An Emulation of the KEYNOTE-189 Trial Using Electronic Health Records


Merola D1, Campbell U2, Lenis D2, Madsen A2, Schneeweiss S3, Wang S3, Carrigan G4, Taylor A5, Huang J5, Chia VM4, Ovbiosa O6, Pinheiro S6, Pace ND6, Bruno A7, Stewart M8, Khosla S9, Zhang Y9, Rimawi M10, Hendricks-Sturrup R11, Locke T11, Jiao X12, Becnel L12, McRoy L12, Rabon-Stith K13, Eckert JC14, Rodriguez-Watson C14, Lunacsek O7, Harvey R15, Greshock J15, Sarsour K15, Belli A16, Wang C16, Fernandes L16, Chen J17, Natanzon Y18, Dhopeshwarkar N19, Wasserman A20, Quinn J20, Taylor B2, Rider J2
1Aetion, Inc, Natick, MA, USA, 2Aetion, Inc, Boston, MA, USA, 3Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA, 4Amgen Inc., Thousand Oaks, CA, USA, 5Gilead Sciences, Foster City, CA, USA, 6AbbVie, North Chicago, IL, USA, 7Bayer Healthcare Pharmaceuticals, Inc., Whippany, NJ, USA, 8Friends of Cancer Research, Washington, DC, USA, 9AstraZeneca, Gaithersburg, MD, USA, 10Baylor College of Medicine, Houston, TX, USA, 11Duke Margolis Center, Washington, DC, USA, 12Pfizer, New York, NY, USA, 13Pfizer, Gaithersburg, MD, USA, 14Reagan-Udall Foundation for the FDA, Washington DC, DC, USA, 15Johnson and Johnson, New Brunswick, NJ, USA, 16COTA, Inc, Boston, MA, USA, 17Tempus, Chicago, IL, USA, 18ConcertAI, Cambridge, MA, USA, 19TriNetX, Cambridge, MA, USA, 20xCures, Oakland, CA, USA

OBJECTIVES: As a pilot exercise to assess feasibility of using routine clinical practice data to duplicate randomized control trial (RCT) design, we attempted to emulate the KEYNOTE-189 RCT using real-world data (RWD), and report findings from comparing the results.

METHODS: We used a US electronic health record (EHR) database linked with a tumor registry to retrospectively construct a study cohort. Consistent with the RCT, patients with metastatic non-squamous non-small cell lung cancer were included; patients with prior first-line treatment for metastatic disease, primary non-lung malignancies, and EGFR/ALK mutations were excluded. Mortality outcomes in initiators of pembrolizumab and chemotherapy vs. chemotherapy alone were compared in intent-to-treat analyses. The mortality hazard ratio and 12-month survival probabilities were estimated using Cox regression and the Kaplan-Meier estimator, respectively. Inverse probability of treatment weighting was used to control for potential baseline confounders.

RESULTS: There were 589 pembrolizumab initiators and 1,265 chemotherapy-only initiators. The mortality hazard ratio was 0.95 (95% CI: 0.78, 1.16) in the RWD study versus 0.49 (95% CI: 0.38, 0.64) in the RCT. The 12-month survival probabilities were 0.60 (95% CI: 0.54, 0.65) vs. 0.58 (95% CI: 0.55, 0.62) in the pembrolizumab and chemotherapy groups, respectively, compared with 0.69 (95% CI: 0.64, 0.74) and 0.49 (95% CI: 0.42, 0.56) in the RCT. In the RWD study, substantial treatment crossover was observed, and the results were robust to sensitivity analyses. A post-hoc subgroup analysis of de novo metastatic patients, identified using the linked tumor registry only, was aligned with the RCT.

CONCLUSIONS: Results of this EHR-based emulation were incongruous with those of the benchmark RCT, but consistent with other investigators’ emulation attempts. Treatment crossover and accuracy of captured diagnoses may explain these findings and should be considered in population selection and other features of future RWD study designs for oncology treatment questions.

Conference/Value in Health Info

2024-05, ISPOR 2024, Atlanta, GA, USA

Value in Health, Volume 27, Issue 6, S1 (June 2024)




Clinical Outcomes, Study Approaches

Topic Subcategory

Comparative Effectiveness or Efficacy, Electronic Medical & Health Records



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