various cardiology subspecialties are involved in patient diagnosis and management. Standard guideline-directed pharmacological treatment for HF is not recommended for patients with ATTRwt-CM because of its limited effectiveness. However, no established algorithms are available regarding HF management in this patient population. This literature review provides an overview of the red flags for ATTRwt-CM and research findings regarding HF management in this patient population. In addition to commonly recognized red flags for ATTRwt-CM (e.g., HF, AF and severe AS), published literature identified potential red flags such as coronary microvascular dysfunction. For HF management in patients with ATTRwt-CM, the use of mineralocorticoid receptor antagonists (MRAs) was reported as a well-tolerated option associated with a low discontinuation rate and reduced mortality. Although there is no concrete evidence for recommendations against sodium-glucose cotransporter 2 inhibitor (SGLT2i) administration, research supporting its use is limited to small-scale studies. Robust evidence is lacking for AF ablation, implantable cardioverter-defibrillators and cardiac resynchronization therapy. Based on the published findings and our clinical experience as Japanese ATTRwt-CM experts, red-flag symptom clusters for each cardiology specialty (HF, arrhythmia and ischaemia/structural heart disease) and a treatment scheme for HF management are presented. As this research area remains at an exploratory stage, our observations would require further discussion among experts worldwide.

Association of Kidney Function with Sodium-Glucose Co-Transporter 2 Inhibitor Discontinuation among US Veterans.

The impact of sodium-glucose co-transporter-2 inhibitors (SGLT2i) on cardiovascular disease and chronic kidney disease (CKD) may be limited if discontinued in persons with CKD. We sought to determine whether CKD at SGLT2i initiation was associated with subsequent discontinuation. This cohort study used electronic health record data of patients who initiated SGLT2i in the Veterans Health Administration from January 2017 through December 2021. The primary exposure was eGFR category at the time of SGLT2i initiation. The risk of SGLT2i discontinuation, defined by a provider order or expiration of an SGLT2i prescription without resumption in the following 180 days, was estimated using proportional hazards models with inverse probability weights for censoring due to death. Analyses were stratified by year of SGLT2i initiation. Among the 222,772 patients initiating an SGLT2i during the study period, median age was 68 (IQR: 60-73) years, 95% were male, and median (IQR) eGFR was 73 (58, 89) mL/min/1.73m2. Median follow-up was 1.6 years; 32% experienced SGLT2i discontinuation. Cumulative risk of discontinuation at one year was 21% to 27% across calendar years; approximately 41% of these discontinuations occurred within the first three months. There was a graded association between lower baseline eGFR and greater risk of discontinuation; this association attenuated across calendar years. Those initiating an SGLT2i in 2017 with baseline eGFR of 45-59 and 30-44 had 1.34- (95%CI: 1.21-1.49) and 2.04-fold (95%CI: 1.58-2.63) risks of discontinuation, respectively, compared to those with eGFR ≥60 ml/min/1.73m2. These hazard ratios reduced to 1.05 (95%CI: 1.02-1.10) and 1.20 (95%CI: 1.14-1.26), respectively, in those initiated in 2021. A substantial proportion of patients experience SGLT2i discontinuation within a year of initiation. Persons with lower eGFR had higher discontinuation rates; however, this trend attenuated over time. Additional studies identifying determining factors of discontinuation are needed to fully realize the benefits of SGLT2i.

Adenomyosis-A Call for Awareness, Early Detection, and Effective Treatment Strategies: A Narrative Review.

To provide a brief summary of the high incidence, symptomatology, different types, and diagnosis of adenomyosis and to explore various aspects of the disease, with the primary aim of raising awareness among gynecologists for appropriate and early detection. Adenomyosis, a benign gynecological condition characterized by the infiltration of endometrial tissue into the myometrium, poses significant challenges to women's reproductive health. A narrative review was conducted by searching PubMed, Scopus, and Cochrane databases and offering a non-systematic summary and critical analysis of current knowledge on the impact of adenomyosis on women's health. Articles published in the English language up to May 2023, including original scientific papers, clinical trials, meta-analyses, and reviews focusing on various aspects of adenomyosis, were included in the synthesis of this review. Approximately 20% of women are affected by adenomyosis, which manifests with various subtypes, distinct epidemiological profiles, symptomatology, and treatment responses. Despite its clinical significance, adenomyosis remains understudied, resulting in a significant disparity in research and the literature compared to other gynecological conditions. The severity of adenomyosis is compounded when coexisting with endometriosis, particularly deep-infiltrating endometriosis (DIE), leading to exacerbated fertility issues and severe symptomatology. The wide range of symptoms, including adverse pregnancy outcomes such as pre-eclampsia, highlights its wider impact and emphasizes the need for increased awareness of the condition. Adenomyosis is frequently associated with treatment failure in endometriosis, contributing to dienogest resistance, elevated discontinuation rates, and persistent pain post-endometriosis surgery. Additionally, the lack of specific treatments tailored to adenomyosis poses a considerable challenge in clinical management.

Adjunctive cenobamate in people with focal onset seizures: Insights from the Italian Expanded Access Program.

This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy. This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses. A total of 236 subjects with a median age of 38 (Q1-Q3 = 27-49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q1-Q3 = 2.50-4.47) at baseline to 2.50 (Q1-Q3 = 1.67-3.50) at 12 months (p < .001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ-aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel. Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult-to-treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam.

A lower initial dose of bosutinib for patients with chronic myeloid leukemia patients resistant and/or intolerant to prior therapy: a single-arm, multicenter, phase 2 trial (BOGI trial)

Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy.

GLP-1RA vs DPP-4i Use and Rates of Hyperkalemia and RAS Blockade Discontinuation in Type 2 Diabetes

Hyperkalemia is a common complication in people with type 2 diabetes (T2D) that may limit the use of guideline-recommended renin-angiotensin system inhibitors (RASis). Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase urinary potassium excretion, which may translate into reduced hyperkalemia risk. To compare rates of hyperkalemia and RASi persistence among new users of GLP-1RAs vs dipeptidyl peptidase-4 inhibitors (DPP-4is). This cohort study included all adults with T2D in the region of Stockholm, Sweden, who initiated GLP-1RA or DPP-4i treatment between January 1, 2008, and December 31, 2021. Analyses were conducted between October 1, 2023, and April 29, 2024. GLP-1RAs or DPP-4is. The primary study outcome was time to any hyperkalemia (potassium level >5.0 mEq/L) and moderate to severe (potassium level >5.5 mEq/L) hyperkalemia. Time to discontinuation of RASi use among individuals using RASis at baseline was assessed. Inverse probability of treatment weights served to balance more than 70 identified confounders. Marginal structure models were used to estimate per-protocol hazard ratios (HRs). A total of 33 280 individuals (13 633 using GLP-1RAs and 19 647 using DPP-4is; mean [SD] age, 63.7 [12.6] years; 19 853 [59.7%] male) were included. The median (IQR) time receiving treatment was 3.9 (1.0-10.9) months. Compared with DPP-4i use, GLP-1RA use was associated with a lower rate of any hyperkalemia (HR, 0.61; 95% CI, 0.50-0.76) and moderate to severe (HR, 0.52; 95% CI, 0.28-0.84) hyperkalemia. Of 21 751 participants who were using RASis, 1381 discontinued this therapy. The use of GLP-1RAs vs DPP-4is was associated with a lower rate of RASi discontinuation (HR, 0.89; 95% CI, 0.82-0.97). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function. In this study of patients with T2D managed in routine clinical care, the use of GLP-1RAs was associated with lower rates of hyperkalemia and sustained RASi use compared with DPP-4i use. These findings suggest that GLP-1RA treatment may enable wider use of guideline-recommended medications and contribute to clinical outcomes in this population.

Real-world outcomes of atypical EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) treated with osimertinib (osi) vs. Afatinib or erlotinib

ObjectivesLimited data are available comparing the efficacy of osi versus earlier generation TKIs for mNSCLC with atypical EGFR mutations (AMs) such as L861Q, G719X, S768I and exon20. MethodsWe performed a single-institution retrospective analysis of patients with EGFR-mutated mNSCLC treated from 2007 to 2023 with 1L TKIs, comparing outcomes for AM patients treated with osi, afatinib, and erlotinib. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the electronic medical record and compared between TKIs using independent sample t-tests and chi-square analyses. Median progression free survival (mPFS) and overall survival (mOS) were compared via Kaplan-Meier log-rank analysis and Cox multivariable regression. ResultsAmong 355 patients with EGFR-mutated mNSCLC, 36 (10 %) harbored AMs in G719X (N=21; 6 %), Exon 20 (N=11; 3 %), L861Q (N=7; 2 %), S768I (N=4; 1 %), C797S (N=1; 0.3 %); 6 patients had compound mutations. Patients with classical mutations (CMs) vs AMs had similar baseline demographic and disease characteristics and usage of TKIs (p = 0.124). Among AM patients, osi yielded superior mPFS (22 m) vs afatinib (12 m; p = 0.005) or erlotinib (9 m; p = 0.001). mOS was likewise superior for osi (32 m) vs afatinib (21 m; p = 0.032) or erlotinib (17 m; p = 0.011). Dose-reduction rates due to AEs were lower for osi (19 %) vs afatinib (24 %; p = 0.003) or erlotinib (23 %; p = 0.002). Discontinuation rates due to AEs were lower for osi vs afatinib (1 % vs 2 %; p < 0.001) or erlotinib (2 %; p = 0.004). ConclusionsIn a large real-world analysis, osi demonstrated superior progression-free and overall survival and improved tolerability compared to afatinib or erlotinib for atypical EGFR-mutated mNSCLC.

Asciminib monotherapy as frontline treatment of chronic-phase chronic myeloid leukemia: results from the ASCEND study

AbstractAsciminib is a myristoyl site BCR::ABL1 inhibitor approved for patients with chronic-phase chronic myeloid leukemia (CP-CML) failing ≥2 prior lines of therapy. The Australasian Leukaemia and Lymphoma Group conducted the Asciminib Evaluation in Newly Diagnosed CML study to assess efficacy of asciminib for newly diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily. Patients with treatment failure, defined as BCR::ABL1 of >10% at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib, or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1% to 10% at 6 months, >0.1% to 1% at 12 months, or >0.01% to 1% at 18 months, the asciminib dose was increased to 80 mg twice daily. With a median follow-up of 21 months (range, 0-36), 82 of 101 patients continue asciminib. Most common reasons for treatment discontinuation were adverse events (6%), loss of response (4%), and withdrawn consent (5%). There were no deaths; 1 patient developed lymphoid blast crisis. The coprimary end points were early molecular response (BCR::ABL1 of ≤10% at 3 months), achieved in 93% (96% confidence interval [CI], 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI, 70-87%), respectively. Cumulative incidence of molecular response 4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline CP-CML therapy leads to high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. This trial was registered at https://www.anzctr.org.au/ as #ACTRN12620000851965.

Comparative analysis of novel hormonal agents in non-metastatic castration-resistant prostate cancer: A Taiwanese perspective.

Non-metastatic castration-resistant prostate cancer (nmCRPC) is an asymptomatic condition with the potential to progress to metastasis. Novel hormonal agents (NHAs) are currently considered the gold standard treatment for nmCRPC, offering significant survival benefits. However, further evidence is needed to determine whether there are differences in the performance of these drugs among Asian populations. This retrospective analysis of nmCRPC patients aims to compare the efficacy and safety of three NHAs-apalutamide, darolutamide, and enzalutamide. Data were collected from two prominent prostate care centers in Taichung, Taiwan. Patient characteristics, treatment details, PSA responses, and adverse events were analyzed. Statistical comparisons were performed, and the study received Institutional Review Board approval. Total of 64 patients were recruited in this study, including 29 darolutamide, 26 apalutamide, and 9 enzalutamide patients. Baseline characteristics varied between the three patient groups, but the treatment response still revealed similar results. The apalutamide group experienced more adverse events, notably skin rash. Discontinuation rates due to adverse events differed among the groups, and patients receiving darolutamide were less likely to discontinue treatment. This real-world study provides insights into NHA utilization in nmCRPC within the Taiwanese population. Adverse event profiles varied, emphasizing the need for individualized treatment decisions. The study underscores the importance of regional considerations and contributes valuable data for optimizing treatment outcomes in nmCRPC.