Pre-specified Exploratory Analyses Research Articles

Palliative care for persons with late-stage Alzheimer’s and related dementias and their caregivers: protocol for a randomized clinical trial

BackgroundLimited access to specialized palliative care exposes persons with late-stage Alzheimer’s disease and related dementias (ADRD) to burdensome treatment and unnecessary hospitalization and their caregivers to avoidable strain and financial burden. Addressing this unmet need, the purpose of this study was to conduct a randomized clinical trial (RCT) of the ADRD-Palliative Care (ADRD-PC) program.MethodsThe study will use a multisite, RCT design and will be set in five geographically diverse US hospitals. Lead investigators and outcome assessors will be masked. The study will use 1:1 randomization of patient-caregiver dyads, and sites will enroll N = 424 dyads of hospitalized patients with late-stage ADRD with their family caregivers. Intervention dyads will receive the ADRD-PC program of (1) dementia-specific palliative care, (2) standardized caregiver education, and (3) transitional care. Control dyads will receive publicly available educational material on dementia caregiving. Outcomes will be measured at 30 days (interim) and 60 days post-discharge. The primary outcome will be 60-day hospital transfers, defined as visits to an emergency department or hospitalization ascertained from health record reviews and caregiver interviews (aim 1). Secondary patient-centered outcomes, ascertained from 30- and 60-day health record reviews and caregiver telephone interviews, will be symptom treatment, symptom control, use of community palliative care or hospice, and new nursing home transitions (aim 2). Secondary caregiver-centered outcomes will be communication about prognosis and goals of care, shared decision-making about hospitalization and other treatments, and caregiver distress (aim 3). Analyses will use intention-to-treat, and pre-specified exploratory analyses will examine the effects of sex as a biologic variable and the GDS stage.DiscussionThe study results will determine the efficacy of an intervention that addresses the extraordinary public health impact of late-stage ADRD and suffering due to symptom distress, burdensome treatments, and caregiver strain. While many caregivers prioritize comfort in late-stage ADRD, shared decision-making is rare. Hospitalization creates an opportunity for dementia-specific palliative care, and the study findings will inform care redesign to advance comprehensive dementia-specific palliative care plus transitional care.Trial registrationClinicalTrials.gov NCT04948866. Registered on July 2, 2021.

Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial

In this multicenter, single-arm phase 2 trial (ChiCTR1900024428), patients with locally advanced gastric/gastroesophageal junction cancers receive one cycle of sintilimab (anti-PD1) and chemotherapy (S-1 and nab-paclitaxel), followed by 5 weeks of concurrent chemoradiotherapy and sintilimab, and another cycle of sintilimab and chemotherapy thereafter. Surgery is preferably scheduled within one to three weeks, and three cycles of adjuvant sintilimab and chemotherapy are administrated. The primary endpoint is the pathological complete response. Our results meet the pre-specified primary endpoint. Thirteen of 34 (38.2%) enrolled patients achieve pathological complete response (95% CI: 22.2-56.4). The secondary objectives include disease-free survival (DFS), major pathological response, R0 resection rate, overall survival (OS), event-free survival (EFS), and safety profile. The median DFS and EFS were 17.0 (95%CI: 11.1-20.9) and 21.1 (95%CI: 14.7-26.1) months, respectively, while the median OS was not reached, and the 1-year OS rate was 92.6% (95%CI: 50.1-99.5%). Seventeen patients (50.0%) have grade ≥3 adverse events during preoperative therapy. In prespecified exploratory biomarker analysis, CD3+ T cells, CD56+ NK cells, and the M1/M1 + M2-like macrophage infiltration at baseline are associated with pathological complete response. Here, we show the promising efficacy and manageable safety profile of sintilimab in combination with concurrent chemoradiotherapy for the perioperative treatment of locally advanced gastric/gastroesophageal junction adenocarcinoma.

Biomarker subgroup analyses of CodeBreaK 200, a phase 3 trial of sotorasib versus (vs) docetaxel in patients (pts) with pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC).

9008 Background: Sotorasib is a first-in-class oral, irreversible KRASG12C inhibitor approved for adults with pretreated KRAS G12C-mutated advanced NSCLC. In CodeBreaK 200, the first KRASG12C inhibitor randomized phase 3 trial, sotorasib demonstrated superior progression-free survival (PFS) and overall response rate (ORR) vs docetaxel and a more favorable safety profile. We report prespecified exploratory biomarker analyses comparing sotorasib vs docetaxel efficacy in molecularly-defined KRAS G12C-mutated advanced NSCLC subsets. Methods: In CodeBreaK 200, 345 pts with KRAS G12C-mutated advanced NSCLC who progressed after platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to oral sotorasib 960 mg daily or IV docetaxel 75 mg/m2 Q3W. Primary endpoint was PFS by blinded independent central review (RECIST 1.1; key secondary endpoint: ORR). In prespecified exploratory analyses, baseline tissue and plasma samples were analyzed for key genomic alterations (eg, STK11, KEAP1, EGFR, MET, TP53), by central targeted next-generation sequencing (Skoulidis N Engl J Med 2021), and PD-L1 protein level by local standard of care testing in biomarker-evaluable cases; biomarker status was correlated with PFS and ORR. Inferred tumor mutation burden by plasma circulating tumor DNA (sum of mutant molecular variant reads) was assessed. Association of baseline genomic alterations with long-term benefit (PFS ≥ 6 m) vs early progression (PFS < 3 m; no complete/partial response) was evaluated. Results: Most prevalent KRAS G12C co-alterations in biomarker-evaluable cases with available tumor and/or plasma samples (n=317) were TP53 (181 [57.1%]), STK11 (119 [37.5%]), and KEAP1 (82 [25.9%]) in CodeBreaK 200, consistent with CodeBreaK 100; 55 (17.4%) pts had STK11 and KEAP1 co-alterations. Sotorasib showed superior clinical benefit vs docetaxel independently of PD-L1 expression and across all prespecified subgroups (eg, STK11, KEAP1, TP53) . No clinical response occurred with either treatment in 26 (8.2%) pts with additional KRAS alterations, including amplifications. High baseline plasma tumor burden was associated with greater odds of early progression vs long-term benefit in both arms (odds ratio, 3.54 [95%CI 1.83-6.85] per tertile increase; p<0.0001). Correlation of KRAS G12C co-alterations with response detected a signal toward shorter median PFS (sotorasib, 2.8 m [95%CI 1.6-3.4]; docetaxel, 7.5 m [95%CI 3.0-NE]) with sotorasib vs docetaxel in pts with KRAS G12C and NOTCH1 co -altered tumors. Conclusions: Sotorasib demonstrated consistent clinical benefit vs docetaxel in all prespecified molecularly-defined subgroups (eg, STK11, KEAP1, TP53) in this exploratory analysis of CodeBreaK 200. No predictive biomarkers were confirmed, but novel hypothesis-generating signals were observed. Clinical trial information: NCT04303780 .

Efficacy, safety and patient reported outcomes (PROs) from the phase III IMbrave050 trial of adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation.

4002 Background: In IMbrave050, adjuvant atezo + bev demonstrated a statistically significant and clinically meaningful improvement in recurrence-free survival (RFS) vs active surveillance in patients (pts) at high risk of HCC recurrence following resection or ablation with curative intent. Further, the safety of atezo + bev was generally manageable. Here, we additionally report PRO data from IMbrave050. Methods: IMbrave050 (NCT04102098) enrolled HCC pts at high risk of recurrence following resection or ablation. Pts were randomized to Arm A (atezo + bev) or Arm B (active surveillance). Pts in Arm A received atezo 1200 mg + bev 15 mg/kg IV q3w for a period of one year (17 cycles). Pts in Arm B underwent active surveillance for one year and were eligible to crossover to atezo + bev following independent review facility (IRF) confirmation of recurrence. The primary endpoint was IRF-assessed RFS. Pre-specified exploratory analyses included change from baseline in global health status (GHS)/quality of life (QoL), physical functioning, role functioning, emotional functioning, and social functioning. Clinically meaningful deterioration was defined as a ≥ 10-point decrease. Pts completed the IL42–EORTC QLQ-C30 (reduced) questionnaire at baseline and then at every odd treatment/surveillance visit through Cycle 17. Results: The ITT population included 334 pts in both Arms A and B. With a median follow-up time of 17.4 mo (clinical cutoff date: 21 Oct 2022), IRF-RFS HR was 0.72 (95% CI: 0.56, 0.93; P = 0.0120). In the safety population, Grade 3 or 4 adverse events occurred in 41% of 332 Arm A pts and 13% of 330 Arm B pts. In ITT pts, IL42 completion rates remained ≥ 93% in both arms from baseline through treatment/surveillance Cycle 17. Mean scores at baseline in both arms were high and similar, as measured by the GHS/QoL and physical, role, emotional and social functioning scales. Mean changes from baseline were not considerable through Cycle 17 and were similar between arms as evidenced by overlapping 95% CIs. Pts’ GHS/QoL and functioning was maintained through Cycle 17, with no clinically meaningful deterioration observed at any time. Conclusions: Statistically significant and clinically meaningful improvement in RFS was seen in pts receiving atezo + bev vs active surveillance. Atezo + bev safety was generally manageable, and consistent with the established safety profiles of each therapeutic agent and with the underlying disease. PRO outcome analyses revealed similar overall health-related QoL (HRQoL) and functioning between atezo + bev and active surveillance, and that treating high-risk pts with HCC with adjuvant atezo + bev following procedures with curative intent did not result in a clinically meaningful deterioration in HRQoL or function. Clinical trial information: NCT04102098 .

Nangibotide for precision immunomodulation in septic shock and COVID-19

Nangibotide for precision immunomodulation in septic shock and COVID-19

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study

ObjectivePembrolizumab demonstrated a clinically meaningful objective response rate in patients with previously treated, advanced MSI-H/dMMR endometrial cancer in the multicohort phase 2 KEYNOTE-158 study (ClinicalTrials.gov, NCT02628067). We present health-related quality of life (HRQoL) results for these patients. MethodsThis analysis included patients from cohorts D (endometrial cancer with any MSI status) and K (any MSI-H/dMMR solid tumor except colorectal) who had previously treated, advanced MSI-H/dMMR endometrial cancer. Patients received pembrolizumab 200 mg Q3W for 35 cycles. EORTC QLQ-C30 and EQ-5D-3L questionnaires were administered at baseline, at regular intervals during treatment, and 30 days after treatment discontinuation. Pre-specified exploratory analyses included changes from baseline to week 9 in QLQ-C30 global health status (GHS)/QoL and EQ-5D-3L visual analog scale (VAS) score for all patients and by best overall response. Results84 of 90 enrolled patients completed ≥1 HRQoL questionnaire and were included in the analysis. QLQ-C30 and EQ-5D-3L compliance rates were 90% and 94%, respectively, at baseline, and 92% and 93% at week 9. Mean (95% CI) QLQ-C30 GHS/QoL scores improved from baseline to week 9 by 6.08 (0.71–11.46) points in the overall population, with greater improvement in patients who achieved complete or partial response (11.67 [5.33–18.00]-point increase). Mean (95% CI) EQ-5D-3L VAS scores improved by 6.00 (2.25–9.75) points in the overall population and 9.11 (5.24–12.98) points in patients with CR/PR. ConclusionsPembrolizumab maintained or improved HRQoL in patients with previously treated, advanced MSI-H/dMMR endometrial cancer, further supporting efficacy and safety results from KEYNOTE-158 and pembrolizumab use in this setting.

Validation of the myocardial-ischaemic-injury-index machine learning algorithm to guide the diagnosis of myocardial infarction in a heterogenous population: a prespecified exploratory analysis

SummaryBackgroundDiagnostic pathways for myocardial infarction rely on fixed troponin thresholds, which do not recognise that troponin varies by age, sex, and time within individuals. To overcome this limitation, we recently introduced a machine learning algorithm that predicts the likelihood of myocardial infarction. Our aim was to evaluate whether this algorithm performs well in routine clinical practice and predicts subsequent events.MethodsThe myocardial-ischaemic-injury-index (MI3) algorithm was validated in a prespecified exploratory analysis using data from a multi-centre randomised trial done in Scotland, UK that included consecutive patients with suspected acute coronary syndrome undergoing serial high-sensitivity cardiac troponin I measurement. Patients with ST-segment elevation myocardial infarction were excluded. MI3 incorporates age, sex, and two troponin measurements to compute a value (0–100) reflecting an individual's likelihood of myocardial infarction during the index visit and estimates diagnostic performance metrics (including area under the receiver-operating-characteristic curve, and the sensitivity, specificity, negative predictive value, and positive predictive value) at the computed score. Model performance for an index diagnosis of myocardial infarction (type 1 or type 4b), and for subsequent myocardial infarction or cardiovascular death at 1 year was determined using the previously defined low-probability threshold (1·6) and high-probability MI3 threshold (49·7). The trial is registered with ClinicalTrials.gov, NCT01852123.FindingsIn total, 20 761 patients (64 years [SD 16], 9597 [46%] women) enrolled between June 10, 2013, and March 3, 2016, were included from the High-STEACS trial cohort, of whom 3272 (15·8%) had myocardial infarction. MI3 had an area under the receiver-operating-characteristic curve of 0·949 (95% CI 0·946–0·952) identifying 12 983 (62·5%) patients as low-probability for myocardial infarction at the pre-specified threshold (MI3 score <1·6; sensitivity 99·3% [95% CI 99·0–99·6], negative predictive value 99·8% [99·8–99·9]), and 2961 (14·3%) as high-probability at the pre-specified threshold (MI3 score ≥49·7; specificity 95·0% [94·6–95·3], positive predictive value 70·4% [68·7–72·0]). At 1 year, subsequent myocardial infarction or cardiovascular death occurred more often in high-probability patients than low-probability patients (520 [17·6%] of 2961 vs 197 [1·5%] of 12 983], p<0·0001).InterpretationIn consecutive patients undergoing serial cardiac troponin measurement for suspected acute coronary syndrome, the MI3 algorithm accurately estimated the likelihood of myocardial infarction and predicted subsequent adverse cardiovascular events. By providing individual probabilities the MI3 algorithm could improve the diagnosis and assessment of risk in patients with suspected acute coronary syndrome.FundingMedical Research Council, British Heart Foundation, National Institute for Health Research, and NHSX.

Bryostatin Placebo-Controlled Trials Indicate Cognitive Restoration Above Baseline for Advanced Alzheimer's Disease in the Absence of Memantine1.

Background:In pre-clinical studies of Alzheimer’s disease (AD) transgenic mice, bryostatin restored synaptic connections, prevented neuronal death, reduced amyloid plaques, and reduced neurofibrillary tangles.Objective:Within pre-specified cohorts of advanced AD patients in two double-blind placebo-controlled bryostatin Phase II trials, to conduct exploratory statistical analyses of patients with identical conditions of enrollment and treatment.Methods:Severe Impairment Battery (SIB) scores above baseline at 5, 9, and 13 weeks were analyzed initially in the complete cases, with multiple imputation methods based on an iterative Markov chain Monte Carlo algorithm used for missing SIB scores. To mitigate confounding by a chance imbalance of 4.9 SIB baseline scores (Study #203), each patient was used as their own control with differences in 13-week SIB from baseline in single trial and pooled analyses to measure benefit at 13 weeks using general estimating equations (GEE) modeling.Results:Patients treated with bryostatin pre-specified at Mini-Mental State Examination scores 10–14, without memantine, showed baseline balance, complete safety, and SIB improvements at 13 weeks with multiple imputation analysis: Study #203 = 4.1 SIB points above baseline (p = 0.005), and Study #202 = 4.2 SIB points above baseline (p = 0.016). An increased power (N = 95) “pooled analysis” showed an increased SIB over time and a higher mean SIB at 13 weeks in the bryostatin treatment group (p < 0.001) but not significant (NS) for the placebo patients.Conclusion:Pre-specified exploratory analyses for the individual trials and the pooled trials confirmed significant bryostatin-induced improvement over baseline (treatment p < 0.001, placebo NS).

Tezepelumab Treatment Reduced Asthma Symptomatic Days in Adults and Adolescents with Severe, Uncontrolled Asthma in the Phase 3 NAVIGATOR Study

Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin (TSLP). The phase 3 NAVIGATOR study (NCT03347279) investigated the efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma. This pre-specified exploratory analysis evaluated the effect of tezepelumab on asthma symptomatic days in NAVIGATOR.

Safety of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis (HLH): Relationship to Treatment Exposure

▪Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune disorder characterized by a hyperinflammatory state in which interferon gamma (IFNγ) is considered a key cytokine. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to allogeneic hematopoietic stem cell transplantation (HSCT), the only curative therapy so far. Current conventional therapy for HLH is based on immunochemotherapies, namely etoposide and glucocorticoids; this treatment, however, is associated with opportunistic infections and severe myelotoxicity. Emapalumab, a fully human, anti-IFNγ monoclonal antibody that neutralizes IFNγ, is the only FDA-approved treatment for primary HLH patients with refractory, recurrent or progressive disease, or intolerance to conventional HLH therapy. In patients with primary HLH, the pharmacokinetics (PK) of emapalumab is highly influenced by body weight, and also by IFNγ production due to target-mediated drug disposition. In the pivotal trial (Locatelli et al NEJM 2020;382:1811-22), treatment of primary HLH patients with emapalumab was associated with a favorable safety and tolerability profile, with no unexpected safety concerns.Objective: To describe prespecified exploratory exposure-safety analyses that were performed on data from patients with primary HLH receiving emapalumab in the pivotal trial.Methods: Data from a multicenter, open-label, pivotal phase 2/3 study (NCT01818492) and its long-term follow-up study (NCT02069899) were included in this analysis. The safety of emapalumab was assessed in 34 patients (27 treatment experienced; 7 treatment naïve) with active primary HLH. Emapalumab was initiated at a dose of 1 mg/kg administered intravenously every 3 days, on a background of dexamethasone 5-10 mg/kg/day. Subsequent doses could be increased to 3, 6 and 10 mg/kg, if required, based on predefined laboratory and clinical response parameters. Treatment duration was up to 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to time of transplantation if needed. Exploratory graphical analyses were performed to determine the incidence of adverse events (AEs) as a function of the exposure parameters at the time of the AE. The relationship between emapalumab exposure and the incidence of treatment-emergent AEs, serious AEs, severe AEs, and AEs related to infections and infusion-related reactions (IRRs) was explored by logistic regression analyses. Selected parameters of renal (creatine clearance [CRCL]) and liver (total bilirubin [TBIL] and alanine aminotransferase [ALT]) function were explored graphically. Exposure parameters were obtained from the population PK/pharmacodynamic (PD) data file that was used for the population PK and PK/PD analyses. Observed individual concentration-time data were used to derive the individual exposure parameters as a function of time. The analyses considered AEs that emerged after the start of the first infusion until last infusion and prior to initiation of HSCT conditioning.Results: Exploratory graphical exposure-safety analyses did not reveal any apparent relationship between the number of AEs and exposure to emapalumab. Logistic exposure-safety regression analyses using the observed exposure to emapalumab at the time of an AE for patients experiencing an event and the highest observed exposure to emapalumab for those patients experiencing no AE, indicated that the incidence of AEs did not increase as a function of increasing emapalumab concentration. In fact, a statistically significant decrease in the incidence of severe AEs and the incidence of AEs related to IRRs was observed. No multivariate effects were identified in the multivariate regression analyses. No clear trend was observed for TBIL, ALT or CRCL as a function of the duration of emapalumab treatment. The exposure of emapalumab did not appear to influence the levels of TBIL, ALT or CRCL in individual patients during treatment.Conclusion: In this study, the exposure-safety evaluation did not reveal any significant relationships between exposure to emapalumab and observed incidence rates of AEs, serious AEs, infections, or IRRs. These findings support the primary evidence of a favorable benefit-risk profile of emapalumab across the dose range used in this fragile patient population. DisclosuresJordan: Sobi: Consultancy. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Jacqmin: Sobi: Consultancy. Laveille: Sobi: Consultancy. Snoeck: Sobi: Consultancy. de Min: Sobi: Consultancy, Ended employment in the past 24 months.

Health-Related Quality of Life of Patients with Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma Treated with Pembrolizumab in KEYNOTE-629.

IntroductionPembrolizumab provided durable responses and acceptable safety in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC) in the KEYNOTE-629 study. In this elderly, fragile population with disfiguring tumours, preservation of health-related quality of life (HRQoL) is critical. Here, we present pre-specified exploratory HRQoL analyses from the first interim analysis of KEYNOTE-629.MethodsPatients with R/M cSCC not amenable to surgery or radiation therapy received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. HRQoL end points included change from baseline to week 12 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status (GHS)/QoL, functioning, symptom and European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) scores and change from baseline through week 48 in EORTC QLQ-C30 GHS/QoL and physical functioning scores. Improvement (≥ 10-point increase post-baseline with confirmation) was assessed using the exact binomial method.ResultsAnalyses included 99 patients for EORTC QLQ-C30 and 100 for EQ-5D-5L. Compliance was > 80% at week 12. Mean scores were stable from baseline to week 12 for GHS/QoL (4.95 points; 95% confidence interval, −1.00 to 10.90) and physical functioning (−3.38 points; 95% confidence interval, −8.80 to 2.04). EORTC-QLQ-C30 functioning, symptom, and EQ-5D-5L scores remained stable at week 12. Post-baseline scores were improved in 29.3% of patients for GHS/QoL, 17.2% for physical functioning, and in a numerically higher proportion of responders versus non-responders (GHS/QoL, 55.6% versus 16.1%; physical functioning, 36.1% versus 7.1%).ConclusionsIn elderly patients with R/M cSCC, the clinical efficacy of pembrolizumab translates into a benefit validated by HRQoL preservation or improvement during treatment.Trial RegistrationClinicalTrials.gov identifier: NCT03284424.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00598-6.

Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib.

Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells. We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated BRAF V600-mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening. Baseline cell-cycle gene expression signature was associated with progression-free survival (P = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months-not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months; 95% CI, 13.4-38.6 months). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased MAPK activity and increased expression of immunosuppressive markers. B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.

130-LB: Dapagliflozin and the Incidence of Type 2 Diabetes in Patients with Chronic Kidney Disease

The DAPA-CKD trial demonstrated a significant reduction in the risk of adverse kidney and cardiovascular outcomes in participants with chronic kidney disease (CKD), with and without type 2 diabetes (T2D), treated with dapagliflozin 10 mg once daily compared to placebo (randomized 1:1). This pre-specified analysis explored the effect of dapagliflozin on incident T2D in the cohort without diabetes enrolled in DAPA-CKD. A subgroup of 1,398 participants with CKD, no prior history of diabetes, and HbA1c &amp;lt;6.5% at baseline were included. In this pre-specified exploratory analysis, surveillance for new-onset T2D (confirmed HbA1c ≥6.5%) was accomplished through periodic HbA1c testing (part of the study protocol) and comparison between treatment groups assessed through Cox proportional hazards model. Over a median follow-up of 2.4 years, T2D developed in 33/701 (4.7%) in the placebo group and 21/697 (3.0%) in the dapagliflozin group. This corresponded to event rates of 2.4/100-patient years and 1.5/100-patient years, respectively. Dapagliflozin led to a 38% reduction in T2D incidence (hazard ratio [95%CI] 0.62 [0.36, 1.08]). There was no heterogeneity in the effect of dapagliflozin on T2D prevention based on most key prespecified subgroups, including age, glycemic status, blood pressure, estimated glomerular filtration rate, albuminuria, race and region, but the effect was more pronounced in females (p interaction 0.03). More than 90% of the participants who developed T2D had prediabetes at baseline (HbA1c 5.7-6.4%). A meta-analysis of DAPA-CKD and DAPA-HF (dapagliflozin in heart failure with reduced ejection fraction) demonstrated that dapagliflozin reduced new-onset diabetes compared to placebo (hazard ratio 0.66 [0.51, 0.87]; p=0.003), without heterogeneity between studies (p interaction 0.78). In this pre-specified explorative analysis of patients with CKD, treatment with dapagliflozin reduced the incidence of new T2D, an effect that was consistent across DAPA-CKD and DAPA-HF. Disclosure P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. A. Langkilde: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. D. C. Wheeler: Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Janssen Global Services, LLC., Mundipharma International, Tricida, Inc., Speaker’s Bureau; Self; Amgen Astellas BioPharma, Astellas Pharma Inc., Napp Pharmaceuticals, Vifor Pharma Management Ltd. H. L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research &amp; Development, LLC, Merck &amp; Co., Inc., Mitsubishi Corporation Life Sciences Limited, Mundipharma International, Novo Nordisk, Retrophin, Inc., Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Research &amp; Development, LLC. Dapa-ckd study group: n/a. P. Vart: None. G. M. Chertow: Advisory Panel; Self; Ardelyx, Baxter, Cricket Health, DURECT Corporation, Gilead Sciences, Inc., Reata Pharmaceuticals, Inc., Other Relationship; Self; Akebia Therapeutics, Inc., AstraZeneca, Vertex Pharmaceuticals Incorporated. F. Hou: Consultant; Self; AstraZeneca. N. Jongs: None. J. J. Mcmurray: Other Relationship; Self; AbbVie Inc., Amgen Inc., AstraZeneca, Bayer AG, Cytokinetics Inc., DalCor Pharmaceuticals, Merck &amp; Co., Inc., Novartis AG, Servier Laboratories, Theracos, Inc. R. Correa-rotter: Consultant; Self; GlaxoSmithKline plc., Other Relationship; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Novo Nordisk Inc., Speaker’s Bureau; Self; AbbVie Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceutical Co. B. Stefansson: Employee; Self; AstraZeneca. R. D. Toto: Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Medscape Education, Otsuka America Pharmaceutical, Inc., Quest Diagnostics, Reata Pharmaceuticals, Inc., Relypsa Inc. Funding AstraZeneca

Performance of a targeted methylation-based multi-cancer early detection test by race/ethnicity.

3071 Background: Disparities in cancer screening and outcomes based on factors such as gender, socioeconomic status, and race/ethnicity are well documented.1 The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was designed to develop and validate a blood-based multi-cancer early detection (MCED) test analyzing plasma cell-free DNA (cfDNA) to detect cancer signals across multiple cancer types and simultaneously predict cancer signal origin. Findings stratified by race/ethnicity from the third and final CCGA validation sub-study are reported. Methods: CCGA is a prospective, multicenter, case-control, observational study with longitudinal follow-up (overall N = 15,254). In this pre-specified exploratory analysis from the third substudy, key objectives were to evaluate test performance for cancer signal detection (specificity, overall sensitivity, and sensitivity by clinical stage) among racial/ethnic groups. Plasma cfDNA from evaluable samples was analyzed using a targeted methylation bisulfite sequencing assay and a machine learning approach. Overall, 4077 participants comprised the independent validation set with confirmed status (cancer: n = 2823; non-cancer: n = 1254). The groups stratified by race/ethnicity were White Non-Hispanic, Black Non-Hispanic, Other Non-Hispanic (including but not limited to Asian, Native Hawaiian, Pacific Islander, American Indian, Alaska Native), Hispanic (all races), and Other/unknown. The study was not powered to detect statistical differences between groups. Results: Cancer and non-cancer groups were predominantly White (2316/2823, 82.0% and 996/1254, 79.4%, respectively). Across racial/ethnic groups, specificity for cancer signal detection was 99.6% (White Non-Hispanic: 992/996, 95% confidence interval [99.0-99.8%]), 100.0% (Black Non-Hispanic: 85/85 [95.7-100.0%]), 100.0% (Other Non-Hispanic: 33/33 [89.6-100.0%]), 98.1% (Hispanic: 101/103 [93.2-99.5%]), and 100% (Other/unknown: 37/37 [90.6-100.0%]). Despite slight differences in cancer type and staging across racial/ethnic groups, overall sensitivity for cancer signal detection among groups ranged from 43.9% to 63.0% (White Non-Hispanic: 50.5%, 1169/2316 [48.4-52.5%], Black Non-Hispanic: 53.9%, 104/193 [46.8-60.8%], Other Non-Hispanic: 43.9%, 25/57 [31.8-56.7%], Hispanic: 63.0%, 121/192 [56.0-69.5%], and Other/unknown: 52.3%, 34/65 [40.4-64.0%]). For all racial/ethnic groups, sensitivity generally increased with clinical stage (with limited exceptions at Stage IV in some groups with small sample sizes). Conclusions: The MCED test demonstrated consistent specificity and sensitivity across racial/ethnic groups, though results are limited by sample size for some groups. These findings indicate broad applicability and support clinical implementation of this MCED test on a population scale. 1. Zavela et al. Brit J Cancer 2021. Clinical trial information: NCT02889978.

Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing.

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.

13772 Safety and efficacy of VP-102 in molluscum contagiosum (MC) by lesion count quartile: Pooled results of two phase 3 multicenter, randomized, vehicle-controlled trials for the topical treatment of MC

Background: Two phase 3 trials were completed using VP-102, a proprietary drug-delivery device combination containing cantharidin (0.7% w/v) for the treatment of molluscum contagiosum (MC). This pre-specified exploratory analysis aimed to determine if lesion count at baseline affected the safety and efficacy outcomes in response to VP-102 by pooling data from both trials.

Atrial Natriuretic Peptide and Treatment With Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction

ObjectivesThis study sought to assess associations between longitudinal change in atrial natriuretic peptide (ANP) and reverse cardiac remodeling following initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF). BackgroundNeprilysin inhibition results in an increase of several vasoactive peptides that may mediate the beneficial effects of sacubitril/valsartan, including ANP. MethodsIn a prospective study of initiation and titration of sacubitril/valsartan in patients with HFrEF, blood was collected at scheduled time points into tubes containing protease inhibitors. This pre-specified exploratory analysis included patients in whom ANP was measured at baseline and serially through 12 months of treatment. ResultsAmong 144 participants (mean age: 64.5 years; left ventricular ejection fraction: 30.8%), following initiation of sacubitril/valsartan, there was an early and significant increase in ANP, with the majority of rise from 99 pg/ml at baseline to 156 pg/ml at day 14 (p < 0.001). There was a further trend toward a second increase from day 30 to day 45 (p = 0.07). At maximal rise, ANP had doubled. In longitudinal analyses, early rise in ANP was followed by a subsequent increase in urinary cycle guanosine monophosphate. Larger early increase in ANP was associated with larger later improvements in left ventricular ejection fraction and left atrial volume index (p < 0.001 for both). ConclusionsConcentrations of ANP doubled after initiation of sacubitril/valsartan in patients with HFrEF. Larger early increases in ANP were associated with a greater magnitude of subsequent reverse cardiac remodeling. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183)

Abstract CT215: RELAY, ramucirumab plus erlotinib (RAM+ERL) versus placebo plus erlotinib (PBO+ERL) in previously untreated EGFR mutation-positive metastatic NSCLC: Next generation sequencing (NGS) results

Abstract RELAY (NCT02411448) showed a superior progression free survival benefit with RAM+ERL versus (v) PBO+ ERL (mPFS 19.4 vs 12.4mo, HR 0.59, p-value &amp;lt;0.0001). We investigated the mutational landscape for potential a) baseline biomarkers and b) treatment emergent (TE) alterations. Eligible patients (untreated metastatic NSCLC, EGFR exon 19 deletion or exon 21 L858R mutation-positive by local testing, ECOG PS of 0 or 1, and without CNS metastases) were randomized to receive ERL (150 mg oral) daily with either RAM (10 mg/kg iv) or PBO Q2W until progressive disease, unacceptable toxicity, withdrawal, non-compliance, or investigator decision. Liquid biopsies (baseline, cycle 4 (C4), and post-treatment discontinuation 30-day follow-up) underwent Guardant360® NGS for pre-specified exploratory biomarker analyses. For baseline analyses, alterations (single nucleotide variants, gene fusions, or copy number changes) in ALK, MET, and TP53 were among the 69 genes with alterations co-occurring at baseline with ex19del or ex21.L858R (not shown). Baseline ALK and MET alterations did not appear to impact the observed PFS or DOR. However, altered baseline TP53 associated with a worse prognosis (p&amp;lt;0.001), and had a trend for better ram efficacy. For evaluating TE alterations, two populations were assessed to address factors like disease progression and ctDNA shedding (footnote). The distribution of TE alterations in the 30-day follow-up samples was similar for RAM+ERL v PBO+ERL (TABLE). Additional results, including associations with baseline characteristics, C4, 30-day follow-up, and PFS will be presented. Understanding the potential clinical impact of co-occurring baseline alterations provides important information to evaluate treatment options. Sample size was limited, but the types and frequency of TE alterations appeared similar between treatment arms. TablePts (≥2 in either treatment group) with treatment emergent alterationsaPop1bPop2bGene NameRAM+ERL (n=36)PBO+ERL (n=60)p-valuecRAM+ERL (n=98)PBO+ERL (n=129)p-valuecEGFRd16 (44)33 (55).3227 (28)47 (36).16TP538 (22)7 (12).1717 (17)16 (12).30NF15 (14)1 (2).027 (7)3 (2).08APC4 (11)1 (2).055 (5)3 (2).26MET3 (8)5 (8)1.006 (6)7 (5).82KRAS2 (6)3 (5).917 (7)3 (2).08FGFR22 (6)2 (3).603 (3)3 (2).73GNAS2 (6)0.052(2)1 (1).41BRAF1 (3)6 (10).163 (3)6 (5).54PI3KA1 (3)4 (7).391 (1)7 (5).06BRCA203 (5).094 (4)6 (5).84ERBB21 (3)3 (5).594 (4)4 (3).69AR02 (3).171 (1)2 (2).73CDK61 (3)2 (3).881 (1)2 (2).73RB11 (3)1 (2).722 (2)3 (2).88CDK41 (3)1 (2).721 (1)2 (2).73SMAD41 (3)1 (2).721 (1)2 (2).73KIT1 (3)1 (2).723 (3)1 (1).19PTEN1 (3)2 (3).882 (2)2 (2).78ARID1A1 (3)1 (2).723 (3)3 (2).73FGFR11 (3)0.162 (2)1 (1).41MAP2K11 (3)0.162 (2)0.07MAPK31 (3)0.162 (2)0.07MTOR01 (2).332 (2)1 (1).41MYC1 (3)0.162 (2)2 (2).78RET00–2 (2)0.07ROS100–2 (2)0.07STK1100–1 (1)2 (2).73Evaluable baseline NGS results were obtained for 390 out of 449 ITT patients (87%).aPts are included in more than one row if alterations arose in more than one gene.bAnalysis population 1 (Pop1, N=96) had disease progression by the 30-day post treatment discontinuation follow-up and had detectable EGFR ex19del or ex21.L858R mutation in baseline and 30 day follow-up blood samples. There is a greater confidence that alterations related to mechanisms of resistance would be detectable in this population since the patients had all progressed by 30-day follow-up and since the EGFR ex19del and ex21.L858R were detectable as shed circulating tumor DNA in the blood. Analysis population 2 (Pop2, N=227) had discontinued study treatment for any reason by the 30-day post treatment discontinuation follow-up and had any alteration detectable at baseline and at 30 day follow-up. Pop2 is a larger population (includes all Pop1 pts) and offers the opportunity to detect less common TE alterations that may not be found in the smaller Pop1. Seven (19%) RAM+ERL v 19 (32%) PBO+ERL of Pop1 and 33 (34%) v 59 (46%) of Pop2 pts had not acquired any of the evaluated alterations.cFisher's exact testdIncludes T790M; the frequencies of TE T790M in RAM+ERL v PBO+ERL for Pop1 were 42% v 50%, respectively, and for Pop2, 19% v 25% Citation Format: Edward Garon, Martin Reck, Kazuto Nishio, John Victor Heymach, Makoto Nishio, Silvia Novello, Luis Paz-Ares, Sanjay Popat, Santiago Ponce Aix, Sameera Wijayawardana, Rebecca R. Hozak, Carla Visseren-Grul, Kazuhiko Nakagawa. RELAY, ramucirumab plus erlotinib (RAM+ERL) versus placebo plus erlotinib (PBO+ERL) in previously untreated EGFR mutation-positive metastatic NSCLC: Next generation sequencing (NGS) results [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT215.

Ultra-Rapid Lispro Efficacy and Safety Compared to Humalog® in Japanese Patients with Type1 Diabetes: PRONTO-T1D Subpopulation Analysis.

IntroductionWe evaluated the efficacy and safety of ultra-rapid lispro (URLi) in comparison to lispro in a subgroup analysis of Japanese adults with type 1 diabetes mellitus from the phase 3 PRONTO-T1D trial.MethodsAfter an 8-week lead-in to optimize basal insulin treatment, patients were randomized to 52-week double-blind mealtime URLi or lispro, or 26-week open-label postmeal URLi. The primary endpoint was change in hemoglobin A1c (HbA1c) from baseline (week 0) to week 26 between mealtime URLi and lispro. The multiplicity adjusted objectives were 1- and 2-h postprandial glucose (PPG) excursions after a meal test between mealtime URLi and lispro, and change in HbA1c from baseline to week 26 between postmeal URLi and mealtime lispro.ResultsThis manuscript presents pre-specified exploratory analyses of 26-week data from Japanese patients randomized to double-blind URLi (n = 62) or lispro (n = 59), or open-label URLi (n = 46). Mean baseline HbA1c levels were 7.52% for mealtime URLi, 7.44% for lispro, and 7.51% for postmeal URLi at randomization. At week 26, the least squares mean (LSM) difference compared to lispro was 0.04% (95% confidence interval [CI] − 0.14 to 0.22) for mealtime URLi, and 0.16% (95% CI − 0.04 to 0.35) for postmeal URLi. In comparison to lispro, mealtime URLi resulted in statistically significantly lower 1- and 2-h PPG excursions during the mixed-meal tolerance test. LSM differences were − 40.5 mg/dL, 95% CI − 59.5 to 21.4 (− 2.25 mmol/L, 95% CI − 3.3 to − 1.2) for 1-h PPG excursions and − 51.7 mg/dL, 95% CI − 81.7 to − 21.8 (− 2.87 mmol/L, 95% CI − 4.5 to − 1.2) for 2-h PPG excursions at week 26. There were no significant treatment differences in rates of severe/overall hypoglycemia, or incidence of treatment-emergent adverse events.ConclusionsMealtime and postmeal URLi provide effective and comparable glycemic control in Japanese patients. Mealtime URLi demonstrated more effective PPG control compared to lispro.Trial RegistrationClinicalTrials.gov, NCT03214367.

Switching to fingolimod in PREFERMS: Effect of treatment history and naïvety on clinical, MRI and treatment satisfaction outcomes✰

BackgroundInjectable disease-modifying therapies (iDMTs) are often used as first-line treatments for relapsing multiple sclerosis. Fingolimod is frequently used following treatment with iDMTs. Whether prior iDMT treatment impacts the effectiveness of subsequent fingolimod therapy is unclear. Here, we assessed switching from iDMTs to fingolimod, and the impact of treatment history on fingolimod escalation using data from the 12-month ‘Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention on Fingolimod versus approved first-line disease-modifying thErapies in adults with Relapsing–remitting Multiple Sclerosis’ (PREFERMS). The study design and results at the end of randomized treatment (EoRT) in PREFERMS have been published. MethodsBoth treatment-naïve patients and those who had previously received an iDMT were eligible for enrolment in PREFERMS, and one treatment switch was permitted on study. Pre-specified exploratory analyses compared outcomes in those randomized to fingolimod or to an iDMT at end of study (EoS), which included time spent on randomized and on switch treatment. Post hoc exploratory analyses (unadjusted for multiplicity owing to the large number of comparisons) among patients randomized to an iDMT who switched to fingolimod, compared outcomes longitudinally before (EoRT) and after (EoS) switching, and compared outcomes at EoRT and EoS among subgroups stratified by iDMT-treatment history. Outcomes included brain volume, various measures of gadolinium-enhancing [Gd+] lesion counts, annualized relapse rate (ARR), Symbol Digit Modalities Test (SDMT) score, patient-reported treatment satisfaction using the Medication Satisfaction Questionnaire (MSQ) and adverse event (AE) rates. ResultsAt EoS, 255 of 439 patients randomized to an iDMT had switched to fingolimod and 27 of 436 patients randomized to fingolimod had switched to an iDMT. By EoS, 44.2% of total treatment exposure in the iDMT group was to fingolimod and the mean time spent on fingolimod in this group was 220 days (approximately 7 months). Outcomes in the fingolimod group at EoS (brain volume, changes in Gd+ lesion counts, ARR, oral SDMT score and MSQ score) were similar to those seen at EoRT, but in the iDMT group these outcomes were more favorable at EoS than at EoRT and were similar to rates seen in the fingolimod group. Among patients who switched from iDMT to fingolimod, there were longitudinal improvements in ARR (EoRT, 0.3 [95% confidence interval (CI), 0.2–0.4]; EoS, 0.2 [0.1–0.3]; odds ratio, 0.5 [0.3–0.9]) and in treatment satisfaction (proportion of patients with MSQ > 5; EoRT, 67.4%; EoS, 90.4%; odds ratio, 5.7 [95% CI, 3.4–9.4]) after fingolimod treatment, and changes in brain volume, Gd+ lesion count, and AEs or AEs causing discontinuation were also more favorable at EoS than at EoRT. In all patient groups stratified by iDMT-treatment history, differences in outcomes narrowed or disappeared after fingolimod treatment. ConclusionThese analyses indicate that patients in PREFERMS had improved outcomes within months of switching to fingolimod from an iDMT and that improvements occurred irrespective of the number of iDMTs previously administered. These data provide a unique opportunity to explore clinical, radiological and safety outcomes associated with a range of clinically relevant treatment pathways.