Surrogate Endpoints In Trials Research Articles

A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials

Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

Assessment of Surrogate End Point Trends in Clinical Trials to Approve Oncology Drugs From 2001 to 2020 in Japan

A surrogate end point (SEP) is an end point used in clinical trials as an alternative for measuring the true clinical benefit. The use of SEPs in trials shortens their duration. To investigate the use of SEPs in clinical trials to support the approval of anticancer drugs and to determine whether confirmatory studies that use overall survival (OS) as an end point are being conducted in Japan. In this cross-sectional study, drug approvals and background information were obtained from publicly available information, such as the Pharmaceuticals and Medical Devices Agency website, for anticancer drugs approved in Japan from January 2001 to December 2020. Data analysis was performed from September 2021 to March 2022. Characteristics of approved oncology drugs in Japan, end points for pivotal clinical trials, and outcomes of confirmatory trials using OS as an end point following drug approval. There were 299 anticancer drugs approved in Japan during the study period. Of these, 142 (47.5%) were molecular-targeted drugs, the most common of which targeted non-small cell lung cancer. There were 111 (37.1%) anticancer drugs with orphan designation. From 2001 to 2005, OS was used as an end point in 1 approval (3.6%); however, from 2006 to 2020, OS was used in 86 approvals (31.7%). Of the 212 anticancer drugs approved on the basis of SEPs, confirmatory studies with OS as the end point were conducted for only 37 approvals (17.5%); for the remaining 175 approvals, studies are under way for 35 approvals (16.5%), were waivered for 75 approvals (35.4%), and were not conducted for 65 approvals (30.7%). Furthermore, in 20 drug approvals (9.4%), the conducted confirmatory studies were not effective in determining the OS, but the drugs were approved following re-examination. The findings of this study suggest that starting from 2005, the use of OS as an end point has increased in studies supporting the approval of anticancer drugs in Japan. However, even after 2005, approximately two-thirds of these approvals were SEP based. Postmarketing surveillance studies of the true end points are necessary to validate the use of SEPs.

Tumor Response, Disease Control, and Progression-Free Survival as Surrogate Endpoints in Trials Evaluating Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: Study- and Patient-Level Analyses.

Background: To assess the usefulness of tumor response and progression-free survival (PFS) as surrogates for overall survival (OS) in non-small cell lung cancer (NSCLC) trials with immune checkpoint inhibitors (ICI), which have not been confirmed. Methods: Patient- and trial-level analyses were performed. The Response Evaluation Criteria in Solid Tumors was preferred for image assessment. For trial-level analysis, surrogacy was assessed using the weighted rank correlation coefficient (r) following "reciprocal duplication." This method duplicates all plots as if the experimental and the reference arms were switched. Monte Carlo simulations were performed for evaluating this method. Results: A total of 3312 cases were included in the patient-level analysis. Patients without response (first line (1L): hazard ratio (HR) 1.95, 95% confidence interval (CI) 1.71-2.23; second or later line (2L-): HR 4.22, 95% CI 3.22-5.53), without disease control (1L: HR 4.34, 95% CI 3.82-4.94; 2L-: HR 3.36, 95% CI 2.96-3.81), or with progression during the first year (1L: HR 3.42, 95% CI 2.60-4.50; 2L-: HR 3.33, 95% CI 2.64-4.20), had a higher risk of death. Systematic searches identified 38 RCTs including 17,515 patients for the study-level analysis. Odds ratio in the objective response rate (N = 38 × 2, r = -0.87) and HR in PFS (N = 38 × 2, r = 0.85) showed an excellent association with HR in overall survival, while this effect was not observed in the disease control rate (N = 26 × 2, r = -0.03). Conclusions: Objective response rate and PFS are reasonable surrogates for OS in NSCLC trials with ICI.

Scoping and targeted reviews to support development of SPIRIT and CONSORT extensions for randomised controlled trials with surrogate primary endpoints: protocol

IntroductionUsing a surrogate endpoint as a substitute for a primary patient-relevant outcome enables randomised controlled trials (RCTs) to be conducted more efficiently, that is, with shorter time, smaller sample size...

Frequency of Failure of St-Segment Resolution after Primary Percutaneous Coronary Intervention in Patients with St-Segment Elevation Acute Myocardial Infarction

Objective: To determine the frequency of failure of ST-segment resolution after primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation acute myocardial infarction (MI). Methodology: This cross-sectional study was carried out at the CCU department of the National Institute of Cardiovascular Diseases (NICVD) Karachi, during six months from January 2017 to July 2017. All patients with ST elevation myocardial infarction admitted at CCC and undergoing primary PCI, the onset of typical pian of chest and related presentation in the last 12 hours that persists at least > 20 minutes, without the previous administration of fibrinolytic therapy assessed with history and previous reports, platelet glycoprotein IIb/IIIa inhibitors without prior administration and of either gender were included. All study subjects were shifted to Angiography department, the arterial sheath was inserted only through to the femoral route to prevent bias, and the interventional cardiologist with a minimum 05 years of professional experience was chosen. Angiography was performed, and the identified occlusion area was by interventional cardiologist ballooned/stented. ST resolution failure was seen after/within 30 minutes of primary angioplasty. All the information was collected via study proforma and SPSS version 26 was used for the data analysis. Results: Mean age of the patients was 56.18±8.70 years, average BMI was 25.56±4.76 kg/m2. Females were 25% and males were 77%. Complete resolution was achieved in 73% patients, while 22% patients Failure of ST-segment resolution post PPCI. Conclusion: Our findings show that ST-segment resolution in the ECG within 30 minutes, as opposed to the traditional 90-min successful PPCI, is a significant predictive predictor. The intriguing discovery that ST-segment resolution has limited predictive value in a cohort of STEMI cases managed by the PPCI deserves additional exploration, especially as it is already widely used as the surrogate end point in trials. Keywords: St-Segment Resolution; Failure; ST-segment elevation myocardial infarction; primary percutaneous coronary intervention; electrocardiogram.

The validity of progression‐free survival 2 as a surrogate trial end point for overall survival

Overall survival (OS) is the gold-standard end point for oncology trials. However, the availability of multiple therapeutic options after progression and crossover to receive investigational agents confound and delay OS data maturation. Progression-free survival 2 (PFS-2), defined as the time from randomization to progression on first subsequent therapy, has been proposed as a surrogate for OS. Using a meta-analytic approach, the authors aimed to assess the association between OS and PFS-2 and compare this with progression-free survival 1 (PFS-1) and the objective response rate (ORR). An electronic literature search was performed to identify randomized trials of systemic therapies in advanced solid tumors that reported PFS-2 as a prespecified end point. Correlations between OS and PFS-2, OS and PFS-1, and OS and ORR as hazard ratios (HRs) or odds ratios (ORs) were assessed via linear regression weighted by trial size. Thirty-eight trials were included, and they comprised 19,031 patients across 8 tumor types. PFS-2 displayed a moderate correlation with OS (r = 0.67; 95% confidence interval [CI], 0.08-0.69). Conversely, correlations of ORR (r = 0.12; 95% CI, 0.00-0.13) and PFS-1 (r = 0.21; 95% CI, 0.00-0.33) were poor. The findings for PFS-2 were consistent for subgroup analyses by treatment type (immunotherapy vs nonimmunotherapy: r = 0.67 vs 0.67), survival post progression (<12 vs ≥12 months: r = 0.86 vs 0.79), and percentage not receiving subsequent treatment (<50% vs ≥50%: r = 0.70 vs 0.63). Across diverse tumors and therapies, the treatment effect on PFS-2 correlated moderately with the treatment effect on OS. PFS-2 performed consistently better than PFS-1 and ORR, regardless of postprogression treatment and postprogression survival. PFS-2 should be included as a key trial end point in future randomized trials of solid tumors.

From Early Morphometrics to Machine Learning-What Future for Cardiovascular Imaging of the Pulmonary Circulation?

Imaging plays a cardinal role in the diagnosis and management of diseases of the pulmonary circulation. Behind the picture itself, every digital image contains a wealth of quantitative data, which are hardly analysed in current routine clinical practice and this is now being transformed by radiomics. Mathematical analyses of these data using novel techniques, such as vascular morphometry (including vascular tortuosity and vascular volumes), blood flow imaging (including quantitative lung perfusion and computational flow dynamics), and artificial intelligence, are opening a window on the complex pathophysiology and structure–function relationships of pulmonary vascular diseases. They have the potential to make dramatic alterations to how clinicians investigate the pulmonary circulation, with the consequences of more rapid diagnosis and a reduction in the need for invasive procedures in the future. Applied to multimodality imaging, they can provide new information to improve disease characterization and increase diagnostic accuracy. These new technologies may be used as sophisticated biomarkers for risk prediction modelling of prognosis and for optimising the long-term management of pulmonary circulatory diseases. These innovative techniques will require evaluation in clinical trials and may in themselves serve as successful surrogate end points in trials in the years to come.

1072P Beyond classical surrogate endpoints in trials of PD1/PD-L1 immune checkpoint inhibitors (ICI) plus chemotherapy (CT)

Several studies showed the inaccuracy of classical surrogate endpoints, such as progression-free survival (PFS) and objective response rate (ORR), in predicting overall survival (OS) in trials of ICI. Patients that respond to immunotherapy have longer median duration of response (mDR) than those that achieve an ORR with standard CT. We aimed to explore the validity of new surrogate endpoints that take into account ORR and mDR in the context of combination ICI trials.

JAK2 V617F as a Marker for Long-Term Disease Progression and Mortality in Polycythemia Vera and its Role in Economic Modeling.

BackgroundIn order to facilitate sound economic evaluations of novel treatments, health-economic models of polycythemia vera (PV) must combine effects on surrogate endpoints in trials with disease progression (DP) and mortality in long-term cohort data.ObjectiveWe validate an economic model for PV that uses Janus Kinase 2 (JAK2) burden as a surrogate endpoint to predict DP (thrombosis, myelofibrosis, and acute leukemia) and overall survival (OS) based on progression-specific mortality.MethodsLong-term observational studies that include information about baseline JAK2 burden were identified via PubMed searches and used to validate the model. Kaplan-Meier (KM) OS curves were extracted using a digitizing software. External validity of the model was analyzed by visually comparing OS curves of the model with the KM curves of the included studies, as well as calculating differences in mean OS estimated as area under the curve (AUC).ResultsThe model’s predictions of cumulative DP were somewhat lower than the published studies. Over 20 years’ time, our base case model predicted a mean OS for a PV patient (15.0–16.5 years), which was in line with the published studies (15.8–17.5 years). Modeled mean OS was almost two years longer (1.6–1.9 years) for patients with JAK2 <50% than patients with JAK2 ≥50%. Only three long-term observational studies that satisfied the predefined criteria were found and could be used in the validation, but these studies did not capture JAK2 evolution over time. Improved model predictions of DP and mortality based on the longitudinal evolution of JAK2 could be derived from real-world data sources. Such data are currently scarce and future observational studies should be designed to capture the long-term impact of JAK2 on DP and mortality in PV.ConclusionsOur model, based on JAK2 burden as a marker for DP, generated OS estimations that are in line with results of published data.

P0228THE NEFIGARD TRIAL: THE EFFECT OF NEFECON® (BUDESONIDE) IN PATIENTS WITH PRIMARY IGA NEPHROPATHY AT RISK OF DEVELOPING END-STAGE RENAL DISEASE

Abstract Background and Aims Since the first description of IgA nephropathy (IgAN) over 50 years ago, it has been recognised that the mucosal immune system plays a crucial role in the pathogenesis of this common global cause of kidney failure. Recently, particular attention has focussed on the importance of the gut-associated lymphoid tissue (GALT) as the potential source of the poorly O-galactosylated IgA1 that triggers the formation of nephritogenic immune complexes in IgAN. Pathway analysis based on a large meta-analysis of genome wide association studies identified the intestinal immune network for IgA production as the most enriched KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway in IgAN. Furthermore, separate studies have shown that the IgA in glomerular IgA deposits is indistinguishable from mucosal IgA. The therapeutic potential of selectively targeting GALT was demonstrated in the NEFIGAN trial (NCT01738035), which assessed the safety and efficacy of a novel targeted-release formulation of budesonide (NEFECON®), designed to deliver budesonide to the GALT-rich distal ileum in patients with IgAN. After 9 months’ treatment, urine protein–creatinine ratio (UPCR) was reduced by 29.3% in the NEFECON® 16 mg group compared with the placebo group. Estimated glomerular filtration rate (eGFR) dropped 4.7 ml/min/1.73 m2 in the placebo group with no deterioration seen in the NEFECON® 16 mg group. Incidence of patients reporting adverse events was similar in all groups. These data led to the design of the NefIgArd study which aims to assess the efficacy, safety, and tolerability of NEFECON® 16 mg in patients with IgAN at risk of end-stage renal disease. Method The NefIgArd study is a randomised, double-blind, placebo-controlled Phase 3 trial, with two parts – PART A a 15–35-day screening period, 9-month treatment and 3-month follow-up period; and PART B a 12-month no-treatment follow-up period (Figure). The study is recruiting across 146 nephrology clinics in 19 countries. Patients must be at least 18 years old with biopsy-confirmed primary IgAN and persistent proteinuria &amp;gt;1 g/24 h and eGFR between 35 and 90 ml/min per 1.73 m2 (CKD-EPI) despite optimised renin–angiotensin system blockade. Patients are randomised on a 1:1 ratio to NEFECON® 16 mg/day or placebo. Consistent with the Kidney Health Initiative White Paper “Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy” published in early 2019, the primary outcome of Part A is to assess the effect of NEFECON® 16 mg on 24 h UPCR at 9 months compared with placebo. The Part B primary outcome is based on data presented at the NKF/FDA/EMA workshop in March 2018 that supported eGFR slope as an endpoint for full approval and will assess the effect of NEFECON® 16 mg on a 2-year eGFR-based endpoint compared with placebo. In comparison with other studies that are recruiting, we believe that the relatively short period required to provide validation of the surrogacy of proteinuria reduction will significantly reduce the risks of non-protocol treatments and loss of patients from the study that could dilute the true treatment effect of NEFECON®. Results As of 1 January 2020, 207 patients have been randomised, and Part A is expected to complete in Q4 2020, with Part B completing in 2022. To ensure the NefIgArd study results are fully translatable to the global IgAN population, NefIgArd will also open in China in 2020. Conclusion The NefIgArd study builds on the experience of the NEFIGAN trial, the largest commercially sponsored study ever completed in IgAN. The design of the NefIgArd study has used state-of-the-art data to evaluate kidney outcomes, using proteinuria as a reasonably likely surrogate of the effect of NEFECON® on long-term kidney outcomes and confirming long-term renoprotection using an NKF/FDA/EMA-suggested eGFR-based endpoint as a basis for full approval.

Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm.

Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood-DNA-methylation measure that is sensitive to variation in pace of biological aging among individuals born the same year. We first modeled change-over-time in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in n = 954 members of the Dunedin Study born in 1972-1973. Rates of change in each biomarker over ages 26-38 years were composited to form a measure of aging-related decline, termed Pace-of-Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace-of-Aging, called DunedinPoAm for Dunedin(P)ace(o)f(A)ging(m)ethylation. Validation analysis in cohort studies and the CALERIE trial provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person's pace of biological aging.

A validated composite organ and hematologic response model for early assessment of treatment outcomes in light chain amyloidosis

Newly diagnosed AL amyloidosis patients were evaluated to develop a model for early assessment of treatment benefit at 6 months, integrating both hematologic (HR) and organ response (OR) assessment (testing cohort, Mayo: n = 473; validation cohort, Pavia: n = 575). Multiple OR were assessed as follows: All OR (AOR): response in all organs, mixed OR (MOR): response in some organs, no OR (NOR)]. AOR rates at 6 months improved with deepening HR; complete response (CR; 38%, 35%), very good partial response (VGPR; 30%, 26%), and partial response (PR; 16%, 21%), respectively. A composite HR/OR (CHOR) model was developed using incremental scoring based on hazard ratios with scores of 0–3 for HR (0—CR, 1—VGPR, 2—PR, 3—no response) and 0–2 for OR (0—AOR, 1—MOR, 2—NOR). Patients could be divided into two distinct CHOR groups (scores 0–3 and 4–5), with median OS in group 1 and group 2: Not reached vs. 34 months, p < 0.001 [Mayo] and 87 vs. 23 months, p < 0.001 [Pavia]. In conclusion, we developed a model that can assess multiple organs concurrently, and integrate both HR and OR assessments to determine early clinical benefit with treatment, which may be used as a surrogate end-point in trials and to compare outcomes with different therapies.

BIOMARKERS OF SENESCENT CELL BURDEN

Senescent cells drive aging. Preclinical studies suggest that targeted elimination of senescent cells offers a unique therapeutic approach to counter numerous chronic diseases and geriatric syndromes. To foster the translation of basic science discoveries to clinical application, we have sought to identify circulating biomarkers that reflect systemic senescent cell burden. We first analyzed the secretome of multiple senescent human cell-types and developed a candidate panel of proteins that could be reliably measured in human blood. Multiple proteins demonstrated significant associations with chronological age in a community-based cohort of adults aged 20-to-90 years. Impressively, in two distinct surgical cohorts (severe aortic stenosis and ovarian cancer), candidate protein concentrations were associated with biological age indices, including frailty and adverse outcomes. Our data suggest senescence biomarkers may have utility for clinical practice as indicators of risk, and for clinical research as surrogate endpoints in trials of interventions targeting senescent cells.

P3556Segmental intramyocardial CMR Fast-SENC objectively quantifies cardiac dysfunction that causes symptoms based on NYHA classification before global longitudinal strain or ejection fraction

Abstract Background Global longitudinal strain (GLS) has become an alternative to ejection fraction (EF) in identifying reduced cardiac function. However, these global metrics are not able to characterize patients in which symptoms occur even while the heart compensates for regional dysfunction. More sensitive metrics are needed to detect subclinical regional dysfunction and determine the relationship to symptoms that may or may not be associated with cardiac causes. Fast-SENC intramyocardial strain (fSENC) is a unique cardiac magnetic resonance imaging (CMR) modality that measures intramyocardial contraction in 1 heartbeat per image plane. This prospective registry compares segmental fSENC to global metrics GLS and LVEF based on NYHA classification. Methods A single center, prospective registry of MRI scans acquired with a 1.5T scanner were evaluated for conventional CMR diagnostics including biventricular EF, volumes and mass. In addition, fSENC scans were acquired and processed with the MyoStrain software to quantify intramyocardial LV &amp; RV strain. Three short axis scans (basal, midventricular, &amp; apical) were used to calculate strain in 16 LV &amp; 6 RV longitudinal segments while three long axis scans (2-, 3- &amp; 4-chamber) were used to calculate 21 LV &amp; 5 RV circumferential segments. All metrics were compared based on NYHA classification. Results A total of 977 scans in 779 patients were included in the study; this population included 210 myocarditis, 46 dilated cardiomyopathy, and 30 ischemic cardiomyopathy cases. Patients had an average (± stdev) age of 55 (17) yrs and BMI of 26 (5) kg/m2; 48% had arterial hypertension, 12% diabetes mellitus, 33% valve disease, 24% cancer, 7% atrial fibrillation, 13% pulmonary disease, 5% left bundle branch block, 35% hypercholesterolemia, and 24% coronary artery disease. Figure 1 shows the relationship between segmental strain, calculated as the percent of normal LV segments (longitudinal &amp; circumferential) based on intramyocardial fSENC &lt;−17%, versus GLS and LVEF. All metrics were compared based on NYHA classification. Figure 1 Conclusion Segmental fSENC identified changes in NYHA classification well before changes in EF or GLS. Measuring segmental fSENC provides an objective view of symptomatic heart failure progression and can serve as surrogate endpoints for trials instead of purely relying on quality of life and subjective symptom perception.

Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy.

IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.

The New HHS Kidney Innovation Accelerator: When Innovation Stalls, HHS Says Floor it!

“It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood; who strives valiantly; who errs, who comes

Abstract 2964: On-treatment changes in circulating tumor DNA (ctDNA) level as an early predictor of clinical outcome in the LOTUS randomized phase 2 trial of 1st-line ipatasertib (IPAT) + paclitaxel (PAC) for metastatic triple-negative breast cancer (mTNBC)

Abstract Purpose: There is high interest in longitudinal analysis of plasma ctDNA as an early predictor of response and long-term outcomes. We report a retrospective longitudinal analysis of ctDNA in the double-blind placebo (PBO)-controlled randomized phase 2 LOTUS (NCT02162719) trial of the oral Akt inhibitor IPAT + PAC for mTNBC. Methods: Pre-treatment plasma samples were analyzed to identify and quantify genomic alterations in ctDNA using a hybrid-capture-based NGS assay that interrogates 62 genes (FoundationACT). A narrow ctDNA panel quantified the same mutations in on-treatment samples collected at 8 wks (d1, cycle 3). The ctDNA fraction (CTF) was defined as the highest mutant allele frequency in each sample. The ratio of CTF in on-treatment vs pre-treatment samples was compared with objective response (RECIST v1.1) and progression-free survival (PFS) in the experimental (IPAT + PAC) and control (PBO + PAC) arms. Results: Paired on-treatment samples were evaluable from 66 of 88 patients with evaluable pre-treatment samples. The most common reason for no on-treatment sample was disease progression (PD) before cycle 3. In 81 baseline samples, 149 mutations were identified. Calculated CTF ratios ranged from 0% (not detected in on-treatment sample) to 648% (increase in on-treatment sample). In both arms and the pooled population, a greater CTF decrease was associated with objective response and longer PFS (Table). Conclusions: On-treatment change in CTF shows a meaningful association with objective response and PFS in LOTUS. This effect was seen in the experimental and control arms, suggesting independence from the specific mechanism of therapy. Evaluation of samples from the time of PD is ongoing. Inclusion of additional timepoints will likely improve the predictive ability of CTF, possibly allowing its use as an early surrogate trial endpoint. IPAT + PAC (n=32)PBO + PAC (n=34)Pooled arms (n=66)Median CTF ratio, % (IQR)Confirmed complete/partial response(n=14)(n=14)(n=28)0.4 (0-14.3)0.2 (0-46.9)0.3 (0-17.8)Stable/progressive disease(n=18)(n=20)(n=38)8.2 (4.4-45.9)26.9 (8.4-91.4)20.7 (4.9-67.9)Median PFS, months (95% CI)CTF ratio ≤5%(n=15)(n=14)(n=29)7.2 (3.7-NE)6.3 (3.6-NE)7.2 (5.1-12.9)CTF ratio &amp;gt;5%(n=17)(n=20)(n=37)3.7 (3.5-5.3)3.7 (2.8-5.4)3.7 (3.6-5.0)PFS hazard ratio (95% CI)0.46 (0.19-1.09)0.43 (0.17-0.97)0.43 (0.23-0.78)CI = confidence interval; IQR = interquartile range; NE = not estimable. Citation Format: Matthew J. Wongchenko, Doron Lipson, Travis Clark, Mark Kennedy, Mandy Greene, Virginia Breese, Alyssa Tsiros, Sung-Bae Kim, Cristina Saura, Mafalda Oliveira, Jose Baselga, Amy V. Kapp, Wai Y. Chan, Stina M. Singel, Steven Gendreau, Rebecca Dent. On-treatment changes in circulating tumor DNA (ctDNA) level as an early predictor of clinical outcome in the LOTUS randomized phase 2 trial of 1st-line ipatasertib (IPAT) + paclitaxel (PAC) for metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2964.

The Search for Surrogate Endpoints in Trials in Diffuse Large B-Cell Lymphoma: The Surrogate Endpoints for Aggressive Lymphoma Project.

This commentary describes the progress of the SEAL [Surrogate Endpoints for Aggressive Lymphoma] research group and invites collaboration in sharing data to continue building a large database of individual patient data from multiple clinical trials in DLBCL.

Nonpublication of trial results for new neurological drugs: A systematic review.

To evaluate nonpublication rates among trials of new successful and unsuccessful neurological drugs. "Licensed" drugs consisted of all novel agents receiving US Food and Drug Administration (FDA) licensure 2005-2012 inclusive in seven neurological disorders. "Stalled" drugs included all experimental agents tested in the same domains that had at least one completed phase III trial in the same time frame, but failed to receive FDA approval. Trials of these drugs were included in our sample if their primary outcome collection occurred before October 1, 2010. We determined the publication status of eligible trials using searches of clinicaltrials.gov, Google Scholar, PubMed, Embase, sponsor websites, and direct electronic query of trial contacts and sponsors. The primary outcome was time to journal publication (or results reporting in other media) after study completion. The adjusted hazard ratio for publication was 1.79 (95% confidence interval, 1.20-2.67) in favor of licensed drugs. Based on the criteria for nonpublication in this report, 14,092 and 33,882 volunteers participated in unpublished trials of licensed and stalled neurological drugs, respectively. Result data were not publicly available in any form for 10% (16 of 163) and 46% (94 of 203) of trials of licensed and stalled drugs, respectively. Results of trials for stalled drugs are heavily under-reported. This deprives research and care communities of evidence about pathophysiology, drug class effects, and the value of surrogate endpoints in trials. Ann Neurol 2017;81:782-789.

Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990-2011.

BackgroundSurrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes.Methods and ResultsWe identified cardiovascular trials with primary surrogate endpoints published in the New England Journal of Medicine, Lancet, and JAMA: Journal of the American Medical Association from 1990 to 2011 and determined the trends in publication of surrogate endpoint trials and the success of the trials in meeting their primary endpoints. We tracked for publication of clinical outcome trials on the interventions tested in surrogate trials. We screened 3016 articles and identified 220 surrogate endpoint trials. From the total of 220 surrogate trials, 157 (71.4%) were positive for their primary endpoint. Only 59 (26.8%) surrogate trials had a subsequent clinical outcomes trial. Among these 59 trials, 24 outcomes trial results validated the positive surrogates, whereas 20 subsequent outcome trials were negative following positive results on a surrogate. We identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit. Findings were consistent in a sample cohort of 383 screened articles inclusive of 37 surrogate endpoint trials from 6 other high‐impact journals.ConclusionsAlthough cardiovascular surrogate outcomes trials frequently show superiority of the tested intervention, they are infrequently followed by a prominent outcomes trial. When there was a high‐profile clinical outcomes study, nearly half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it.