Endpoint Analysis Research Articles

Trial Design with Win Statistics for Multiple Time-to-Event Endpoints with Hierarchy

The conventional approach to the analysis of composite endpoints is time-to-first event analysis. However, this approach has been criticized because it ignores the differences in clinical severity and may end up emphasizing the less severe time-to-event. To overcome this limitation, win statistics (win ratio, win odds, or net benefit) have become popular in analysis of hierarchical time to event endpoints. However, design of randomized clinical trials using the win statistics is lagging behind. In this article, we derive formulas for the win statistics and probability of ties under specific assumptions that can be useful in practice. We also address two design issues: the selection of meaningful and justifiable design parameters and power calculations, when the win statistics method is the primary analysis method for multiple time-to-event endpoints for a pre-specified hierarchy. Finally, we identify patterns where the win statistics approach would have greater statistical power than time-to-first event analysis. Several examples are used to illustrate the usefulness of the formula-based power calculations.

Treatment of sleep apnoea early after myocardial infarction with adaptive servo-ventilation: a proof-of-concept randomised controlled trial.

Sleep disordered breathing (SDB) has been associated with less myocardial salvage and smaller infarct size reduction after acute myocardial infarction (AMI). The Treatment of sleep apnoea Early After Myocardial infarction with Adaptive Servo-Ventilation (TEAM-ASV I) trial investigated the effects of adding adaptive servo-ventilation (ASV) for SDB to standard therapy on the myocardial salvage index (MSI) and change in infarct size within 12 weeks after AMI. In this multicentre, randomised, open-label trial, patients with AMI and successful percutaneous coronary intervention within 24 h after symptom onset plus SDB (apnoea-hypopnoea index ≥15 events·h-1) were randomised to standard medical therapy alone (control) or plus ASV (starting 3.6±1.4 days post-AMI). The primary outcome was the MSI at 12 weeks post-AMI. Cardiac magnetic resonance (CMR) imaging was performed at ≤5 days and 12 weeks after AMI. 76 individuals were enrolled from February 2014 to August 2020; 39 had complete CMR data for analysis of the primary end-point. The MSI was significantly higher in the ASV versus control group (difference 14.6% (95% CI 0.14-29.1%); p=0.048). At 12 weeks, absolute (6.6 (95% CI 4.8-8.5) versus 2.8 (95% CI 0.9-4.8) % of left ventricular mass; p=0.003) and relative (44 (95% CI 30-57) versus 21 (95% CI 6-35) % of baseline; p=0.013) reductions in infarct size were greater in the ASV versus control group. No serious treatment-related adverse events occurred. Early treatment of SDB with ASV improved the MSI and decreased infarct size at 12 weeks after AMI. Larger randomised trials are required to confirm these findings.

The effect of exercise and educational programs for breast cancer patients on the development of breast cancer-related lymphoedema: secondary endpoint from a randomized controlled trial in the Setouchi Breast Project-10.

Although the association between higher physical activity and preventive effect on breast-cancer-related lymphoedema (BCRL) has been reported, it is unclear what intervention is optimal. We aimed to investigate the effect of exercise and educational programs on BCRL development. This study was a secondary endpoint analysis from a prospective randomized controlled trial. We enrolled patients with stage 0-III breast cancer from March 2016 to March 2020 and randomly assigned them to the control (n = 111), education (n = 115), or exercise (n = 104) group. As secondary endpoint, we assessed the incidence of and preventive effect on BCRL at 12months post-intervention. There were no significant differences in the incidence of BCRL at 12months post-intervention between the exercise and control groups (9.8% and 10.8%, P = 0.83) and the education and control groups (11.6% and 10.8%, P = 1.00). There were no significant differences in time to BCRL onset from the day of surgery between the exercise and control groups (event rate at 12months: 20.7% and 17.2%, log-rank, P = 0.54) and the education and control groups (18.8% and 17.2%, log-rank, P = 0.57). The multivariable analyses indicated that axillary dissection and obesity significantly increased the risk of BCRL [hazard ratio (HR): 2.36, 95% confidence interval (CI) 1.52-3.67 and HR: 1.68, 95% CI 1.07-2.63, respectively]. The intervention did not decrease the risk of BCRL, and axillary dissection and obesity were the risk factors of BCRL. UMIN000020595 at UMIN Clinical Trial Registry.

Dendritic Cell-Based Immunotherapy in Patients With Resected Pancreatic Cancer.

Immunotherapies have shown limited responses in patients with advanced pancreatic cancer. Recently, we reported that dendritic cell (DC)-based immunotherapy induced T-cell responses against pancreatic cancer antigens. The primary objective of this study was to determine the efficacy of DC-based immunotherapy to prevent recurrence of disease. This was a single-center, open-label, single-arm, combined phase I/II trial. The primary end point was the 2-year recurrence-free survival (RFS) rate. A 2-year RFS rate of ≥60% was defined as a clinically meaningful improvement. We included patients with pancreatic cancer after resection and completion of standard-of-care (SOC) treatment without recurrent disease on cross-sectional imaging. Patients were treated with autologous DCs pulsed with an allogeneic mesothelioma tumor cell lysate, comprising antigens also expressed in pancreatic ductal adenocarcinoma. Thirty-eight patients were included in the analysis of the primary end point (47% male, 53% female). The median age was 62 years (IQR, 55-68). Twenty-eight patients (74%) received five DC vaccinations and completed the study protocol. Three patients (8%) received four vaccinations, and seven patients (16%) received three vaccinations. After a median follow-up of 25.5 months, 26 patients (68%) had not developed recurrence of disease. The estimated 2-year RFS was 64%. Vaccination led to the enrichment of circulating activated CD4+ T cells and the detection of treatment-induced immune responses in vitro. T-cell receptor-sequencing analyses of a resected solitary lung metastasis showed influx of vaccine-specific T cells. This study reached its primary end point of a 2-year RFS rate of ≥60% following pancreatectomy after SOC treatment and adjuvant DC-based immunotherapy in patients with pancreatic cancer. These results warrant a future randomized trial.

Lomitapide in Pediatric Patients with Homozygous Familial Hypercholesterolemia – Analysis of Secondary and Safety Endpoints from the APH-19 Study

Lomitapide in Pediatric Patients with Homozygous Familial Hypercholesterolemia – Analysis of Secondary and Safety Endpoints from the APH-19 Study

Prevalence of Acute on Chronic Liver Failure in Autoimmune Hepatitis, Treatment Response and Mortality Burden Assessment: A Region-Predominant Systematic Review and Meta-Analysis.

Acute-on-chronic liver failure (ACLF) is a global health problem. Little scientific evidence exists on its prevalence in autoimmune hepatitis. Treatment response and mortality outcomes have also been reported differently. The study was conducted to estimate the overall prevalence of ACLF among patients with autoimmune hepatitis (AIH) and determine the associated treatment response and mortality. We scrutinized wide literature in Scopus, PubMed, Embase, Web of Science, and Cochrane, and assessed published articles completely, studies performed and reported from around the globe, until December 07, 2023, according to the PROSPERO registered protocol (CRD42023412176). Studies (retrospective and prospective cohort study type) that stated the ACLF development among established AIH cases were considered. Features of the study, duration of follow-up, and numeric patient information were retrieved from the studies included. The research paper quality was checked for risk of bias. Random effect meta-analysis with metaregression and subsection scrutinies were performed with R. The main outcome was the collective prevalence of ACLF in the AIH patients, whereas treatment response and mortality in AIH-associated ACLF were secondary outcomes. Six studies were involved with confirmed diagnoses in 985 AIH patients for the data synthesis. The pooled prevalence of ACLF in the explored patients was 12% (95% CI: 8-17) ( P =0.01). Heterogeneity was found to be high in the present meta-analysis ( I2 =72%; P < 0.01). For the secondary endpoint analysis, the pooled prevalence of complete remission at 1-year follow-up was 71% (0.52; 0.85), and mortality from the ACLF-AIH patient population was 32% (95% CI: 18-50). Sensitivity analysis showed no influence on the overall estimations of the pooled prevalence of ACLF by omitting studies one by one. One in 10 AIH patients likely present with ACLF. The response to treatment is seen in two-thirds of patients, and mortality is high.

Local radiotherapy and measurable residual disease-driven immunotherapy in patients with early-stage follicular lymphoma (FIL MIRO): final results of a prospective, multicentre, phase 2 trial

The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach. This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11. Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients. Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested. AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.

Establishing Optimal Control Cohorts for Phase 1 Trials: Retrospective Analysis of Clinical and Biological Outcomes in Neonates and Infants Undergoing Two-Ventricle Repair.

Phase 1 trials are primarily conducted to evaluate the safety and feasibility of new interventions, usually without recruiting control patients. This retrospective study aims to characterize clinical and biological outcomes in historical and contemporary cases of neonates and infants undergoing two-ventricle repair to facilitate future secondary endpoint analyses for such trials. This retrospective study included neonates/infants (ages ≤ 6months) who underwent two-ventricle repair between 2015 and 2021 using the same criteria as our phase 1 trial (n = 199). Patients were allocated into the ventricular septal defect (n = 61), the Tetralogy of Fallot (TOF, n = 88), and the transposition of the great arteries (n = 50) groups with an additional comparison between two eras (2015-2019 vs. 2020-2021). Patient characteristics and most variables assessed were different between the three diagnostic groups indicating the importance of diagnostic matching for secondary analyses. Although the era did not alter cerebral/somatic oxygenation, ventricular function, neuroimaging findings, and complication rates, we observed improvement of inotropic and/or vasoactive-inotropic scores in all groups during the more recent era. In 2020-2021, the age and the body weight at the operation were higher, and hospital stay was shorter in the TOF group, suggesting the possible impact of the pandemic. Results also indicated that matching altered characteristics such as age at operation that may limit the temporal effects and optimize secondary analyses. Using optimal contemporary cases and historical data based on this study will assist in developing a comprehensive study design for a future efficacy/effectiveness trial.

Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial

In Asia, adjuvant chemotherapy after gastrectomy with D2 or more extensive lymph-node dissection is standard treatment for people with pathological stage III gastric or gastro-oesophageal junction (GEJ) cancer. We aimed to assess the efficacy and safety of adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy administered in this setting. ATTRACTION-5 was a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial conducted at 96 hospitals in Japan, South Korea, Taiwan, and China. Eligible patients were aged between 20 years and 80 years with histologically confirmed pathological stage IIIA-C gastric or GEJ adenocarcinoma after gastrectomy with D2 or more extensive lymph-node dissection, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and available tumour tissue for PD-L1 expression analysis. Patients were randomly assigned (1:1) to receive either nivolumab plus chemotherapy or placebo plus chemotherapy via an interactive web-response system with block sizes of four. Investigational treatment, either nivolumab 360 mg or placebo, was administered intravenously for 30 min once every 3 weeks. Adjuvant chemotherapy was administered as either tegafur-gimeracil-oteracil (S-1) at an initial dose of 40 mg/m2 per dose orally twice per day for 28 consecutive days, followed by 14 days off per cycle, or capecitabine plus oxaliplatin consisting of an initial dose of intravenous oxaliplatin 130 mg/m2 for 2 h every 21 days and capecitabine 1000 mg/m2 per dose orally twice per day for 14 consecutive days, followed by 7 days off treatment. The primary endpoint was relapse-free survival by central assessment. The intention-to-treat population, consisting of all randomly assigned patients, was used for analysis of efficacy endpoints. The safety population, defined as patients who received at least one dose of trial drug, was used for analysis of safety endpoints. This trial is registered with ClinicalTrials.gov (NCT03006705) and is closed. Between Feb 1, 2017, and Aug 15, 2019, 755 patients were randomly assigned to receive either adjuvant nivolumab plus chemotherapy (n=377) or adjuvant placebo plus chemotherapy (n=378). 267 (71%) of 377 patients in the nivolumab group and 263 (70%) of 378 patients in the placebo group were male; 110 (29%) of 377 patients in the nivolumab group and 115 (31%) of 378 patients in the placebo group were female. 745 patients received assigned treatment (371 in the nivolumab plus chemotherapy group; 374 in the placebo plus chemotherapy group), which was the safety population. Median time from first dose to data cutoff was 49·1 months (IQR 43·1-56·7). 3-year relapse-free survival was 68·4% (95% CI 63·0-73·2) in the nivolumab plus chemotherapy group and 65·3% (59·9-70·2) in the placebo plus chemotherapy group; the hazard ratio for relapse-free survival was 0·90 (95·72% CI 0·69-1·18; p=0·44). Treatment-related adverse events occurred in 366 (99%) of 371 patients in the nivolumab plus chemotherapy group and 364 (98%) of 374 patients in the placebo plus chemotherapy group. Discontinuation due to adverse events was more frequent in the nivolumab plus chemotherapy group (34 [9%] of 371 patients) than the placebo plus chemotherapy group (13 [4%] of 374 patients). The most common treatment-related adverse events were decreased appetite, nausea, diarrhoea, neutrophil count decreased, and peripheral sensory neuropathy. The results of this trial do not support the addition of nivolumab to postoperative adjuvant therapy for patients with untreated, locally advanced, resectable gastric or GEJ cancer. Ono Pharmaceutical and Bristol Myers Squibb.

LGG-37. A PHASE III STUDY COMPARING TWO CARBOPLATIN CONTAINING REGIMENS FOR CHILDREN AND YOUNG ADULTS WITH PREVIOUSLY UNTREATED LOW-GRADE GLIOMA

Abstract BACKGROUND Low-grade glioma (LGG) is the most common childhood central nervous system tumor. Carboplatin/vincristine (CV) is a standard of care regimen used for incompletely resected tumors. Monthly carboplatin is an alternative regimen that has not been prospectively compared to CV previously in untreated patients. METHODS Patients ≤ 21 years with LGG and no treatment besides surgery were eligible. Patients were stratified according to NF1 status and randomized to Arm A (carboplatin/vincristine) or Arm B (carboplatin monthly). The primary endpoint was 3-year progression-free survival (PFS). Secondary endpoint analysis is underway and includes quality of life, tumor response rates, toxicity and association of molecular alterations on outcomes. Analyses included log-rank test and descriptive statistics. RESULTS There were 95 evaluable patients with a median age of 5 (range 0-18) years; 67 non-NF1 subjects (32 Arm A, 35 Arm B) and 28 NF1 subjects (14 Arm A, 14 Arm B). Three-year PFS was superior for patients without NF1 treated on Arm A (58%; 95% CI: 38%, 74%) versus Arm B (33%; 95% CI: 18%, 49%) (p=0.04). In patients with NF1, there was no statistical difference in PFS between those treated on Arm A (71%; 95% CI: 41%, 88%) and Arm B (93%; 95% CI: 59%, 99%) (p=0.08). Grade 3/4 toxicity neutropenia was more commonly seen in Arm A patients compared to Arm B for both NF and non-NF1 patients. Peripheral neuropathy was also more commonly seen in non-NF1 patients (Grade 1-4; 32%) compared to NF1 patients (7%) for patients treated on Arm A. There were 15 carboplatin reactions (Grade 1-4); 7 non-NF1 on Arm A, 3 non-NF1 on Arm B, and 5 NF1 on Arm A. CONCLUSIONS Non-NF1 patients treated with carboplatin and vincristine show statistically significant improved PFS compared to monthly carboplatin. Patients with NF1 are statistically underpowered due to low accrual.

Environmental Impact Assessment of a 1 kW Proton-Exchange Membrane Fuel Cell: A Mid-Point and End-Point Analysis

Proton-exchange membrane fuel cells (PEMFCs) are highly regarded as a promising technology for renewable energy generation; however, the environmental burden in their life cycle is a subject of concern. This study aimed to assess the environmental impact of producing a 1 kW PEMFC by a well-detailed cradle-to-gate evaluation, using mid-point and end-point impact assessment methods. The environmental impacts are related to the extraction of raw materials, consumption of energy, and transportation processes. Mid-point analysis shows that raw materials extraction and processing have a significant share in some impacts, including freshwater eutrophication, human carcinogenic toxicity, and terrestrial acidification. On the other hand, the energy consumed in fuel cell production plays a significant role in the impact categories of fossil resource depletion and global warming. The highest impact is attributed to the human health end-point analysis (0.000866 DALY), followed by the damage to ecosystems (1.04 × 10−6 species/yr) and resources (USD2013 6.16844). Normalization results further strengthen the importance of human health impacts and the necessity to solve problems regarding toxicity. The results of this work can provide directions toward enhancing the environmental sustainability of PEMFC technology and present a case for adopting a holistic approach to sustainability by looking across the life cycle of the technology.

Meta-analysis of combined azithromycin and inhaled budesonide treatment for Chinese pediatric patients with mycoplasma pneumonia.

Budesonide, capable of reducing vascular permeability, suppressing mucus secretion, and alleviating edema and spasms, is widely used in China for combined infectious disease treatment. This study assesses budesonide's efficacy and safety as an adjunct to azithromycin in pediatric Mycoplasma pneumonia management in China, aiming to establish a strong theoretical foundation for its clinical application. We conducted a comprehensive search for qualifying studies across 5 English databases and 4 Chinese databases, covering publications until October 31, 2023. Endpoint analyses were performed using standard software (Stata Corporation, College Station, TX). This study was conducted in compliance with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A total of 24 randomized controlled trials were involved in the current study, including 2034 patients. Our findings indicate that the combination of budesonide with azithromycin for the treatment of pediatric Mycoplasma pneumonia delivers superior therapeutic efficacy (Intravenous: odds ratio [OR], 0.156, P < .001; Sequential: OR, 0.163, P = .001; Oral: OR, 0.139, P < .001), improved pulmonary function (Forced expiratory volume in 1 second: weighted mean differences [WMD], -0.28, P = .001; Peak expiratory flow: WMD, -0.554, P = .002; Forced vital capacity: WMD, -0.321, P < .001), diminished lung inflammation (IL-6: WMD, 4.760, P = .002; c-reactive protein: WMD, 5.520, P < .001; TNF-α: WMD, 9.124, P < .001), reduced duration of fever, faster resolution of cough and rales, all without increasing the occurrence of adverse events. The combination of budesonide and azithromycin demonstrates enhanced therapeutic effectiveness, promotes improved pulmonary function, shortens the duration of symptoms, and effectively mitigates the overexpression of inflammatory factors like c-reactive protein, TNF-α, and IL-6, all without an associated increase in adverse reactions in pediatric mycoplasma pneumonia.

Effectiveness of an Aerosol Inhalation Monitor in an Ambulatory Primary Care Pharmacy Clinic.

Background: Poor inhaler technique can worsen respiratory disease. An Aerosol Inhalation Monitor (AIM) may provide insight into a patient's capability of utilizing inhaled medications. Objective: The purpose of this quality assessment was to determine if the addition of the Vitalograph AIM device by ambulatory care pharmacists within an outpatient primary care clinic improves patient's disease control through changes in pharmacotherapy. Methods: This was a retrospective, longitudinal, quality assessment review. Pharmacists met with patients for initial and follow-up appointments. A chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) or Asthma Control Test (ACT) and AIM assessment were performed and pharmacotherapy was subsequently adjusted. The primary endpoint was the change in initial to last recorded ACT and CAT score and was analyzed by Wilcoxon sign-rank test. Results: Twenty asthma and 17 COPD patients were included; 13 asthma and 13 COPD patients were included in the primary and secondary endpoint analysis. Initial median (interquartile range [IQR]) ACT score was 17 (14-23), first follow-up was 20 (18-24), and last recorded score was 22 (18-23). Initial median (IQR) CAT score was 17 (12-22), first follow-up score was 14 (6-20), and last recorded score was 11 (6-19). There was no statistical difference between initial CAT or ACT to first follow-up or last recorded CAT or ACT. Most patients continued their current inhaler regimen. Conclusions: This review demonstrates the positive effect pharmacists can have on respiratory disease management. The improvement in ACT and CAT scores suggests a positive, clinically significant outcome. Future research should evaluate pharmacist's effect on asthma and COPD readmission rates.

Safety and efficacy of Holmium-166 selective internal radiotherapy of primary and secondary liver cancer confirmed by real-world data.

Holmium-166 has emerged as a promising option for selective internal radiotherapy (SIRT) for hepatic malignancies, but data on routine clinical use are lacking. The purpose of this study was to describe the safety and effectiveness of Holmium-166 SIRT in real-world practice through retrospective analysis of a multicenter registry. Retrospective analysis was conducted on Holmium-166 SIRT procedures performed between July 15, 2019, and July 15, 2021, across seven European centers. Treatment planning, treatment realization and post-treatment follow-up were conducted according to routine local practice. Safety and effectiveness data were extracted from the patients' health records. Primary endpoint analysis was assessed for the entire study population with separate analysis for subgroups with hepatocellular carcinoma, metastatic colorectal cancer and intrahepatic cholangiocarcinoma. A total of 167 SIRT procedures in 146 patients (mean age 66 ± 11 years, 68% male) were retrospectively evaluated. Most common tumor entities were hepatocellular carcinoma (n=55), metastatic colorectal cancer (n=35), intrahepatic cholangiocarcinoma (n=19) and metastatic neuroendocrine tumors (n=10). Nine adverse events grade ≥ 3 according to Common Terminology Criteria for Adverse Events were recorded, including one fatal case of radioembolization-induced liver disease. Response rates and median overall survival for the above mentioned subgroups were comparable to results from previous Holmium-166 trials as well as to results from Yttrium-90 registries. This study confirms that the safety and effectiveness of Holmium-166 SIRT derived from prospective trials also applies in routine clinical practice, reinforcing its potential as a viable treatment option for primary and secondary liver cancer.

NEOPRISM-CRC: Neoadjuvant pembrolizumab stratified to tumour mutation burden for high risk stage 2 or stage 3 deficient-MMR/MSI-high colorectal cancer.

LBA3504 Background: The prognostic advantage of early stage deficient-MMR/MSI-High colorectal cancer (CRC) is lost after relapse. Hence, there is a clinical imperative to maximise the chance of cure in early-stage disease. Tumour mutation burden (TMB) is an emerging biomarker for response and clinical benefit to immunotherapy in the advanced setting. NEOPRISM-CRC (Neoadjuvant PembRolizumab In Stratified Medicine – ColoReCtal) is the first multicentre Phase II Trial to determine if neoadjuvant pembrolizumab is efficacious and safe, prospectively stratified to TMB. Methods: The trial population included patients (pts) with operable high-risk stage 2 or stage 3 dMMR/MSI-High CRC. Pts with tumours that were TMB high or medium (≥6 mutations/Mb on FoundationOneCDx test) received 3 cycles of pembrolizumab (200mg every 3 weeks) and underwent surgery within 4-6 weeks of last cycle. Pts with TMB low tumours (≤5 mutations/Mb) underwent surgery 4-6 weeks after 1 cycle of pembrolizumab. The primary end point was pathological complete response rate (pCR). Secondary endpoints included 3-year relapse free survival, overall survival, safety, and health-related quality of life. The trial also incorporated translational endpoints to explore relationships between possible predictive novel biomarkers and response to pembrolizumab in blood, tumour tissue and microbiome. We required 19 pts with TMB high or medium tumours to detect a pCR after 3 cycles of neoadjuvant pembrolizumab of 33% (minimum of 10%), with one-sided 5% significance level and 80% power (A’Hern single stage). The trial would be considered a success if ³5/19 of those pts achieved pCR. To achieve this number, we aimed to recruit 32 patients in total. Results: The trial opened on 20th July 2022 and 32 pts were rapidly enrolled. The pCR primary endpoint analysis was performed on 1st March 2024. The primary endpoint was exceeded with the pCR in the intent to treat pts (N=32) as well as the pCR in evaluable tumours shown in Table 1. Median TMB was 42 mutations/Mb (4-82). There was only 1 TMB low tumour and no TMB medium tumours. In the TMB high-medium cohort there were 32 evaluable resected tumours as 1 pt had 3 synchronous primaries, and 1 pt did not undergo surgery due to toxicity as well as pt choice. There were no immune-related toxicities &gt;Grade 3. At a median follow-up of 6 months (range 2-15), no pts have had disease recurrence. Conclusions: Neoadjuvant pembrolizumab for early stage deficient-MMR/MSI-High CRC is highly efficacious and safe. Longer follow up is needed to assess relapse free survival and translational biomarker work is ongoing. Clinical trial information: NCT05197322 . [Table: see text]

Clinical impact of using [18F]AlF-NOTA-octreotide PET/CT instead of [68Ga]Ga-DOTA-SSA PET/CT: Secondary endpoint analysis of a multicenter, prospective trial.

[18F]AlF-NOTA-octreotide ([18F]AlF-OC) is a promising alternative for [68Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the somatostatin receptor (SSTR). Our aim is to assess changes in TNM staging and differences in patient management between [18F]AlF-OC PET/CT and [68Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [18F]AlF-OC and [68Ga]Ga-DOTA-TATE or [68Ga]Ga-DOTA-NOC PET/CT in our multicenter study (Pauwels et al., J Nucl Med.2023;63:632-638) with a NET were included for analysis. TNM staging was determined and compared for both tracers. For each patient, the blinded [68Ga]Ga-DOTA-SSA or [18F]AlF-OC PET/CT images were presented in random order at a multidisciplinary team board. The images were presented together with clinical information and compared with previous SSTR and [18F]FDG PET/CT imaging. After a consensus decision for patient management was recorded, the board was presented with the PET/CT images from the other SSTR tracer and a decision was made for the second tracer. Differences in management were classified as major if it entailed an intermodality change and minor if it led to an intramodality change. Compared with [68Ga]Ga-DOTA-SSA, the use of [18F]AlF-OC led to a change in 16/75 patients: TNM staging changes in 10/75 patients (13.3%; downstaging in 3/10, upstaging in 7/10) and differences in clinical management were seen in 10/75 patients (13.3%), leading to a major difference in 7/10 cases and a minor change in 3/10 cases. All 10 cases with a difference in patient management between both PET tracers were caused by additional lesion detection by [18F]AlF-OC. The use of [18F]AlF-OC did not impact TNM staging or clinical management in the large majority of the patients (86.7%), further validating the potential for routine clinical use of [18F]AlF-OC PET/CT as an alternative for [68Ga]Ga-DOTA-SSA PET/CT. The trial is registered under ClinicalTrials.gov identifier NCT04552847 and EudraCT 2020-000549-15.

Effect of timing of recurrence on outcomes in patients with metastatic breast cancer treated with CDK4/6 inhibitors.

e13067 Background: CDK4/6 inhibitors (CDKi) + endocrine therapy (ET) comprise the standard 1st line treatment for ER+ HER2- metastatic breast cancer (MBC). However, there is a gap in understanding how timing of MBC recurrence affects clinical outcomes on CDKi. We conducted a study to compare clinical outcomes of MBC patients on CDKi based on timing of MBC recurrence. Methods: This retrospective study enrolled ER+ HER2- MBC patients diagnosed from Jan 2015 to Jan 2023, who received CDKi + ET as 1st line treatment for MBC. Patients were categorized as de novo MBC (dMBC), if they had 1. Stage 4 disease at initial diagnosis or 2. MBC diagnosed &lt; 6 months of the primary breast cancer (PBC) diagnosis and before starting any systemic treatment for PBC. Patients with distant recurrence occurring &lt; 5 years, 5-10 years, and &gt;10 years from PBC were categorized as early, intermediate, and late MBCs (eMBC, iMBC, laMBC). Endpoints were Progression-Free Survival (PFS) and Overall Survival (OS) from MBC diagnosis. Baseline variables were compared using t-tests (continuous) and Chi-square tests (categorical). Endpoint analyses were conducted using Kaplan-Meier method and compared using Log rank test. Multivariate analyses were performed using Cox models. Results: Out of 280 patients enrolled, 67 were dMBC, 75 eMBC, 56 iMBC, and 82 laMBC. The laMBC group had a higher mean age (years) compared to other groups (71 vs. 62 in dMBC+ eMBC + iMBC, p&lt;0.001). 64.5% of laMBC had visceral disease compared to 50.5% of dMBC + eMBC + iMBC (p=0.031). 65.7% of dMBC patients were treated with palbociclib compared to 80.8% of eMBC + iMBC + laMBC (p=0.010). Higher % of eMBC were PR- vs other cohorts (41.3 vs 23.9 dMBC + iMBC + laMBC, p&lt;0.001). Among the 3 non dMBC groups, prior ET sensitivity (no recurrence for 2 years on adjuvant ET) was lower in eMBC (45.3%) compared to iMBC + laMBC (81.9%, p&lt;0.001). 61.3% of eMBC patients were on adjuvant ET at recurrence compared to 17.4% of iMBC + laMBC (p&lt;0.001). Other variables were similar. Table shows unadjusted endpoint analyses. In multivariate analyses, the risk of PFS events were not significantly different among cohorts (age&lt;=65, ECOG performance status (PS) &gt;=2 and PR- were independently associated with shorter PFS); risk of death was higher in eMBC vs laMBC (HR 1.73, p=0.047). Conclusions: In this retrospective study of ER+ HER2- MBC patients treated with 1st line CDKi + ET, timing of MBC recurrence was not associated with PFS differences after adjusting for other variables. However, patients with MBC recurring &lt; 5 years of PBC had the higher likelihood of death compared to those recurring &gt;10 years of PBC. [Table: see text]

BIOLUMA: A phase II trial of nivolumab and ipilimumab in lung cancer—Results from the SCLC TMBhigh cohort.

8099 Background: Therapeutic options and prognosis for patients with small-cell lung cancer (SCLC) remain poor. Treatment with checkpoint inhibition can achieve remarkable responses, but this holds true for a small percentage of SCLC patients only. While tumor mutation burden (TMB) emerged as possible predictive biomarker for nivolumab and ipilimumab combination therapy in SCLC patients, to our knowledge, tissue-based TMB has never been evaluated prospectively in SCLC patients. Here, we present the results of the cohort 2b of the BIOLUMA trial, which evaluates efficacy and safety of nivolumab in combination with ipilimumab in SCLC patients with high tumor mutation burden. Methods: BIOLUMA is an investigator initiated multicentre non-randomised phase II trial in 2nd line patients with SCLC. The initial all-comer SCLC cohort was amended for inclusion of patients with high TMB only. FFPE tumor tissue was used for TMB pre-screening by whole exome sequencing (WES) at time of first diagnosis. TMBhigh was defined as the upper tertile of total missense mutations. After progression on platinum-based therapy, patients received 4 cycles of nivolumab 1 mg/kg q3w in combination with ipilimumab 3 mg/kg q3w and subsequently nivolumab 240 mg flat dose as monotherapy. Primary endpoint was overall response rate (ORR) of the combination therapy. Additionally, exploratory analyses of sequential tumor biopsies and blood samples were performed at different time points. Results: TMB analysis was feasible for most patients without necessity of performing additional tumor biopsy. Evaluation of TMB on FFPE tumor tissue obtained at first diagnosis was sufficient for TMB analysis in 92.5% of cases. TMB status was determined for 297 patients: 45.8% belonged to the TMB high group, while 54.2% had low or medium TMB. In total, 45 TMBhigh patients were enrolled in the study with 44 subjects evaluable for primary endpoint analysis. Six patients (13.6%) showed response to therapy, of whom in 4 patients (9%) response could be confirmed according to RECIST 1.1 criteria. One patient, who is not evaluable for endpoint analysis experienced a remarkably long lasting PR, which is still ongoing for more than three years. This patient received concomitant palliative radiation during induction with nivolumab and ipilimumab. Disease control rate (DCR) was 20.4% (n=9), three more patients showed unconfirmed SD. Three patients with confirmed PR or SD experienced long lasting treatment benefit, which is still ongoing at data cut-off. Conclusions: This represents the first trial to prospectively evaluate the combination therapy of nivolumab and ipilimumab in TMBhigh SCLC patients. The primary endpoint ORR was not reached. However, we observed an impressive clinical benefit in single patients, which warrants further investigation in order to get more insight into the mechanisms leading to these long-lasting tumor responses. Clinical trial information: NCT03083691 .

Exposure-response analyses for optimal therapeutic dose selection of ABBV-383 in patients with relapsed/refractory multiple myeloma (RRMM).

7541 Background: ABBV-383 is a fully human, B-cell maturation antigen (BCMA) × CD3 T-cell–engaging IgG4 bispecific with an effector-silenced Fc region, 2 high-affinity BCMA- and a low-affinity CD3-binding domains. ABBV-383 monotherapy has shown promising activity in patients (pts) with RRMM (Blood 2023;142[suppl 1]:3378). Here, exposure-response (ER) analyses of efficacy and safety endpoints supporting the optimal therapeutic ABBV-383 dose selection are reported in alignment with US FDA’s Project Optimus. Methods: Efficacy (n=218) and safety (n=220) data from the phase 1 study (NCT03933735) escalation cohorts of 0.025 - 120 mg Q3W and expansion cohorts of 20, 40, 60 mg Q3W and 60 mg Q4W including objective response rate (ORR), very good partial response or better (≥VGPR), stringent complete response (sCR)/CR, adverse events (≥G3 and serious), infections (≥G3, overall and serious), cytokine release syndrome (CRS; any-grade, G1, G2, and ≥G2) were modeled. Total(unbound + bound to soluble BCMA) and free (unbound + partially bound to soluble BCMA) Cycle 1 AUCinf, Cmax, and Ctrough and population pharmacokinetic model-derived up to the time of event Cavg and avgCtrough metrics were utilized in the ER analyses (logistic regression; R Version 4.2.2). Relevant pt-specific covariates were tested. Dexamethasone premedication (36 vs 10 mg) was included in CRS models. The ER relationships were utilized to predict the probabilities of efficacy and safety endpoints for relevant doses and thereby, support justification of the optimal therapeutic dose selection. Results: Based on overall assessment, ORR, ≥VGPR, sCR/CR and ≥G3 neutropenia strongly correlated with free Cavg; CRS endpoints (any-grade CRS and G1 only CRS) strongly correlated with Cycle 1 total Cmax (p &lt;0.05). No other endpoints had ER relationships (p &gt;0.05). Only MM type (IgG vs Others) was selected in ≥VGPR and sCR/CR models. ER relationships suggested high response rates of &gt;63% ORR, &gt;53% ≥VGPR, and ≥30% sCR/CR for 40, 60 mg Q3W and 60 mg Q4W. Predictions demonstrated that 20 mg Q3W (&lt;39% ORR and ≥VGPR; &lt;13% sCR/CR) and untested 40 mg Q4W (&lt;60% ORR, &lt;45% ≥VGPR and &lt;23% sCR/CR) provide suboptimal efficacy. The 60 mg Q4W with 36 mg dexamethasone in Cycle1 (limited follow-up and data) was predicted to have ~30% sCR/CR and 31% ≥G3 neutropenia (≈ 40 mg Q3W) and substantially lower any-grade CRS events compared with 40 and 60 mg doses with 10 mg dexamethasone in Cycle 1. Conclusions: While ER analyses indicated promising efficacy and acceptable safety profiles for 40, 60 mg Q3W, and 60 mg Q4W, they support 60 mg Q4W as the optimal ABBV-383 therapeutic dose due to its predicted better therapeutic benefit/risk profile (high response rates, improved/equivalent ≥G3 neutropenia, and lower CRS events) and extended dosing interval. ABBV-383 at 60 mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM.

Exposure-response (ER) analyses of efficacy and safety of trastuzumab deruxtecan (T-DXd) to inform dosing recommendation in HER2-mutant non-small cell lung cancer (NSCLC).

e20545 Background: T-DXd, a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, was evaluated at doses of 5.4 and 6.4 mg/kg every three weeks in Phase 1 or 2 trials in HER2 mutant (HER2m) NSCLC subjects, including Destiny-Lung01 (DL-01) and DL-02 trials1,2. ER analyses of key efficacy and safety endpoints were conducted to support the dosing recommendation of T-DXd in HER2m NSCLC. Methods: Exposure-efficacy (EE) analysis was performed using confirmed objective response (cORR) data from HER2m NSCLC in Phase 1-2 trials (N = 181). The dataset included primary analysis data cut from DL-011 and interim analysis data cut from DL-02. Exposure-safety (ES) analyses of T-DXd were performed, using pooled data from 11 Phase 1-3 trials (N = 1850) across tumor types, including DL-01 and DL-02, for safety endpoints of adverse events (AEs) associated with dose reduction or discontinuation, Grade3+ (G3+) AEs, serious AEs, G3+Anemia, G3+neutropenia, G3+thrombocytopenia, adjudicated any grade interstitial lung disease (ILD), and G3+ ILD. cORR and all safety endpoints, except ILD were analyzed by logistic regression; any grade ILD was analyzed by parametric time-to-event analysis. The T-DXd or DXd exposure metric and numerous patient-specific covariates were tested in the analysis. Results: T-DXd exposure had a positive but shallow relationship with cORR. The predicted cORR varied from 57% (95% credible interval (CrI): [36, 77]) to 65% (95% CrI: [41, 84]) across 5th and 95th percentile of T-DXd exposure respectively. No clinically meaningful difference in cORR was estimated across 5.4 and 6.4 mg/kg doses with predicted cORR values of 53% (95% CrI: [44, 60]) and 55% (95% CrI: [47, 62]) at T-DXd doses of 5.4 mg/kg and 6.4 mg/kg, respectively. ES relationships were consistent with previous T-DXd ES analyses in breast cancer (BC). Model-predicted AE rates were lower (up to 9%) in 5.4 mg/kg compared to the 6.4 mg/kg dose. Model-predicted safety at 5.4 mg/kg dose in HER2m NSCLC was similar to the approved dose of 5.4 mg/kg in BC. Conclusions: The ER analyses showed no clinically meaningful difference in efficacy between 5.4 and 6.4 mg/kg doses of T-DXd; and safety events were lower in 5.4 mg/kg, thus supporting the 5.4 mg/kg recommended dose for HER2m NSCLC. These findings were later confirmed based on primary analysis in DL-022 and support the utility of ER analyses in dosing recommendation. Reference: Li BT et al. N Engl J Med 2022;386:241-51 Goto K et al. J Clin Oncol 41:4852-4863. Clinical trial information: NCT03505710 , NCT04644237 .