CARE Initiative: Real-world Emulation of the KEYNOTE-189 Trial [DS3]

The Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation (CARE) Initiative is a program designed to build an empirical evidence base for the use of real-world data (RWD) in clinical and regulatory decision-making. Using randomized controlled trials (RCTs) as a benchmark for causal effect estimates, a series of RCT emulations will be conducted across varying trials, real world data sources, and study design elements to better understand under what conditions non-interventional studies, using data generated during routine clinical care, can provide reliable conclusions about drug effectiveness.

In this study, real-world electronic health record (EHR) data will be used to emulate the KEYNOTE-189 efficacy trial of pembrolizumab as first-line therapy in patients with metastatic non-small cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) sensitizing mutations. Similarly to the KEYNOTE-189 trial, this study will compare real-world overall survival (rwOS) and real-world progression-free survival (rwPFS) between patients who initiate pemetrexed, platinum-based chemotherapy, and pembrolizumab, and patients who initiate pemetrexed and platinum-based chemotherapy alone.

Inclusion criteria

• Non-small cell lung cancer (NSCLC) diagnosis
• Histology not indicative of squamous cell carcinoma
• Metastatic disease
• Epidermal growth factor receptor (EGFR) and Anaplastic lymphoma kinase (ALK)-negative or Kirsten rat sarcoma viral oncogene homolog (KRAS)-positive
• No prior systemic treatment for metastatic NSCLC
• No record of adjuvant or neoadjuvant therapy in the 12 months before metastatic diagnosis
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or missing or Karnofsky performance status >=70 or missing
• No lab results indicating inadequate organ function, as defined in the KEYNOTE-189 RCT protocol

Exclusion criteria

• Histology indicative of squamous cell carcinoma or small cell elements
• Prior systemic treatment for metastatic NSCLC
• Prior antineoplastic biological therapy
• History of major cancer-related surgery in the 3 weeks before study drug initiation
• Radiation therapy to the lung >30 Gy in the 6 months before study drug initiation
• Prior diagnosis of clinically active diverticulitis, intra-abdominal abscess, or gastrointestinal obstruction
• Diagnosis of a second primary malignant neoplasm
• Diagnosis of brain, central nervous system, and/or spinal cord metastases
• Diagnosis of autoimmune disease and treatment with corticosteroids or immunosuppressive drugs after diagnosis and within the 2 years prior to study drug initiation
• Treatment with a non-topical systemic steroid in each of the 6 months prior to study drug initiation
• Prior treatment with pembrolizumab or any other anti-PD-1, PD-L1, PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms
• Treatment with non-topical antibiotics, antifungals, or antivirals within 2 weeks after an infection diagnosis in the month prior to study drug initiation
• Diagnosis of human immunodeficiency virus infection
• Diagnosis of acute hepatitis B or C
• Diagnosis of ascites or plural effusion in the 3 months prior to study drug initiation
• Prior diagnosis of interstitial lung disease or diagnosis of pneumonitis and record of treatment with glucocorticoids within 30 days