Emulation of the KEYNOTE-189 Trial Using Electronic Health Records

Emulation of a Comparative Effectiveness Study of Pembrolizumab and Chemotherapy vs. Chemotherapy for the First-line Treatment of Metastatic Non-small Cell Lung Cancer

Investigators are building an empirical evidence base supporting the utility of real-world data through the emulation of randomized controlled trials in the oncology setting. The purpose of this work is to demonstrate whether real-world evidence studies can provide reliable conclusions on treatment effectiveness to inform further applications of real-world data in pharmaceutical product label expansion, post-marketing safety, and other purposes that are complementary to RCTs.

Study Overview

• Status: Completed
• Conditions: Metastatic Lung Cancer; Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Pembrolizumab + Pemetrexed-Platinum; Drug: Pemetrexed-Platinum

Detailed Description

This is a non-randomized observational study that is being conducted as a part of the Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation (CARE) Initiative, a multi-stakeholder collaboration led by Aetion. The study is intended to emulate the trial listed below/above. Although many features of the trial cannot be directly replicated in real-world data sources, key elements of the study design, including outcomes, exposures, and inclusion/exclusion criteria, were selected to proxy those features from the trial as closely as possible. Investigators assume that the trial provides the reference standard treatment effect estimate and that failure to replicate trial findings is indicative of the inadequacy of the real-world data source for replication for a range of possible reasons and does not provide information on the validity of the original trial finding.

• Study Type: Observational
• Enrollment (Actual): 1854

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02109
      • Aetion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Non-small cell lung cancer patients with evidence of metastatic disease and a subsequent record indicating a first-line treatment.

Description

Inclusion Criteria:

• Has evidence in electronic health record indicating a 'lung' tumor site, non-squamous morphology (e.g., adenocarcinoma, large cell, etc), and a stage IV or metastatic disease in the form of diagnosis codes or derived variables from physician notes or linked data from a tumor registry. There is no evidence of other lung cancer types (i.e., mesothelioma, small cell, etc.).
• Does not have evidence of HGVS codes in health record indicating EGFR or ALK mutations.
• Has no evidence of use of guideline-recommended systemic cancer therapy* for NSCLC on or after first date associated with stage IV (or metastatic) disease and prior to index treatment.

Exclusion Criteria:

• Has evidence of squamous cell lung cancer morphology in the form of diagnosis codes or derived variables from physician notes or linked information from a tumor registry.
• Has evidence of systemic cancer therapy utilization on or after first date associated with stage IV (or metastatic) disease and prior to index treatment. Patient has no evidence of biologic therapy at any time prior to the first record indicating an exposure of interest.
• Has evidence in medical record or tumor registry of primary malignancies beyond the lung tissue, except basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers.
• Has evidence of central nervous system (CNS) metastases and/or carcinomatous meningitis in the 2 weeks prior to initiation.
• Has a record of use of one of the following agents in the 2 years prior to the index date: methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, azathioprine, etanercept, adalimumab, infliximab, certolizumab, golimumab, anakinra, tocilizumab, sarilumumab, abatacept, rituximab, tofacitinib, barivitinib, upadacitinib, mycophenolate.
• Has at least two records 60 days apart indicating use of one of the following agents in the 3 months prior to the index date: prednisone, prednisolone, methylprednisolone, dexamethasone, hydrocortisone.
• Has evidence of use of one of the following agents prior to the index date: pembrolizumab, nivolumab, cemiplimab, atezolizumab, durvalumab.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Pembrolizumab + Chemotherapy; Exposure Group	Drug: Pembrolizumab + Pemetrexed-Platinum; Medication records in EHR database used to define exposure group
Chemotherapy; Reference Group	Drug: Pemetrexed-Platinum; Medication records in EHR database used to define comparator group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival - Mortality Hazard Ratio	Relative hazard of mortality due to any cause	Through study completion (earliest of 640 days or censoring)
Overall Survival - Mortality Risk	12-month survival probability	1 year, year 1

Collaborators and Investigators

• Sponsor: Aetion, Inc.
• Investigators: Principal Investigator: David Merola, PharmD, PhD, Aetion, Inc.

Publications and helpful links

General Publications

• Merola D, Campbell U, Gautam N, Rubens A, Schneeweiss S, Wang SV, Carrigan G, Chia V, Ovbiosa OE, Pinheiro S, Bruno A, Jiao X, Stewart M, Hendricks-Sturrup R, Rodriguez-Watson C, Khosla S, Zhang Y, Rimawi M, Huang J, Taylor A, Becnel L, McRoy L, Eckert J, Taylor B. The Aetion Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation Initiative: Oncology. Clin Pharmacol Ther. 2023 Jun;113(6):1217-1222. doi: 10.1002/cpt.2800. Epub 2022 Dec 7.

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2023
• Primary Completion (Actual): August 31, 2023
• Study Completion (Actual): August 31, 2023

Study Registration Dates

• First Submitted: June 7, 2023
• First Submitted That Met QC Criteria: June 14, 2023
• First Posted (Actual): June 18, 2023

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 8, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: oncology; comparative effectiveness research; pharmacoepidemiology; real-world data; real-world evidence
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Folic Acid Antagonists; Pembrolizumab; Pemetrexed
• Other Study ID Numbers: 1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data analysis code and de-identified patient-level data files may be made available, provided that it is determined that this will not violate the investigators' data usage agreements and patient privacy requirements.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No