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

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%.