Implementing Multilevel Network Meta-Regression for Time-To-Event Outcomes: A Case Study in Relapsed Refractory Multiple Myeloma.

OBJECTIVES: Multilevel network meta-regression (ML-NMR) leverages individual patient data (IPD) and aggregate data from a network of randomized controlled trials (RCTs) to assess the comparative efficacy of multiple treatments, while adjusting for between-study differences. We provide an overview of ML-NMR for time-to-event outcomes and apply it to an illustrative case study, including example R code. METHODS: The case study evaluated the comparative efficacy of idecabtagene vicleucel (ide-cel), selinexor+dexamethasone (Sd), belantamab mafodotin (BM), and conventional care (CC) for patients with triple-class exposed relapsed/refractory multiple myeloma in terms of overall survival. Single-arm clinical trials and real-world data were naively combined to create an aggregate data artificial RCT (aRCT) (MAMMOTH-CC versus DREAMM-2-BM versus STORM-2-Sd) and an IPD aRCT (KarMMa-ide-cel versus KarMMa-RW-CC). With some assumptions, we incorporated continuous covariates with skewed distributions, reported as median and range. The ML-NMR models adjusted for number of prior lines, triple-class refractory status, and age and were compared using the leave-one-out information criterion. We summarized predicted hazard ratios and survival (95% credible intervals) in the IPD aRCT population. RESULTS: The Weibull ML-NMR model had the lowest leave-one-out information criterion. Ide-cel was more efficacious than Sd, BM, and CC in terms of overall survival. Effect modifiers had minimal impact on the model, and only triple-class refractory was a prognostic factor. CONCLUSIONS: We demonstrate an application of ML-NMR for time-to-event outcomes and introduce code that can be used to aid implementation. Given its benefits, we encourage practitioners to utilize ML-NMR when population adjustment is necessary for comparisons of multiple treatments.

Pembrolizumab plus chemotherapy for first-line treatment of advanced triple-negative breast cancer.

Aim: A systematic review and network meta-analysis (NMA) was performed to evaluate the efficacy of first-line treatments for locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) patients. Materials & methods: Databases were searched for randomized controlled trials evaluating first-line treatments for locally recurrent unresectable or metastatic TNBC patients. NMA was performed to estimate relative treatment effects on overall and progression-free survival between pembrolizumab + chemotherapy and other interventions. Results: NMA including eight trials showed that the relative efficacy of pembrolizumab + chemotherapy was statistically superior to that of other immunotherapy- or chemotherapy-based treatment regimens. Conclusion: Pembrolizumab + chemotherapy confers benefits in survival outcomes versus alternative interventions for the first-line treatment of locally recurrent unresectable or metastatic TNBC patients.

Clinical value of initial treatments for patients with advanced triple-negative breast cancerWhat is this article about? Around 15% of breast cancer patients have the triple-negative breast cancer (TNBC) subtype, which has the worst prognosis. Treatments targeting the immune system, such as pembrolizumab, were recently found to improve the outcomes of patients with cancer that is at an advanced stage or resistant to standard therapies. However, clinical trials evaluating the efficacy of cancer treatments typically compare only two alternative treatments. Therefore, we conducted this study to understand the relative efficacy of several commonly used initial treatments for advanced TNBC by indirectly comparing the results of all available clinical trials that were sufficiently similar. We identified trials by systematically searching the medical literature and analyzed the results of several clinical trials together to estimate the efficacy of pembrolizumab + chemotherapy compared with several other initial treatment regimens for patients with advanced TNBC.What were the results? We identified eight randomized controlled trials evaluating treatment regimens containing chemotherapeutic or immunotherapeutic agents in patients with previously untreated advanced TNBC. Considering all these trials together, pembrolizumab + chemotherapy was found to prolong patient survival to a greater extent than several other treatment regimens including carboplatin, docetaxel, paclitaxel, nab-paclitaxel/paclitaxel, bevacizumab + paclitaxel, ixabepilone + paclitaxel and ixabepilone + bevacizumab depending on the specific set of trials analyzed.What do the results of the study mean? These results indicate that pembrolizumab + chemotherapy has beneficial effects on patient survival compared with other initial treatment regimens for patients with advanced TNBC.

Matching-Adjusted Indirect Comparison of Brexucabtagene Autoleucel (ZUMA-2) and Pirtobrutinib (BRUIN) in Patients with Relapsed/Refractory Mantle Cell Lymphoma Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor.

INTRODUCTION: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor T cell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. METHODS: Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81-38.46]) and complete response (OR 10.11 [95% CI 4.26-24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25-0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. CONCLUSIONS: Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.

Correlation Between Early Time-to-Event Outcomes and Overall Survival in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma Receiving Definitive Chemoradiation Therapy: Systematic Review and Meta-Analysis.

Background: Overall survival (OS) is the most patient-relevant outcome in oncology; however, in early cancers, large sample sizes and extended follow-up durations are needed to detect statistically significant differences in OS between interventions. Use of early time-to-event outcomes as surrogates for OS can help facilitate faster approval of cancer therapies. In locally advanced head and neck squamous cell carcinoma (LA-HNSCC), event-free survival (EFS) was previously evaluated as a surrogate outcome (Michiels 2009) and demonstrated a strong correlation with OS. The current study aimed to further assess the correlation between EFS and OS in LA-HNSCC using an updated systematic literature review (SLR) focusing on patients receiving definitive chemoradiation therapy (CRT). Methods: An SLR was conducted on May 27, 2021 to identify randomized controlled trials assessing radiotherapy alone or CRT in the target population. Studies assessing CRT and reporting hazard ratios (HRs) or Kaplan-Meier data for OS and EFS were eligible for the analysis. CRT included any systemic treatments administered concurrently or sequentially with radiation therapy. Trial-level EFS/OS correlations were assessed using regression models, and the relationship strength was measured with Pearson correlation coefficient (R). Correlations were assessed across all CRT trials and in trial subsets assessing concurrent CRT, sequential CRT, RT+cisplatin, targeted therapies and intensity-modulated RT. Subgroup analysis was conducted among trials with similar EFS definitions (i.e. EFS including disease progression and/or death as events) and longer length of follow-up (i.e.≥ 5 years). Results: The SLR identified 149 trials of which 31 were included in the analysis. A strong correlation between EFS and OS was observed in the overall analysis of all CRT trials (R=0.85, 95% confidence interval: 0.72-0.93). Similar results were obtained in the sensitivity analyses of trials assessing concurrent CRT (R=0.88), sequential CRT (R=0.83), RT+cisplatin (R=0.82), targeted therapies (R=0.83) and intensity-modulated RT (R=0.86), as well as in trials with similar EFS definitions (R=0.87), with longer follow-up (R=0.81). Conclusion: EFS was strongly correlated with OS in this trial-level analysis. Future research using individual patient-level data can further investigate if EFS could be considered a suitable early clinical endpoint for evaluation of CRT regimens in LA-HNSCC patients receiving definitive CRT.

Quantitative phase measurements of tendon collagen fibres.

Collagen is the main component of structural mammalian tissues. In tendons, collagen is arranged into fibrils with diameters ranging from 30 nm to 500 nm. These fibrils are further assembled into fibres several micrometers in diameter. Upon excessive thermal or mechanical stress, damage may occur in tendons at all levels of the structural hierarchy. At the fibril level, reported damage includes swelling and the appearance of discrete sites of plastic deformation that are best observed at the nanometer-scale using, for example, scanning electron microscopy. In this paper, digital in-line holographic microscopy is used for quantitative phase imaging to measure both the refractive index and diameter of collagen fibres in a water suspension in the native state, after thermal treatments, and after mechanical overload. Fibres extracted from tendons and subsequently exposed to 70 °C for 5, 15, or 30 minutes show a significant decrease in refractive index and an increase in diameter. A significant increase in refractive index is also observed for fibres extracted from tendons that were subjected to five tensile overload cycles.