CARE Initiative: Real-world Emulation of the KEYNOTE-189 Trial [DS4]

The goal of this non-interventional study is to emulate the KEYNOTE-189 randomized controlled trial of pembrolizumab for the treatment of metastatic non-small cell lung cancer using real-world, electronic health record data. The main questions this study aims to answer are:

1. Do patients with metastatic non-small cell lung cancer (NSCLC) treated with pemetrexed, cisplatin/carboplatin, and pembrolizumab have improved real-world overall survival (rwOS) and real-world progression-free survival (rwPFS) compared with patients treated with pemetrexed and cisplatin/carboplatin alone?
2. How do the results of this non-interventional study compare to those of the KEYNOTE-189 randomized controlled trial?

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.

Eligibility Criteria:
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
* Receipt of an investigational agent or device in the 4 weeks before study drug initiation

  * 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 rheumatic disease in the 2 years prior to study drug initiation
  * Prior treatment with pembrolizumab or any other anti-PD-1, PD-L1, PDL2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms
  * Diagnosis of human immunodeficiency virus infection