Abstract P2-13-03: Feasibility of generating an external control comparator using RWD by matching with previously conducted RCTs: CDK4/6 Inhibitors for the treatment of Metastatic Breast Cancer
Authors: Osgood Christy , Fan Jiaxin , Gao Xin , Keane Catherine , Bryan Jonathan , Roose James P. , Bloomquist Erik , Torres Aracelis , Baxi Shrujal , Nussbaum Nathan , Rizvi Fatima , Tang Shenghui , Nunes Irene , Beaver Julia , Rivera Donna R. , Howie Lynn , Paliwal Prashni , Amiri-Kordestani Laleh 
Published: March 2023

Abstract
Objectives: Real-world data (RWD) from the clinical care of patients captured through Electronic Health Records (EHRs) is a valuable resource for research. Understanding the relationship between characteristics and outcomes of patients treated in the real world and in oncology clinical trials by producing evaluable trial-like populations from RWD can advance clinical and regulatory knowledge.
Methods: RWD from the Flatiron Health EHR-derived, de-identified, longitudinal database were compared with pooled patient-level data from the three randomized controlled trials (RCTs) supporting regular approval of CDK4/6 inhibitors for patients with previously untreated hormone receptor-positive, HER- metastatic breast cancer (mBC). The RCT group included patients who received aromatase inhibitor (AI) monotherapy (RCT-control), and an experimental group (RCT-experimental) that received a cyclin dependent kinase 4/6 (CDK4/6) inhibitor + AI. The real-world control group (rwCG) of patients initiating AI monotherapy was selected using the key eligibility criteria across the RCTs. Patients from the rwCG were matched to the RCT-control and the RCT-experimental patients, respectively. Matching (1:1) was performed through the propensity score (PS) method adjusting for baseline covariates of age, race, site of disease, ECOG PS, and metastatic disease (recurrent, De novo). Multiple imputation (MI) was adopted to impute missing ECOG PS in the rwCG due to the high percentage of missingness. Progression-free survival (PFS) and overall survival (OS) were analyzed for the following groups: A) rwCG and RCT- control B) rwCG and RCT-experimental and C) RCT-control and RCT-experimental. To assess the feasibility of RCT control arm replication, we assessed whether the trial replication hazard ratio (HR) estimates from analysis B were within the published trial estimates’ 95% confidence intervals (CIs). HR and their 95% CIs were estimated using Cox proportional hazard model.
Results: A total of 1292 patients were selected from the EHR-derived database to comprise the rwCG and 1827 patients were pooled across the RCTs (1106 for RCT-experimental and 721 patients for RCT-control). With MI, 520 rwCG patients were matched to the RCT-control for analysis A, and 658 rwCG patients were matched to the RCT-experimental for analysis B. The results are summarized in Table 1. The point estimate of the PFS HR comparing the rwCG to the RCT-experimental was within the 95% CIs for three RCTs. For OS, the point estimate of the HR was within the 95% CI for MONALESSA-2 but not for PALOMA-2.
Conclusion: PFS and OS appeared longer in the RCT-control than in the rwCG, and the difference was more pronounced in OS. While it appears that there is greater similarity for PFS than for OS based on the results of the matched analysis of RCT- experimental vs. rwCG, evaluation of PFS results are limited by substantial differences in assessment and outcome definitions for progression between RCT-control (RECIST) and rwCG. Despite PS matching, there are apparent differences between patients treated in RCTs and routine practice, highlighting the importance of clinical setting, trial selection, study design, and use of randomization. There are still outstanding feasibility questions on the evaluation of OS and further research is required to understand factors potentially impacting the outcomes between RCTs and RWD.
Table 1: Estimated Treatment Effects in PFS and OS, rwCG vs RCT-control vs RCT-experimental
Citation Format: Christy Osgood, Jiaxin Fan, Xin Gao, Catherine Keane, Jonathan Bryan, James P. Roose, Erik Bloomquist, Aracelis Torres, Shrujal Baxi, Nathan Nussbaum, Fatima Rizvi, Shenghui Tang, Irene Nunes, Julia Beaver, Donna R. Rivera, Lynn Howie, Prashni Paliwal, Laleh Amiri-Kordestani. Feasibility of generating an external control comparator using RWD by matching with previously conducted RCTs: CDK4/6 Inhibitors for the treatment of Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-03.