Advances in Therapy最新文献

Introduction

Tislelizumab + chemotherapy has shown promising results as first-line treatment for advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC). We present long-term safety and efficacy outcomes from the RATIONALE-305 trial after 3 years of follow-up, focusing on the intent-to-treat (ITT) population and subgroups based on programmed death ligand-1 (PD-L1) expression.

Methods

RATIONALE-305, a randomized, double-blind, placebo-controlled, phase 3 trial conducted across 146 centers in Asia, Europe, and North America (December 2018–February 2024), enrolled 997 adults with human epidermal growth factor receptor 2–negative advanced GC/GEJC, randomized 1:1 to receive tislelizumab + chemotherapy or placebo + chemotherapy. The primary endpoint was overall survival (OS) in patients with PD-L1 Tumor Area Positivity (TAP) score ≥ 5% and the ITT population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and tolerability. At 3-year follow-up, 959 (96.2%) patients had discontinued or completed treatment. The minimum follow-up duration was 36.6 months.

Results

In all randomized patients (n = 997), 69.4% male and 30.6% female, tislelizumab + chemotherapy improved OS versus placebo + chemotherapy [15.0 months (95% CI 13.6–16.5) vs. 12.9 months (95% CI 12.1–14.1); stratified hazard ratio (HR) 0.79]. Investigator-assessed PFS was also improved [6.9 months (95% CI 5.7–7.2) vs. 6.2 months (95% CI 5.6–6.9); stratified HR 0.79]. The ORR was higher with tislelizumab + chemotherapy. In patients with a PD-L1 TAP score ≥ 5% [n = 546 (54.8%)], similar OS and PFS benefits were observed compared to the ITT population. OS was 16.4 (95% CI 13.6–19.1) months versus 12.8 (95% CI 12.0–14.5) months, stratified HR 0.71 for tislelizumab + chemotherapy versus placebo + chemotherapy, respectively. PFS was 7.2 (95% CI 5.8–8.4) months versus 5.9 (95% CI, 5.6–7.0) months, stratified HR 0.69. No new safety signals were identified.

Conclusion

Results from RATIONALE-305 continued to show durable and improved efficacy outcomes with tislelizumab + chemotherapy versus placebo + chemotherapy at 3 years in advanced GC/GEJC, supporting PD-L1 as a potential prognostic biomarker.

Trial Registration

ClinicalTrials.gov Identifier: NCT03777657.

The introduction of biosimilars into global markets has increased utilisation and reduced costs of biological therapies. However, the uptake varies by country because of differences in biosimilar knowledge and concerns about their safety and efficacy. This review examines clinical and real-world data on the effects of switching between reference and biosimilar (SDZ-ETN, SB4, LBEC0101, YLB113) etanercept on treatment efficacy and safety in patients with inflammatory rheumatic and musculoskeletal diseases. To date, all controlled clinical trials and real-world studies indicate that switching between reference and biosimilar etanercept does not affect treatment efficacy and safety. These findings support broader biosimilar adoption to improve patient access and reduce healthcare costs. However, published data on multiple biosimilar switches and patient-reported outcomes remain limited, warranting further research efforts in these areas.

Introduction

Immunoglobulin A (IgA) nephropathy is a rare renal condition associated with a high risk of kidney failure. However, conducting phase 3 clinical trials with kidney failure as a primary endpoint is generally not feasible because of sample size and protracted follow-up requirements. Hence, surrogate outcomes are necessary when assessing new treatments in randomized controlled trials. Previous meta-analyses have assessed the validity of early change in proteinuria as a surrogate endpoint, and the present research updates the analysis with additional patient-level data.

Methods

The same methodology as two previously published individual patient-level meta-analyses was used, with additional data from the PROTECT study included. Early change in proteinuria was defined as change from baseline at 9 months, and the clinical endpoint was defined as the composite of doubling of serum creatinine level, kidney failure or death. The association of treatment effects was ascertained using individual patient data via a Bayesian mixed-effect regression model to relate treatment effects on the clinical outcome to treatment effects on proteinuria with study as the unit of analysis.

Results

The updated individual patient-level meta-analysis including data from PROTECT resulted in an overall slope of 1.03 (95% Bayesian credible interval − 0.40 to 2.34) between treatment effects on early change in proteinuria versus longer-term treatment effects on the clinical outcome, with an R² of 0.80 (95% Bayesian credible interval 0.07 to1.00). This corroborates the use of early proteinuria as a valid surrogate endpoint for a treatment’s effect on progression to kidney failure in studies of IgA nephropathy.

Conclusions

The FDA and EMA have accepted proteinuria as a valid surrogate outcome for use in clinical trials of new interventions for the treatment of IgA nephropathy, and the present analysis provides further indications that interventions that reduce proteinuria in a short-term trial are likely to improve kidney outcomes over the long term.

Introduction

Although patients with extensive-stage small cell lung cancer (ES-SCLC) typically respond well to first-line (1L) platinum-based chemotherapy (PBC)-containing regimens, disease recurrence is common, and survival is short. Treatment options beyond 1L are limited, leaving an urgent need for more effective treatment options. Understanding patient characteristics, treatment patterns, and clinical outcomes in this setting may inform clinical development of novel therapies for ES-SCLC.

Methods

This study is a retrospective, observational analysis of real-world data from a US nationwide electronic health record-derived de-identified database. Patients with ES-SCLC who received 1L PBC between January 1, 2018, and June 30, 2023, were included. Treatment patterns were analyzed in all patients, and clinical outcomes from third-line (3L) therapy initiation were assessed in those who also received 3L treatment. The study period (January 1, 2018, through December 31, 2023) allowed for ≥ 6 months’ potential follow-up.

Results

Of 2573 patients (50.5% female; 49.5% male) included in the overall population, 992 (38.6%), 344 (13.4%), and 114 (4.4%) received ≥ 1, ≥ 2, and ≥ 3 subsequent treatment lines, respectively. Treatment patterns beyond 1L were fragmented: the most common second-line treatments were lurbinectedin-containing regimens (26.5%), and in 3L were lurbinectedin-containing regimens (21.8%) or topoisomerase inhibitors (21.8%). From 3L therapy initiation, median real-world overall survival (rwOS) was 4.53 months (95% confidence interval [CI] 3.71–5.39), median real-world time to treatment discontinuation or death (rwTTD/D) was 2.56 months (95% CI, 2.27–2.79), median real-world time to next treatment or death (rwTTNT/D) was 2.92 months (95% CI, 2.69–3.12), and real-world response rate among 77 evaluable patients was 11.7% (95% CI, 5.5–21.0).

Conclusions

This study demonstrated the heterogeneity of treatments after 1L PBC-containing therapy for patients with ES-SCLC, with no clear standard of care identified. In 3L, rwTTD/D, rwTTNT/D, and rwOS were short, demonstrating the substantial unmet need for novel treatments in this setting.

Introduction

A post-marketing surveillance study of EX-PRESS™ Glaucoma Filtration Device was conducted to confirm the safety and efficacy of the product in clinical settings.

Methods

Patients with glaucoma with insufficient intraocular pressure (IOP) reduction despite glaucoma medication, laser therapy or prior glaucoma surgery underwent EX-PRESS™ filtration surgery and were followed for 3 years.

Results

The study was conducted from July 2012 to December 2017 and included 890 eyes of 835 patients from 52 medical institutions across Japan. The efficacy analysis of 821 eyes showed that the mean ± SD IOP changed from 25.0 ± 9.1 mmHg at baseline to postoperative 14.0 ± 5.4, 14.2 ± 5.8, and 14.5 ± 5.8 mmHg at 12, 24, and 36 months, respectively. The mean ± SD number of glaucoma medications used reduced from 3.5 ± 1.4 at baseline to postoperative 1.0 ± 1.5, 1.4 ± 1.7, and 1.7 ± 1.7 at 12, 24, and 36 months, respectively. The survival analysis showed that the rate of success, defined as IOP ≤ 21 mmHg and a percent reduction of ≥ 20% with or without glaucoma medication, was 64.6% at 3 years postoperatively. In the safety analysis of 824 eyes, the incidence of malfunctions was 31.9% and the incidence of adverse events (AEs) for which a causal relationship could not be ruled out was 22.2%. There were no reports of infection. The most common malfunctions were device–iris touch (26.9%), device malfunction (2.9%), device–cornea touch (2.7%), and device obstruction (1.7%). The most common AEs were IOP increased (11.9%), corneal endothelial cell loss (5.7%), glaucoma filtration surgery (5.0%), device removal (5.0%), hypotony (3.2%), and bleb reconstruction (2.4%). Five cases of reduced visual acuity and one case of visual field defect aggravation were reported as adverse events related to vision. The mean endothelial cell density (ECD) decreased after surgery but remained above 2000 cells/mm² at 36 months postoperatively. Percent change of ECD at 36 months from baseline was − 8.2 ± 22.5%.

Conclusion

The current study confirmed the efficacy and safety of the EX-PRESS™ Glaucoma Filtration Device.

Treprostinil is a prostacyclin analog available in four formulations: parenteral, oral, inhalation solution, and inhalation powder. All formulations of treprostinil are indicated for the treatment of pulmonary arterial hypertension; the inhaled formulations are also approved for pulmonary hypertension associated with interstitial lung disease. Transitions between formulations are frequent in clinical practice but lack standardized guidance. This review summarizes published evidence regarding safety, efficacy, and techniques of transitioning between treprostinil formulations. The evidence includes over 100 patients across various settings, with crossover transition strategies most frequently employed. Approximately 80% of cases reviewed were deemed successful; however, it should be noted there was no standardized definition for success across publications. Unsuccessful transitions were often linked to disease progression or intolerance to therapy. These findings underscore the importance of individualized transition strategies, informed by clinical status, patient preferences, and formulation-specific pharmacokinetics. By consolidating the current evidence, this review aims to support clinicians in optimizing transitions and maintaining continuity of treprostinil therapy.

Graphical abstract available for this article.

Graphical Abstract

Introduction

Obesity management medications can reduce body weight and have an impact on patients’ appetite and eating behaviors. Existing patient-reported outcome (PRO) measures do not fully capture appetite and eating behavior concepts relevant to individuals living with obesity, including those receiving treatment. Here we describe the development and content evaluation of the Eating Behavior and Appetite Questionnaire (EBAQ), a new PRO measure to enable a comprehensive assessment of appetite and eating behaviors which are important to individuals living with obesity.

Methods

The EBAQ was developed on the basis of findings from a targeted literature review, findings from exit interviews with participants (N = 40) in a phase 2 trial for retatrutide (NCT04881760), and interviews with clinicians specializing in obesity medicine (N = 3). Cognitive interviews were conducted with USA-based adults with obesity or with overweight and ≥ 1 obesity-related complications (hypertension, dyslipidemia, cardiovascular disease) (N = 24) to evaluate the content of the EBAQ.

Results

All 24 cognitive interview participants reported a positive overall impression of the EBAQ and that they understood the instructions and recall period. Most participants (n = 23, 96%) found the response options to be clear and appropriate. Items in the EBAQ were considered clear and relevant by the participants. The 21-item EBAQ is a new PRO measure with three domains to evaluate eight appetite and eating behavior concepts relevant to obesity and which may change with obesity treatment.

Conclusion

The EBAQ may be used in clinical trials, clinical practice, or observational research to evaluate the impact of obesity and the effect of obesity treatment on appetite and eating behaviors.

Therapeutic adherence is defined as the extent to which patients’ medication-taking behaviour corresponds with agreed recommendations from a clinician. Adherence to cardiovascular therapies significantly improves outcomes and improves patient quality of life. However, adherence is often suboptimal in patients with cardiovascular disease. This narrative review aims to describe key barriers to adherence and identify practical actions that can be undertaken by all stakeholders to improve treatment adherence. Key barriers fall into categories related to the patient, medication, healthcare system, disease and society. These include, but are not limited to, logistical challenges faced by patients incorporating medication into their daily lives, fragmented care, the patient-physician relationship, the complexity of the regimen and medication costs. While macro-initiatives to remove health system and societal barriers are encouraged, there are many practical ways in which patients can also be supported to adhere to medication. These include improving communication techniques to build a trusting physician-patient relationship, engaging other healthcare professionals (e.g. nurses and pharmacists), referral to patient advocacy groups for reliable information and peer support, simplifying treatment regimens where safe and appropriate, the use of digital tools or devices (e.g. pill boxes and symptom trackers) that help patients to take their medication in the right dose and at the right time and consideration of the patient’s budgetary constraints when prescribing. Prescribing formulations for once-daily administration and single-pill combinations can also help to simplify treatment regimens. No single solution will fit all patients, and initiatives to enhance adherence must also be tailored wherever possible to the individual patient’s abilities, circumstances, values and beliefs.

Introduction

Relugolix is the only oral androgen deprivation therapy (ADT) approved for advanced prostate cancer (PC). Real-world evidence on treatment patterns and prostate-specific antigen (PSA) responses of relugolix, especially as a function of race, remain limited. This study assessed these outcomes and compared differences between Black and White patients.

Methods

Veterans Health Administration data were analyzed to identify male adults with PC who initiated relugolix between December 2020 and December 2023. Adherence to relugolix was assessed for up to 1 year after treatment initiation and was compared between races using generalized linear models. Discontinuation of relugolix, switching to another ADT, and initiating an add-on PC treatment were assessed using Kaplan–Meier analyses and compared between races using Cox regressions. PSA responses during relugolix treatment, including ≥ 50% and ≥ 90% decline from baseline and achieving < 0.2 ng/mL, were assessed among ADT-naïve patients.

Results

A total of 507 patients were identified (141 Black and 313 White patients). During the first 12 months of treatment, both races had > 90% adherence to relugolix with no significant differences between them. During follow-up (median 10.7 and 12.6 months for Black and White patients, respectively), 27.0% Black and 21.1% White patients discontinued relugolix; 9.2% Black and 3.8% White patients switched to another ADT; and 11.3% Black and 10.5% White patients initiated an add-on PC treatment. Among ADT-naïve patients, 87.2% Black and 87.2% White patients achieved PSA decline ≥ 50% from baseline; 69.2% and 64.1% achieved ≥ 90% decline; 51.3% and 47.4% achieved PSA < 0.2 ng/mL.

Conclusion

Adherence to relugolix was very high during the first year of treatment. These data support that in the real world, patients can adhere to relugolix with PSA responses on par with clinical trials regardless of race. Black patients were more likely to discontinue or switch to another ADT than White patients, but the reasons for this require further study.

Trial registration

ClinicalTrials.gov identifier, NCT06462014.

For people living with eosinophilic granulomatosis with polyangiitis (EGPA), the journey to diagnosis can be long and complicated. EGPA is a rare inflammatory disorder, typically characterized by high levels of blood eosinophils and vasculitis in the lungs and/or other end organ(s). It is associated with asthma, pulmonary infiltrates, neuropathy, sinus disease and the presence of anti-neutrophil cytoplasmic antibodies. Patients can present with a number of symptoms and complications, which often go unrecognized or misdiagnosed and can result in considerable delays in appropriate treatment and worsening of underlying disease. Following correct diagnosis, patients are often treated with oral corticosteroids and other immunosuppressive drugs. While these treatments can be effective at controlling disease, they are also associated with significant side effects, which can lead to diminished quality of life. The emergence in recent years of anti-interleukin-5/receptor (anti-IL-5/R) therapies, such as benralizumab and mepolizumab, has revolutionized the management of EGPA. Interleukin-5 (IL-5) is a key cytokine in the maturation, proliferation and activation of eosinophils. Anti-IL-5/R therapies work by binding IL-5 or the receptor for IL-5, thereby significantly decreasing eosinophilic inflammation, the key pathogenic driver in EPGA. Not only are anti-IL-5/R therapies effective at controlling disease, but they are also well tolerated and can facilitate corticosteroid tapering. In this podcast, a patient and physician discuss the lived experience of EGPA, including difficulties with diagnosis, impact of disease on daily life and disease management with both traditional treatments and with the newer anti-IL-5/R therapies. The discussion highlights the importance of EGPA awareness and of physicians recognizing seemingly unconnected symptoms and different disease components, as well as the need to minimize corticosteroid use because of long-term risks. Furthermore, access to an experienced and coordinated healthcare team and establishing a strong support network are emphasized as essential to help patients manage this complex and rare disease.