Emulation of the KEYNOTE-042 (NCT02220894) Trial Using Specialty Oncology Electronic Health Records Databases

Investigators are building an empirical evidence base for real world data through large-scale emulation of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)
• Intervention / Treatment: Drug: Initiation of pembrolizumab; Drug: Initiation of chemotherapy

Detailed Description

Randomized controlled trials (RCTs) are generally regarded as the gold-standard of evidence for establishing efficacy of medical products. However, real-world data (RWD) are increasingly used to complement evidence from RCTs. Yet, to have confidence in the accuracy of non-interventional studies medical products and their outcomes in oncology, investigators need to know what questions can be validly answered, with which non-interventional study designs, and which analysis methods are appropriate, given the data that is available. Building on a process from the RCT DUPLICATE initiative, EmulatioN of Comparative Oncology trials with Real-world Evidence (ENCORE) is the trial emulation discussed in this protocol, which is part of the expansion project specific to oncology and aims to emulate 12 randomized oncology RCTs using multiple EHR data sources.

The purpose of this protocol is to describe the emulation of the KEYNOTE-042.5 KEYNOTE-042 was Phase III, double-blind, randomised study assessing the efficacy and safety of pembrolizumab monotherapy (200 mg intravenously every 3 weeks for up to 35 cycles) versus investigator's choice of platinum-based chemotherapy (carboplatin plus paclitaxel or pemetrexed for 4-6 cycles, with optional pemetrexed maintenance for non-squamous histology) in patients with previously untreated advanced or metastatic non-small-cell lung cancer (NSCLC) without sensitising EGFR mutations or ALK translocations, and whose tumours expressed programmed death-ligand 1 (PD-L1) with a tumour proportion score (TPS) of 1% or greater. The trial had 3 co-primary analyses that focused on patients with PD-L1 TPS ≥50%, PD-L1 TPS ≥20%, and PD-L1 TPS ≥1%, respectively. The investigators will focus on the PD-L1 ≥50% subgroup as the primary analysis for this emulation because the vast majority of patients treated with pembrolizumab in clinical practice have PD-L1 ≥50%.

• Study Type: Observational
• Enrollment (Estimated): 770

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Somerville, Massachusetts, United States, 02145
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Subjects with histologically or cytologically confirmed advanced or metastatic NSCLC that is not amenable to curative-intent treatment

Description

Study Period:

ENCORE database 1 (EDB1): Patient identification period: 01/01/2011-04/30/2024 with follow-up information through data cut-off date on 04/30/2024

ENCORE database 2 (EDB2): Follow-up information through February 2023 (there is no specific time period restrictions for patient eligibility)

ENCORE database 4 (EDB4): Patient identification period: 10/01/2018-09/30/2023 with follow-up information through data cut-off date on 09/30/2023.

Inclusion Criteria:

• Age ≥18 years at treatment initiation
• Subjects with histologically or cytologically confirmed advanced or metastatic NSCLC that is not amenable to curative-intent treatment
• ECOG 0 or 1
• Line of therapy setting classified as "advanced" (EDB1) or "metastatic" (EDB2), or evidence of metastatic disease at treatment initiation (EDB4)
• PD-L1 ≥ 50%

Exclusion Criteria:

• Patients with documentation of prior chemotherapy administration for advanced/metastatic NSCLC
• Pembrolizumab group: patients with documented EGFR/ALK positivity
• Chemotherapy group: patients with documented EGFR/ALK positivity or missing/unknown EGFR/ALK status
• Missing/unknown or PD-L1 < 50%
• Patients with any documentation of an investigational agent within 4 weeks prior to initiation of first-line pembrolizumab/chemotherapy
• Squamous patients with any documentation of prior carboplatin plus paclitaxel
• Patients with any documentation of chemotherapy or biologic therapy within 3 weeks prior to initiation of first-line pembrolizumab/chemotherapy
• Patients with documentation of prior immunotherapy administration
• Patients with any prior non-lung malignancy diagnosis (exceptions: basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, and in situ cervical cancer)
• Patients with documented autoimmune diseases within 2 years prior to treatment initiation
• Patients with documented interstitial lung disease
• Patients with documented CNS metastases

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Initiation of pembrolizumab; Exposure group	Drug: Initiation of pembrolizumab; Initiation of pembrolizumab (IV infusion) described in electronic health records is used as the exposure.
Initiation of chemotherapy; Reference group	Drug: Initiation of chemotherapy; Initiation of chemotherapy (carboplatin plus paclitaxel or pemetrexed for 4-6 cycles) described in electronic health records is used as the reference.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival [OS] - Time to all-cause mortality (OS)	Hazard ratio (95% CI) for overall survival	Time from the end of the treatment assessment window defined by the vendor's business rules to identify the line of therapy until the earliest of outcome, censoring, or end of data availability

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Food and Drug Administration (FDA)
• Investigators: Principal Investigator: Shirley Wang, PhD, ScM, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2026
• Primary Completion (Estimated): September 12, 2026
• Study Completion (Estimated): March 12, 2027

Study Registration Dates

• First Submitted: March 13, 2026
• First Submitted That Met QC Criteria: March 16, 2026
• First Posted (Actual): March 20, 2026

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: 2022P002556-ENC-KEYNOTE-042

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No