Liquid Biopsy Based NGS in Newly Diagnosed NSCLC

Study Overview
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Brief Summary
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This study expands the application of an electronic health record (EHR) nudge used to prompt physicians' clinical practice to order molecular testing at the time of initial diagnosis for patients with specific types of advanced lung cancer. The primary goal is to have these test results available prior to starting treatment so that physicians can make molecularly-informed treatment decisions. The second goal is to better understand factors that contribute to whether or not the EHR-nudge implementation is successful.

Detailed Description
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At the University of Pennsylvania Health System (UPHS), a behavioral economics (BE) informed nudge strategy was piloted to guide physicians' clinical practice to include concurrent use of plasma and tissue-based next generation sequencing (NGS) testing at the time of initial diagnosis for patients with newly diagnosed metastatic non-squamous (mNSq) non-small cell lung cancer (NSCLC). These findings have demonstrated that behavioral, electronic health record (EHR)-based nudges are feasible and can promote guideline concordant diagnostic testing at both community and academic sites. The overarching goal of this current trial is to expand the application of this BE informed nudge approach, which has been operationalized within Epic, the EHR used at UPHS, to six satellite hospitals. Our central hypothesis is that this approach will dramatically increase adoption of comprehensive molecular testing and enhance the delivery of molecularly informed 1L therapy in patients with newly diagnosed mNSq NSCLC. Molecular testing will be defined as i) comprehensive: EGFR, ALK, BRAF, ROS1, MET, RET, and NTRK testing, ii) incomplete: <6 genes tested, and iii) no testing performed. Clinically actionable mutations will be defined as an alteration in one of the seven genes on the comprehensive gene list with an FDA approved targeted therapy in the 1L setting, plus KRAS G12C, EGFR exon 20 insertion, and ErbB2 mutations. Molecularly informed first line therapy will be defined as one that is informed by results of NGS, obtained by plasma, tissue or both. Intervention An EHR-based nudge intervention that allows for default placement of a plasma based molecular genotyping order at time of the first new patient visit will be implemented. Subsequently, results detected on the default plasma NGS order will be conveyed to providers in the form of an electronic clinical decision support notification. As part of the downstream EHR-based nudge intervention workflow, an electronic clinical decision support (e-CDS) system for alterations detected on plasma genotyping will be created and implemented into the EHR as a Research (non-chargeable) Encounter to alert the provider team caring for the patient. This support program will be created to notify clinicians of targetable mutations, as well as absence of mutations detected on plasma testing as a means of improving the timely delivery of molecularly informed therapy. Study Design Objective 1: In a stepped wedge cluster randomized trial of patients with newly diagnosed mNSq NSCLC, test the effectiveness of a behavioral economics (BE) informed EHR nudge intervention to increase timely receipt of comprehensive molecular test results before 1L therapy by integration of concurrent tissue and plasma molecular testing. The design of this trial will include 3 clusters, representing 6 community hospitals. There will be an initial period in which no clusters are exposed to the intervention. Subsequently, at regular intervals (the steps) one cluster (or a group of clusters) will be randomized to cross from the control to the intervention under evaluation. This process will continue until all clusters have crossed over to be exposed to the intervention. At the end of the study there will be a period when all clusters are exposed. Data collection will continue throughout the study, so that each cluster will contribute observations under both control and intervention observation periods. Two years of baseline data will be obtained from all study sites for comparison. Objective 2: Evaluate contextual mechanisms contributing to the adoption, reach, and effectiveness of EHR nudge interventions with a lens for health equity. Using rigorous approaches proven successful in our prior work, the investigators will recruit 10-15 patient and clinician participants from each site (estimated 40-60 participants total) to complete semi-structured interviews following the active trial period. The goal of this objective is to understand contextual mechanisms (e.g., patient, clinician, clinic, structural factors) shaping adoption, reach, and effectiveness of each intervention and identify how response may differ by race and ethnicity, socioeconomic status, and other key social determinants of health. These data will be analyzed using qualitative comparative analysis, a mixed method approach well suited to identify mechanisms in pragmatic trials with smaller sample sizes.

Official Title
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iNUDGE: INtegration of liqUiD Biopsy Based Next Generation Gene sEquencing in Newly Diagnosed NSCLC - A Stepped Wedge Cluster Randomized Clinical Trial

Conditions
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Non Small Cell Lung Cancer Metastatic, Newly Diagnosed NSCLC, Non-Squamous Non-Small Cell Neoplasm of Lung

Intervention / Treatment
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* Behavioral: iNUDGE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with a histological, or cytological diagnosis of metastatic non-squamous (mNSq) non-small cell lung cancer (NSCLC) who have not yet received systemic treatment for metastatic disease. Participants must be seen at Lancaster General Health (LGH), Penn Presbyterian Medical Center (PPMC), Penn Medicine Cherry Hill (PMCH), Penn Medicine Princeton Health (PMPH), Penn Medicine Voorhees (PMV) or Penn Medicine Washington Township (PMWT) for mNSq NSCLC. Exclusion Criteria: Participants with incomplete staging information. Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This study employs a stepped-wedge cluster randomized clinical trial design. Randomization will occur at the group (site) level. Sites will be turned on according to the stepped-wedge cluster randomized design but will run in parallel.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Penn Medicine New Jersey<br>All sites with be randomized to implement the nudge at different points in time. Prospective data with be compared with each site's respective baseline numbers over a two-year period. | Behavioral: iNUDGE<br>* Electronic health record nudge which prompts physicians to order plasma-based NGS testing for eligible patients with newly diagnosed lung cancer.<br>|
| Other: Penn Medicine Lancaster General Health<br>All sites with be randomized to implement the nudge at different points in time. Prospective data with be compared with each site's respective baseline numbers over a two-year period. | Behavioral: iNUDGE<br>* Electronic health record nudge which prompts physicians to order plasma-based NGS testing for eligible patients with newly diagnosed lung cancer.<br>|
| Other: Penn Presbyterian Medical Center<br>All sites with be randomized to implement the nudge at different points in time. Prospective data with be compared with each site's respective baseline numbers over a two-year period. | Behavioral: iNUDGE<br>* Electronic health record nudge which prompts physicians to order plasma-based NGS testing for eligible patients with newly diagnosed lung cancer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Availability of comprehensive molecular test results prior to first line therapy for patients with newly diagnosed mNSq NSCLC | Were comprehensive molecular test results available prior to initiation of 1L therapy? (Yes/No) | Measured up to 6 weeks from initial diagnosis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Successful EHR based nudge delivery | Amongst eligible patients, calculate the proportion of patients for whom the EHR nudge fired successfully (Yes/No). Applicable for the patients enrolled in the time periods following randomization. | Measured up to 6 weeks from randomization | 
| Turnaround time of delivery of provider focused alerts | Reported as number of days, median. Applicable for the patients enrolled in the time periods following randomization. | Measured up to 6 weeks from randomization | 
| Completion of comprehensive molecular testing & modality used | Relative and absolute change in completion of comprehensive testing by tissue and plasma, plasma alone, or tissue alone will be tabulated. | Measured up to 3 months from initial diagnosis | 
| Reasons for failure to complete comprehensive molecular testing: | Summarize reasons for failure of completion of testing i. Tissue related (QNS) ii. Patient related factors (unable to biopsy, patient declined biopsy etc.) iii. Assay related factors (plasma assay does not detect mutations) iv. Other | Measured up to 3 months from initial diagnosis | 
| Time to molecularly informed treatment initiation | i. Calculated as time to therapy from the date of diagnosis of Stage IV disease (date of biopsy) ii. Calculated as time to therapy from the date of first new patient visit with medical oncology | Measured up to 6 weeks from initial diagnosis | 
| Type of therapy received | i. Targeted therapy ii. Chemo-immunotherapy iii. Immunotherapy iv. Clinical trial or n v. None | Measured up to 3 months from initial diagnosis | 
| Overall survival | i. Time from initial diagnosis to date of death or last follow up. ii. 1 year and 2-year overall survival rates will be calculated for the intervention group, and compared to baseline. | Measured up to 1 year from the time of randomization to death from any cause | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Next Generation Sequencing, Liquid biopsy, Newly diagnosed, Molecular testing, Plasma based next generation sequencing, Electronic health record, Nudge intervention, Targeted therapy, Behavioral economics