IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer

Biliary tract cancer; Cancer immunotherapy; CholangiocarcinomaCàncer del tracte biliar; Immunoteràpia contra el càncer; ColangiocarcinomaCáncer del tracto biliar; Inmunoterapia contra el cáncer; ColangiocarcinomaBackground: Biliary tract cancers (BTCs) are heterogenous, highly aggressive tumors that harbor a dismal prognosis for which more effective treatments are needed. The role of cancer immunotherapy in BTC remains to be characterized. The tumor microenvironment (TME) of BTC is highly immunosuppressed and combination treatments are needed to promote effective anticancer immunity. Vascular endothelial growth factor (VEGF) drives immunosuppression in the TME by disrupting antigen presentation, limiting T-cell infiltration, or potentiating immune-suppressive cells. Many VEGF-regulated mechanisms are thought to be relevant to repressed antitumor immunity in BTC, making dual targeting of VEGF and programmed cell death protein 1 (PD-1)/PD-L1 pathways a rational approach. Gemcitabine and Cisplatin (Gem/Cis) can also modulate anticancer immunity through overlapping and complementary mechanisms to those regulated by VEGF. Anti-PD-L1/VEGF inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit. Methods: IMbrave 151 is a randomized, double-blind, placebo-controlled, multicenter, international phase II study to evaluate atezolizumab (a PD-L1 inhibitor) in combination with chemotherapy (gemcitabine and cisplatin) and bevacizumab (an anti-VEGF monoclonal antibody) as a first-line treatment for advanced BTC. Approximately 150 patients with previously untreated, advanced BTC will be randomized to either Arm A (atezolizumab + bevacizumab + Gem/Cis) or Arm B (atezolizumab + placebo + Gem/Cis). Randomization is stratified by the presence of metastatic disease, primary tumor location, and geographic region. The primary efficacy endpoint is investigator-assessed progression-free survival (PFS) per RECIST 1.1. Secondary endpoints include objective response rate (ORR), duration of response (DoR), disease control rate (DCR), overall survival (OS), and safety and patient reported outcomes (PROs). Tissue, blood, and stool samples will be collected at baseline and on-treatment in order to perform correlative biomarker analyses. Discussion: IMbrave 151 represents the first randomized study to evaluate combined PD-L1/VEGF blockade on a chemotherapy backbone in BTC. Trial registration: NCT identifier: NCT04677504; EUDRACT number: 2020-003759-14The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study is funded by F. Hoffmann-La Roche Ltd

Premature Discontinuation of Pediatric Randomized Controlled Trials : A Retrospective Cohort Study

Objectives To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for recruitment failure in pediatric and adult RCTs. Study design A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists. Results We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants). Conclusion Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure.Peer reviewe

Activity-Based Funding of Hospitals and Its Impact on Mortality, Readmission, Discharge Destination, Severity of Illness, and Volume of Care: A Systematic Review and Meta-Analysis

Background: Activity-based funding (ABF) of hospitals is a policy intervention intended to re-shape incentives across health systems through the use of diagnosis-related groups. Many countries are adopting or actively promoting ABF. We assessed the effect of ABF on key measures potentially affecting patients and health care systems: mortality (acute and post-acute care); readmission rates; discharge rate to post-acute care following hospitalization; severity of illness; volume of care.     Methods: We undertook a systematic review and meta-analysis of the worldwide evidence produced since 1980. We included all studies reporting original quantitative data comparing the impact of ABF versus alternative funding systems in acute care settings, regardless of language. We searched 9 electronic databases (OVID MEDLINE, EMBASE, OVID Healthstar, CINAHL, Cochrane CENTRAL, Health Technology Assessment, NHS Economic Evaluation Database, Cochrane Database of Systematic Reviews, and Business Source), hand-searched reference lists, and consulted with experts. Paired reviewers independently screened for eligibility, abstracted data, and assessed study credibility according to a pre-defined scoring system, resolving conflicts by discussion or adjudication.     Results: Of 16,565 unique citations, 50 US studies and 15 studies from 9 other countries proved eligible (i.e. Australia, Austria, England, Germany, Israel, Italy, Scotland, Sweden, Switzerland). We found consistent and robust differences between ABF and no-ABF in discharge to post-acute care, showing a 24% increase with ABF (pooled relative risk = 1.24, 95% CI 1.18–1.31). Results also suggested a possible increase in readmission with ABF, and an apparent increase in severity of illness, perhaps reflecting differences in diagnostic coding. Although we found no consistent, systematic differences in mortality rates and volume of care, results varied widely across studies, some suggesting appreciable benefits from ABF, and others suggesting deleterious consequences.     Conclusions: Transitioning to ABF is associated with important policy- and clinically-relevant changes. Evidence suggests substantial increases in admissions to post-acute care following hospitalization, with implications for system capacity and equitable access to care. High variability in results of other outcomes leaves the impact in particular settings uncertain, and may not allow a jurisdiction to predict if ABF would be harmless. Decision-makers considering ABF should plan for likely increases in post-acute care admissions, and be aware of the large uncertainty around impacts on other critical outcomes

How to use a noninferiority trial: users' guides to the medical literature

Clinical investigators are increasingly testing treatments that have the primary benefit of decreased burden or harms relative to an existing standard. The goal of the resulting randomized trials—called noninferiority trials—is to establish that the novel treatment's effectiveness is not substantially less than the existing standard. Conclusions from these trials are, however, based on noninferiority thresholds specified by authors whose judgments may not coincide with those of patients and clinicians. This article highlights issues related to validity, interpretation, and applicability of results specific to noninferiority trials. Suboptimal administration of standard treatment or exclusive reliance on the analyze-as-randomized approach that is standard for conventional superiority trials may produce misleading results in noninferiority trials. Clinicians should judge whether the novel treatment's impact on effectiveness outcomes—the prime reason for wanting to prescribe it—is sufficiently close to that of standard treatment that they are comfortable substituting it for the existing standard. Trading off desirable and undesirable consequences is an individual decision: given the benefits of a novel treatment, some patients may perceive the uncertainty regarding a reduction in treatment effectiveness as acceptable while others may not