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%.

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