Pathological response in resectable non-small cell lung cancer: a systematic literature review and meta-analysis.

BACKGROUND: Surrogate endpoints for overall survival in patients with resectable non-small cell lung cancer receiving neoadjuvant therapy are needed to provide earlier treatment outcome indicators and accelerate drug approval. This study's main objectives were to investigate the association among pathological complete response, major pathological response, event-free survival and overall survival and to determine whether treatment effects on pathological complete response and event-free survival correlate with treatment effects on overall survival. METHODS: A comprehensive systematic literature review was conducted to identify neoadjuvant studies in resectable non-small cell lung cancer. Analysis at the patient level using frequentist and Bayesian random effects (hazard ratio [HR] for overall survival or event-free survival by pathological complete response or major pathological response status, yes vs no) and at the trial level using weighted least squares regressions (hazard ratio for overall survival or event-free survival vs pathological complete response, by treatment arm) were performed. RESULTS: In both meta-analyses, pathological complete response yielded favorable overall survival compared with no pathological complete response (frequentist, 20 studies and 6530 patients: HR = 0.49, 95% confidence interval = 0.42 to 0.57; Bayesian, 19 studies and 5988 patients: HR = 0.48, 95% probability interval = 0.43 to 0.55) and similarly for major pathological response (frequentist, 12 studies and 1193 patients: HR = 0.36, 95% confidence interval = 0.29 to 0.44; Bayesian, 11 studies and 1018 patients: HR = 0.33, 95% probability interval = 0.26 to 0.42). Across subgroups, estimates consistently showed better overall survival or event-free survival in pathological complete response or major pathological response compared with no pathological complete response or no major pathological response. Trial-level analyses showed a moderate to strong correlation between event-free survival and overall survival hazard ratios (R2 = 0.7159) but did not show a correlation between treatment effects on pathological complete response and overall survival or event-free survival. CONCLUSION: There was a strong and consistent association between pathological response and survival and a moderate to strong correlation between event-free survival and overall survival following neoadjuvant therapy for patients with resectable non-small cell lung cancer.

Analysis of Breast Cancer Mortality in the US-1975 to 2019.

Importance: Breast cancer mortality in the US declined between 1975 and 2019. The association of changes in metastatic breast cancer treatment with improved breast cancer mortality is unclear. Objective: To simulate the relative associations of breast cancer screening, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer with improved breast cancer mortality. Design, Setting, and Participants: Using aggregated observational and clinical trial data on the dissemination and effects of screening and treatment, 4 Cancer Intervention and Surveillance Modeling Network (CISNET) models simulated US breast cancer mortality rates. Death due to breast cancer, overall and by estrogen receptor and ERBB2 (formerly HER2) status, among women aged 30 to 79 years in the US from 1975 to 2019 was simulated. Exposures: Screening mammography, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer. Main Outcomes and Measures: Model-estimated age-adjusted breast cancer mortality rate associated with screening, stage I to III treatment, and metastatic treatment relative to the absence of these exposures was assessed, as was model-estimated median survival after breast cancer metastatic recurrence. Results: The breast cancer mortality rate in the US (age adjusted) was 48/100 000 women in 1975 and 27/100 000 women in 2019. In 2019, the combination of screening, stage I to III treatment, and metastatic treatment was associated with a 58% reduction (model range, 55%-61%) in breast cancer mortality. Of this reduction, 29% (model range, 19%-33%) was associated with treatment of metastatic breast cancer, 47% (model range, 35%-60%) with treatment of stage I to III breast cancer, and 25% (model range, 21%-33%) with mammography screening. Based on simulations, the greatest change in survival after metastatic recurrence occurred between 2000 and 2019, from 1.9 years (model range, 1.0-2.7 years) to 3.2 years (model range, 2.0-4.9 years). Median survival for estrogen receptor (ER)-positive/ERBB2-positive breast cancer improved by 2.5 years (model range, 2.0-3.4 years), whereas median survival for ER-/ERBB2- breast cancer improved by 0.5 years (model range, 0.3-0.8 years). Conclusions and Relevance: According to 4 simulation models, breast cancer screening and treatment in 2019 were associated with a 58% reduction in US breast cancer mortality compared with interventions in 1975. Simulations suggested that treatment for stage I to III breast cancer was associated with approximately 47% of the mortality reduction, whereas treatment for metastatic breast cancer was associated with 29% of the reduction and screening with 25% of the reduction.

Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery.

PURPOSE: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. PATIENTS AND METHODS: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. RESULTS: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. CONCLUSIONS: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Lecanemab for Patients With Early Alzheimer Disease: Bayesian Analysis of a Phase 2b Dose-Finding Randomized Clinical Trial.

Importance: Bayesian clinical trial designs are increasingly common; given their promotion by the US Food and Drug Administration, the future use of the bayesian approach will only continue to increase. Innovations possible when using the bayesian approach improve the efficiency of drug development and the accuracy of clinical trials, especially in the context of substantial data missingness. Objective: To explain the foundations, interpretations, and scientific justification of the bayesian approach in the setting of lecanemab trial 201, a bayesian-designed phase 2 dose-finding trial; to demonstrate the efficiency of using a bayesian design; and to show how it accommodates innovations in the prospective design and also treatment-dependent types of missing data. Design, Setting, and Participants: This study was a bayesian analysis of a clinical trial comparing the efficacy of 5 lecanemab 201 dosages for treatment of early Alzheimer disease. The goal of the lecanemab 201 trial was to identify the effective dose 90 (ED90), the dose achieving at least 90% of the maximum effectiveness of doses considered in the trial. This study assessed the bayesian adaptive randomization used, in which patients were preferentially assigned to doses that would give more information about the ED90 and its efficacy. Interventions: Patients in the lecanemab 201 trial were adaptively randomized to 1 of 5 dose regimens or placebo. Main Outcomes and Measures: The primary end point of lecanemab 201 was the Alzheimer Disease Composite Clinical Score (ADCOMS) at 12 months with continued treatment and follow-up out to 18 months. Results: A total 854 patients were included in trial treatment: 238 were in the placebo group (median age, 72 years [range, 50-89 years]; 137 female [58%]) and 587 were assigned to a lecanemab 201 treatment group (median age, 72 years [range, 50-90 years]; 272 female [46%]). The bayesian approach improved the efficiency of a clinical trial by prospectively adapting to the trial's interim results. By the trial's end more patients had been assigned to the better-performing doses: 253 (30%) and 161 (19%) patients to 10 mg/kg monthly and 10 mg/kg biweekly vs 51 (6%), 52 (6%), and 92 (11%) patients to 5 mg/kg monthly, 2.5 mg/kg biweekly, and 5 mg/kg biweekly, respectively. The trial identified 10 mg/kg biweekly as the ED90. The change in ADCOMS of the ED90 vs placebo was -0.037 at 12 months and -0.047 at 18 months. The bayesian posterior probability that the ED90 was superior to placebo was 97.5% at 12 months and 97.7% at 18 months. The respective probabilities of super-superiority were 63.8% and 76.0%. The primary analysis of the randomized bayesian lecanemab 201 trial found in the context of missing data that the most effective dose of lecanemab nearly doubles its estimated efficacy at 18 months of follow-up in comparison with restricting analysis to patients who completed the full 18 months of the trial. Conclusions and Relevance: Innovations associated with the bayesian approach can improve the efficiency of drug development and the accuracy of clinical trials, even in the context of substantial data missingness. Trial Registration: ClinicalTrials.gov Identifier: NCT01767311.

Consistency of efficacy results across various clinical measures and statistical methods in the lecanemab phase 2 trial of early Alzheimer's disease.

BACKGROUND: Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aß species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer's disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) at 18 months. The results have been published previously. Herein, we describe the results of sensitivity analyses evaluating the consistency of the lecanemab efficacy results in Study 201 at the identified dose, the ED90, across multiple statistical methods and multiple endpoints over the duration of the study. METHODS: The protocol-specified analysis model was a mixed model for repeated measures (MMRM). Sensitivity analyses address the consistency of the conclusions using multiple statistical methods. These include a disease progression model (DPM), a natural cubic spline (NCS) model, a quadratic mixed model (QMM), and 2 MMRMs with additional covariates. RESULTS: The sensitivity analyses showed positive lecanemab treatment effects for all endpoints and all statistical models considered. The protocol-specified ADCOMS analysis showed a 29.7% slower decline than placebo for ADCOMS at 18 months. The various other analyses of 3 key endpoints showed declines ranging from 26.5 to 55.9%. The results at 12 months are also consistent with those at 18 months. CONCLUSIONS: The conclusion of the primary analysis of the lecanemab Study 201 is strengthened by the consistently positive conclusions across multiple statistical models, across efficacy endpoints, and over time, despite missing data. The 18-month data from this trial was utilized in the design of the confirmatory phase 3 trial (Clarity AD) and allowed for proper powering for multiple, robust outcomes.

Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer.

HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51-52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer.Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379.

Evaluation of cell-free DNA approaches for multi-cancer early detection.

In the Circulating Cell-free Genome Atlas (NCT02889978) substudy 1, we evaluate several approaches for a circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test by defining clinical limit of detection (LOD) based on circulating tumor allele fraction (cTAF), enabling performance comparisons. Among 10 machine-learning classifiers trained on the same samples and independently validated, when evaluated at 98% specificity, those using whole-genome (WG) methylation, single nucleotide variants with paired white blood cell background removal, and combined scores from classifiers evaluated in this study show the highest cancer signal detection sensitivities. Compared with clinical stage and tumor type, cTAF is a more significant predictor of classifier performance and may more closely reflect tumor biology. Clinical LODs mirror relative sensitivities for all approaches. The WG methylation feature best predicts cancer signal origin. WG methylation is the most promising technology for MCED and informs development of a targeted methylation MCED test.

Association of hematologic response and assay sensitivity on the prognostic impact of measurable residual disease in acute myeloid leukemia: a systematic review and meta-analysis.

Measurable residual disease (MRD) is associated with relapse and survival in acute myeloid leukemia (AML). We aimed to quantify the impact of MRD on outcomes across clinical contexts, including its association with hematologic response and MRD assay sensitivity. We performed systematic literature review and meta-analysis of 48 studies that reported the association between MRD and overall survival (OS) or disease-free survival (DFS) in AML and provided information on the MRD threshold used and the hematologic response of the study population. Among studies limited to patients in complete remission (CR), the estimated 5-year OS for the MRD-negative and MRD-positive groups was 67% (95% Bayesian credible interval [CrI], 53-77%) and 31% (95% CrI, 18-44%), respectively. Achievement of an MRD-negative response was associated with superior DFS and OS, regardless of MRD threshold or analytic sensitivity. Among patients in CR, the benefit of MRD negativity was highest in studies using an MRD cutoff less than 0.1%. The beneficial impact of MRD negativity was observed across MRD assays and timing of MRD assessment. In patients with AML in morphological remission, achievement of MRD negativity is associated with superior DFS and OS, irrespective of hematologic response or the MRD threshold used.

Challenges and opportunities associated with the MD Anderson IMPACT2 randomized study in precision oncology.

We investigated the challenges of conducting IMPACT2, an ongoing randomized study that evaluates molecular testing and targeted therapy (ClinicalTrials.gov: NCT02152254). Patients with metastatic cancer underwent tumor profiling and were randomized between the two arms when eligibility criteria were met (Part A). In Part B, patients who declined randomization could choose the study arm. In Part A, 69 (21.8%) of 317 patients were randomized; 78.2% were not randomized because of non-targetable alterations (39.8%), unavailability of clinical trial (21.8%), other reasons (12.6%), or availability of US Food and Drug Administration (FDA)-approved drugs for the indication (4.1%). In Part B, 32 (20.4%) of 157 patients were offered randomization; 16 accepted and 16 selected their treatment arm; 79.0% were not randomized (patient's/physician's choice, 29.3%; treatment selection prior to genomic reports, 16.6%; worsening performance status/death, 12.7%; unavailability of clinical trials, 6.4%; other, 6.4%; non-targetable alterations, 5.7%; or availability of FDA-approved drugs for the indication, 1.9%). In conclusion, although randomized controlled trials have been considered the gold standard for drug development, the execution of randomized trials in precision oncology in the advanced metastatic setting is complicated. We encountered various challenges conducting the IMPACT2 study, a large precision oncology trial in patients with diverse solid tumor types. The adaptive design of IMPACT2 enables patient randomization despite the continual FDA approval of targeted therapies, the evolving tumor biomarker landscape, and the plethora of investigational drugs. Outcomes for randomized patients are awaited.

The Bayesian Time Machine: Accounting for temporal drift in multi-arm platform trials.

BACKGROUND: Multi-arm platform trials investigate multiple agents simultaneously, typically with staggered entry and exit of experimental treatment arms versus a shared control arm. In such settings, there is considerable debate whether to limit analyses for a treatment arm to concurrent randomized control subjects or to allow comparisons to both concurrent and non-concurrent (pooled) control subjects. The potential bias from temporal drift over time is at the core of this debate. METHODS: We propose time-adjusted analyses, including a "Bayesian Time Machine," to model potential temporal drift in the entire study population, such that primary analyses can incorporate all randomized control subjects from the platform trial. We conduct a simulation study to assess performance relative to utilizing concurrent or pooled controls. RESULTS: In multi-arm platform trials with staggered entry, analyses adjusting for temporal drift (either Bayesian or frequentist) have superior estimation of treatment effects and favorable testing properties compared to analyses using either concurrent or pooled controls. The Bayesian Time Machine generally provides estimates with greater precision and smaller mean square error than alternative approaches, at the risk of small bias and small Type I error inflation. CONCLUSIONS: The Bayesian Time Machine provides a compromise between bias and precision by smoothing estimates across time and leveraging all available data for the estimation of treatment effects. Prior distributions controlling the behavior of dynamic smoothing across time must be pre-specified and carefully calibrated to the unique context of each trial, appropriately accounting for the population, disease, and endpoints.

PET-CR as a potential surrogate endpoint in untreated DLBCL: meta-analysis and implications for clinical trial design.

This study's focus is the association of end-of-therapy (EOT) PET results with progression-free (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma receiving first-line chemoimmunotherapy. We develop a Bayesian hierarchical model for predicting PFS and OS from EOT PET-complete response (PET-CR) using a literature-based meta-analysis of 20 treatment arms and a substudy of 4 treatment arms in 3 clinical trials for which we have patient-level data. The PET-CR rate in our substudy was 72%. The modeled estimates for hazard ratio (PET-CR/non-PET-CR) were 0.13 for PFS (95% CI 0.10, 0.16) and 0.10 for OS (CI 0.07, 0.12). Hazard ratios varied little by patient subtype and were confirmed by the overall meta-analysis. We link these findings to designing future clinical trials and show how our model can be used in adapting the sample size of a trial to accumulating results regarding treatment benefits on PET-CR and a survival endpoint.

Redefining breast cancer subtypes to guide treatment prioritization and maximize response: Predictive biomarkers across 10 cancer therapies.

Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating tumor biology beyond clinical hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status to better predict drug responses. We assess the predictive performance of mechanism-of-action biomarkers from ∼990 patients treated with 10 regimens targeting diverse biology. We explore >11 subtyping schemas and identify treatment-subtype pairs maximizing the pathologic complete response (pCR) rate over the population. The best performing schemas incorporate Immune, DNA repair, and HER2/Luminal phenotypes. Subsequent treatment allocation increases the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. pCR gains from reclassification and improved patient selection are highest in HR+ subsets (>15%). As new treatments are introduced, the subtyping schema determines the minimum response needed to show efficacy. This data platform provides an unprecedented resource and supports the usage of response-based subtypes to guide future treatment prioritization.

Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial.

BACKGROUND: Hypothermia is neuroprotective in some ischemia-reperfusion injuries. Ischemia-reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia-reperfusion injury and improve global neurologic outcome. METHODS: This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. RESULTS: Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. CONCLUSIONS: This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups.

Designing Clinical Trials for Combination Immunotherapy: A Framework for Glioblastoma.

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.

A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression. METHODS: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of ≥1.25 points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold. RESULTS: Overall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC-NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged. DISCUSSION: The study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.

Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial.

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms 'graduate' in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.

Development and validation of a prognostic 40-day mortality risk model among hospitalized patients with COVID-19.

OBJECTIVES: The development of a prognostic mortality risk model for hospitalized COVID-19 patients may facilitate patient treatment planning, comparisons of therapeutic strategies, and public health preparations. METHODS: We retrospectively reviewed the electronic health records of patients hospitalized within a 13-hospital New Jersey USA network between March 1, 2020 and April 22, 2020 with positive polymerase chain reaction results for SARS-CoV-2, with follow-up through May 29, 2020. With death or hospital discharge by day 40 as the primary endpoint, we used univariate followed by stepwise multivariate proportional hazard models to develop a risk score on one-half the data set, validated on the remainder, and converted the risk score into a patient-level predictive probability of 40-day mortality based on the combined dataset. RESULTS: The study population consisted of 3123 hospitalized COVID-19 patients; median age 63 years; 60% were men; 42% had >3 coexisting conditions. 713 (23%) patients died within 40 days of hospitalization for COVID-19. From 22 potential candidate factors 6 were found to be independent predictors of mortality and were included in the risk score model: age, respiratory rate ≥25/minute upon hospital presentation, oxygenation <94% on hospital presentation, and pre-hospital comorbidities of hypertension, coronary artery disease, or chronic renal disease. The risk score was highly prognostic of mortality in a training set and confirmatory set yielding in the combined dataset a hazard ratio of 1.80 (95% CI, 1.72, 1.87) for one unit increases. Using observed mortality within 20 equally sized bins of risk scores, a predictive model for an individual's 40-day risk of mortality was generated as -14.258 + 13.460*RS + 1.585*(RS-2.524)^2-0.403*(RS-2.524)^3. An online calculator of this 40-day COVID-19 mortality risk score is available at www.HackensackMeridianHealth.org/CovidRS. CONCLUSIONS: A risk score using six variables is able to prognosticate mortality within 40-days of hospitalization for COVID-19. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04347993.

Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial.

The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel [DOP]) was investigated in the phase II I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%-37%), hormone receptor (HR)-positive/HER2-negative (14%-28%), and triple-negative breast cancer (TNBC) (27%-47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients.

A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aß protofibril antibody.

BACKGROUND: Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aß), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia. METHODS: BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer's Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging. RESULTS: A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (-0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly. CONCLUSIONS: BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer's disease is underway. TRIAL REGISTRATION: Clinical Trials.gov NCT01767311 .