Advances in Therapy最新文献

Platinum-based chemotherapy has been the cornerstone of first-line treatment for advanced urothelial carcinoma for decades, based on its proven efficacy and well-characterized safety profile. Although enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy versus platinum-based chemotherapy in the EV-302 phase 3 trial, common and potentially cumulative toxicities associated with EV plus pembrolizumab may make this combination less suitable for some patients, such as those with pre-existing neuropathy, hyperglycemia, or hepatic impairment, or patients likely to have favorable outcomes with platinum-based chemotherapy. The availability of EV plus pembrolizumab in various countries may also be limited by financial considerations. Thus, platinum-based chemotherapy is likely to remain a valuable option for advanced urothelial carcinoma. Eligibility for cisplatin- or carboplatin-based regimens can be determined by assessing renal function, performance status, and specific comorbidities. In cisplatin-eligible and -ineligible patients without disease progression following platinum-based chemotherapy, avelumab first-line maintenance is standard of care based on findings from the JAVELIN Bladder 100 phase 3 trial, which showed that avelumab first-line maintenance plus best supportive care prolonged overall survival and progression-free survival compared with best supportive care alone across clinically relevant subgroups. Adverse events associated with avelumab were generally consistent with those observed with other immune checkpoint inhibitors, and long-term follow-up showed no new safety concerns with prolonged treatment. Efficacy benefits and safety profiles were similar in patients who received avelumab first-line maintenance after cisplatin- or carboplatin-based chemotherapy. The effectiveness and safety of avelumab first-line maintenance have been confirmed in several real-world studies. Overall, these data support the use of avelumab first-line maintenance for all platinum-treated patients without disease progression. In this podcast, we discuss the evolving role of platinum-based chemotherapy in this disease setting in the context of EV-302 trial results and describe practical considerations in patients receiving first-line cisplatin- or carboplatin-based chemotherapy followed by avelumab maintenance therapy.

Introduction: Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening inflammatory skin disease. Interleukin (IL)-36 signalling may play a central role in GPP pathogenesis. Spesolimab is a humanized anti-IL-36 monoclonal antibody inhibiting the IL-36 signalling pathway. Here, we investigated the pharmacokinetics and safety of spesolimab in healthy Chinese subjects.

Methods: In this Phase 1, single-dose, parallel-group, open-label study, healthy Chinese subjects aged 18-45 years received a single spesolimab dose by intravenous infusion (IV; 450 mg, 900 mg, or 1200 mg) or subcutaneous (SC) administration (300 mg or 600 mg). Primary endpoints were spesolimab exposure (area under the plasma concentration-time curve and maximum plasma concentration); secondary endpoints were treatment-emergent adverse events (TEAEs) and drug-related adverse events (AEs).

Results: Fifty subjects received IV (n = 30) or SC (n = 20) spesolimab (n = 10 per dose group); 60.0% were male, mean ± standard deviation age was 31.5 ± 6.6 and 31.0 ± 6.5 years in the IV and SC groups, respectively. Spesolimab exposure increased in a dose-proportional manner in both groups. TEAEs were reported in 83.3% and 80.0% of subjects in the IV and SC groups, the most common TEAE was upper respiratory tract infection (20.0% and 25.0%, respectively). One serious AE of hand fracture was reported in the 900 mg IV group that was not considered drug-related. Drug-related AEs were reported in 53.3% and 55.0% of subjects in the IV and SC groups. All laboratory-related AEs were mild and resolved.

Conclusion: Spesolimab exposure increased in a dose-proportional manner after a single dose by IV and SC administration. Spesolimab was well tolerated in healthy Chinese subjects.

Clinical trial registration: Clinicaltrials.gov registration: NCT04390568.

Introduction: Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapy is a standard of care for advanced non-squamous non-small cell lung cancer (NSQ-NSCLC); however, the lack of safety data limits its clinical application in Japan.

Methods: This study compared the safety of ABCP with that of bevacizumab, carboplatin, and paclitaxel (BCP) combination for the treatment of advanced NSQ-NSCLC in Japanese patients by evaluating the clinical background and incidence of adverse events (AEs) based on data extracted from the Diagnosis Procedure Combination (DPC) database. Incidence rates and restricted mean survival times (RMSTs) for up to 1 year were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method.

Results: A search conducted using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes identified 350,987 patients, of whom 202 were included in the ABCP cohort and 232 in the BCP cohort. Among the 19 AEs, the incidence of skin disorder and febrile neutropenia (FN) was significantly higher in the ABCP cohort versus the BCP cohort. The adjusted incidence rate ratios were 2.65 [95% confidence interval (CI) 1.43-4.91] for skin disorder and 1.70 (95% CI 1.01-2.85) for FN. The adjusted RMST differences were - 64.2 days (95% CI - 93.0 to - 35.4 days) and - 46.0 days (95% CI - 73.5 to - 18.5 days) for skin disorder and FN, respectively. These results were comparable to those of other pivotal clinical trials.

Conclusions: The findings of this DPC database study highlight the safety of ABCP in Japanese clinical practice, and this methodology may facilitate more efficient research in real-world settings.

Trial registration: UMIN Clinical Trials Registry ID UMIN000041507.

Introduction: Symptom status and treatment changes among patients with chronic obstructive pulmonary disease (COPD) using inhaler treatment in real-world clinical settings are not well understood, particularly according to class of treatment. We investigated the proportion of symptomatic patients among those with COPD using inhaler treatment, based on COPD Assessment Test (CAT) scores in clinical practice, and changes in inhaler treatments and symptoms at 1-year follow-up.

Methods: This was a retrospective analysis of data from a multicenter, prospective cohort study conducted at medical institutions with respiratory specialists in Japan. The primary endpoint was the proportion of patients with CAT scores ≥ 10 or < 10 in each inhaler treatment group at registration.

Results: Of 414 patients in the full analysis set, 76 (18.4%), 261 (63.0%), and 77 (18.6%) were using long-acting muscarinic antagonist (LAMA), LAMA + long-acting β₂-agonist (LABA), and inhaled corticosteroids (ICS) + LABA, respectively, at registration. The proportions of patients with CAT scores ≥ 10 or < 10 per inhaler treatment group at registration, respectively, were 32.9% and 67.1% in the LAMA group, 55.0% and 45.0% in the LAMA + LABA group, and 50.0% and 50.0% in the ICS + LABA group. Most patients (> 75%) in each inhaler treatment group showed no change in inhaler treatment at 1 year, regardless of their CAT score at registration. Approximately 70-80% of patients with CAT scores ≥ 10 at registration still had CAT scores ≥ 10 at 1 year; 10-30% of patients with CAT scores < 10 at registration had CAT scores ≥ 10 at 1 year.

Conclusion: In real-world Japanese clinical practice, a considerable proportion of patients have persistent symptoms (CAT score ≥ 10) despite using mono or dual inhaler treatment; > 75% of symptomatic patients with COPD using inhaler treatment did not undergo treatment escalation at 1-year follow-up and remained symptomatic.

Trial registration: ClinicalTrials.gov identifier, NCT05903989.

Introduction: There is a medical need for a safe, effective nonopioid postoperative analgesic for older subjects, including those with mild to moderate renal impairment.

Methods: Participants (≥ 65 years) were stratified by no, mild, or moderate renal impairment defined as creatinine clearance 60-89 mL/min for mild and 30-59 mL/min for moderate. Subjects were randomized to receive a loading dose of 6.25 mg of ketorolac tromethamine drug candidate NTM-001 followed by a 1.75 mg/h continuous intravenous (IV) infusion over 24 h or an IV bolus injection of ketorolac tromethamine (KETO-BOLUS) of 15 mg every 6 h. There were four treatment periods of 24 h for each subject with a minimum 7-day washout between them. This was a crossover study so subjects served as their own controls. Blood drawn from the subjects was used to plot concentration-time profiles against target profiles. Adverse events were monitored.

Results: Thirty-nine subjects enrolled. Concentration-time profiles showed low intersubject variability. Model-predicted curves for those with renal impairment closely matched observed plasma concentrations. Continuous infusion maintained higher mean plasma concentrations than the bolus regimen. No serious or unexpected adverse events were observed. No deaths occurred.

Conclusions: NTM-001 was considered safe and well tolerated in this population of participants ≥ 65 years, including in those with mild or moderate renal impairment. There were fewer adverse events in the continuous infusion group. The predictable pharmacologic properties and blood concentration levels suggest that continuous IV infusion of ketorolac can be used as an effective postoperative pain reliever in older subjects.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective for glycemic control, with many also demonstrating cardiovascular (CV) benefit, in people with type 2 diabetes (T2D). This study aimed to find a consensus on the barriers and strategies for the optimal use of GLP-1 RAs in people with T2D and high CV risk or established cardiovascular disease (CVD) in Spain.

Methods: A two-round Delphi survey (53 questions) was conducted among members of four national scientific societies in Spain, including physicians experienced in the management of people with T2D. The degree of consensus was evaluated with a 7-point Likert scale, establishing consensus when ≥ 70% of the panelists agreed (6-7) or disagreed (1-2).

Results: A total of 97 physicians participated in the first round (endocrinology: 34%, family and community medicine: 21%, internal medicine: 23%, and cardiology: 23%), and 96 in the second round. The main barriers identified were: therapeutic inertia and late use of GLP-1 RAs; lack of a comprehensive approach to CV risk; lack of knowledge on the usefulness of GLP-1 RAs in CVD prevention and treatment; and economic/administrative barriers. Strategies with a highest consensus included: the need to establish simple protocols that integrate awareness of CV risk monitoring; training professionals and patients; and the use of new technologies.

Conclusion: Physicians identified clinical, healthcare, and economic/administrative barriers that limit the use of GLP-1 RAs in people with T2D and high CV risk or established CVD in Spain, highlighting the importance of integrating these therapies according to clinical practice guidelines.

Introduction: This study compared the clinical effectiveness of switching from tumor necrosis factor inhibitor (TNFi) to upadacitinib (TNFi-UPA), another TNFi (TNFi-TNFi), or an advanced therapy with another mechanism of action (TNFi-other MOA) in patients with rheumatoid arthritis (RA).

Methods: Data were drawn from the Adelphi RA Disease Specific Programme™, a cross-sectional survey administered to rheumatologists and their consulting patients in Germany, France, Italy, Spain, the UK, Japan, Canada, and the USA from May 2021 to January 2022. Patients who switched treatment from an initial TNFi were stratified by subsequent therapy of interest: TNFi-UPA, TNFi-TNFi, or TNFi-other MOA. Physician-reported clinical outcomes including disease activity (with formal DAS28 scoring available for 29% of patients) categorized as remission, low/moderate/high disease activity, as well as pain were recorded at initiation of current treatment and ≥ 6 months from treatment switch. Fatigue and treatment adherence were measured ≥ 6 months from treatment switch. Inverse-probability-weighted regression adjustment compared outcomes by subsequent class of therapy: TNFi-UPA versus TNFi-TNFi, or TNFi-UPA versus TNFi-other MOA.

Results: Of 503 patients who switched from their first TNFi, 261 were in TNFi-UPA, 128 in TNFi-TNFi, and 114 in TNFi-other MOA groups. At the time of switch, most patients had moderate/high disease activity (TNFi-UPA: 73%; TNFi-TNFi: 52%; TNFi-other MOA: 60%). After adjustment for differences in characteristics at point of switch, patients in TNFi-UPA group (n = 261) were significantly more likely to achieve physician-reported remission (67.7% vs. 40.3%; p = 0.0015), no pain (55.7% vs. 25.4%; p = 0.0007), and complete adherence (60.0% vs. 34.2%; p = 0.0049) compared with patients in TNFi-TNFi group (n = 121). Similar findings were observed for TNFi-UPA versus TNFi-other MOA groups (n = 111).

Conclusion: Patients who switched from TNFi to UPA had significantly better clinical outcomes of remission, no pain, and complete adherence than those who cycled TNFi or switched to another MOA.

Introduction: The prevalence of obesity has increased worldwide over the past decades. Regional variations exist in the relationship between body mass index (BMI), body fat, and health risks: Asians typically have a lower BMI than people of European descent, but a higher risk of obesity-related comorbidities. However, there is a paucity of evidence for anti-obesity medications (AOMs) in East Asian populations. In this study, we aimed to systematically review evidence regarding the safety and efficacy of AOMs among adults with obesity disease in East Asia, and to assess the feasibility of conducting an indirect treatment comparison (ITC) between the semaglutide and mazindol trials.

Methods: The Embase, MEDLINE, and ICHUSHI databases were searched via the Ovid SP platform for randomized controlled trials, in English or Japanese, reporting data on semaglutide or mazindol therapy with placebo or diet and exercise as comparators. The potential risks of bias in conducting a population-adjusted ITC were determined based on the heterogeneity of potential effect modifiers and variations in study design.

Results: Of 21 publications, 2 were included in this study based on the eligibility criteria. The STEP 6 study established the clinical efficacy of subcutaneous semaglutide compared with placebo in the reduction of body weight and cardiometabolic risk factors [glycated hemoglobin (HbA_1c), total cholesterol, and systolic blood pressure] among Japanese and South Korean people with obesity disease. Mazindol also proved beneficial in reducing body weight and total cholesterol compared with placebo in Japan. Both semaglutide and mazindol were associated with higher rates of adverse events and treatment discontinuation than placebo. An ITC between the two studies was not deemed feasible based on the potential risks of bias.

Conclusions: Semaglutide and mazindol are associated with significant body weight reduction among people with obesity in East Asia. Further research based on label indications and up-to-date real-world data among East Asian people with obesity would help determine additional clinical benefits.

Introduction: The Nucala Effectiveness Study (NEST) assessed the effectiveness of mepolizumab in patients with severe asthma (SA) in countries previously underrepresented in real-world studies.

Methods: A multi-country, bi-directional, self-controlled, observational cohort study conducted in Colombia, Chile, India, Türkiye, Saudi Arabia, United Arab Emirates, Kuwait, Oman, and Qatar. Historical and/or prospective data from patients with SA were assessed 12 months pre- and post-mepolizumab initiation.

Primary endpoint: incident rate ratio (IRR) of clinically significant exacerbations (CSEs). Key secondary endpoints: healthcare resource utilisation (HCRU), oral corticosteroid (OCS) use, lung function and symptom control (Asthma Control Test [ACT] scores).

Results: Overall, 525 patients with SA burden pre-initiation (geometric mean blood eosinophil count [BEC] 490.7 cells/µl; 31.4% prior biologic use; 37.3% obese) received at least one dose of mepolizumab 100 mg subcutaneously. Post-initiation, a significant reduction in CSEs was observed (76% [p < 0.001]; IRR [95% confidence interval] 0.24 [0.19-0.30]); 72.0% of patients had no CSEs. Mepolizumab treatment led to a reduction in OCS use (52.8% pre-initiation vs. 16.6% post-initiation) and a mean (standard deviation [SD]) change in OCS dose of - 18.1 (20.7) mg post-initiation; 36.1% of patients became OCS-free. Fewer patients were hospitalised post-initiation (22.5% pre-initiation vs. 6.9% post-initiation). Improvements in mean (SD) forced expiratory volume in 1 s (62.8 [20.2]% pre-initiation vs. 73.0 [22.7]% post-initiation) and ACT scores (15.0% pre-initiation vs. 64.5% of patients post-initiation with well-controlled asthma) were observed. Proportion of patients with BEC ≥ 500 cells/µl decreased from 84.4% pre-initiation to 18.1% post-initiation.

Conclusion: Mepolizumab was effective in reducing the burden of SA by significantly reducing CSEs, reducing OCS use and HCRU, and improving lung function and asthma control, which could translate to improvements in health-related quality of life in patients with SA and high OCS dependency in the countries studied. A graphical abstract is available with this article.

Introduction: Concomitant gallbladder and common bile duct (CBD) stones, known as cholecystocholedocholithiasis, are clinically prevalent. There is currently no consensus on sequential versus simultaneous management approaches, and, if simultaneous, which approach to adopt. This meta-analysis evaluates the safety and efficacy of one-stage laparoscopic cholecystectomy (LC) with intraoperative endoscopic retrograde cholangiopancreatography (ERCP) versus two-stage ERCP followed by LC for treating concomitant gallbladder and CBD stones.

Methods: A comprehensive literature search was conducted in five databases, PubMed, Embase, Web of Science, VIP, and Wanfang, for all randomized controlled trials (RCTs), cohort and retrospective studies published up to February 2024. Data extraction was performed independently by two reviewers. The primary outcomes were CBD stone clearance rate and postoperative complications morbidity. Secondary outcomes included conversion to other procedures and length of hospital stay. Statistical analyses were performed using R (v.4.3.2) with weighted mean differences and odds ratios (ORs) calculated for continuous and dichotomous variables, respectively, with 95% confidence intervals (CIs).

Results: A total of 17 studies involving 2120 patients have been included, with 898 patients receiving single-stage and 1222 patients undergoing two-stage treatment. Of these studies, 9 were RCTs and 8 were retrospective cohort study. The one-stage group demonstrated superior outcomes in terms of CBD stone clearance (OR = 2.07, p = 0.0004), overall morbidity (OR = 0.35, p < 0.0001), post-operative pancreatitis (OR = 0.49, p = 0.006), conversion to other procedures (OR = 0.38, p = 0.0006), and length of hospital stay (MD = - 2.6456, 95% CI - 3.5776; - 1.7136, p < 0.0001). No significant differences were observed in post-operative cholangitis (OR = 0.44, p = 0.12), post-operative bleeding (OR = 0.76, p = 0.47), or bile leakage (OR = 1.28, p = 0.54).

Conclusion: For patients with concomitant gallbladder and CBD stones, the one-stage approach combining ERCP and LC appears safer and more effective, with advantages including higher stone clearance rates, reduced postoperative complications (particularly pancreatitis), shorter hospital stays, fewer residual stones, and decreased need for additional procedures. However, additional high-quality clinical trials are needed to establish the optimal treatment approach for various patient scenarios.