OBJECTIVES: External controls based on real-world data (RWD) are increasingly used to complement clinical trial data when assessing effectiveness of treatments in oncology. In the absence of randomization, comparisons between clinical trial and RWD have well-recognized risk of bias, arising from potential differences across these settings in patient populations, diagnostic testing, background therapies and outcome assessments. Suitability of RWD as external controls should be determined on a case-by-case basis considering the RWD source, study outcomes compared, and study design and analysis steps employed to address bias. Empirical assessment of consistency in outcomes across trial and RWD settings can also help assess suitability of external controls based on RWD.

METHODS: We compared overall survival (OS) in patients with metastatic BRAF V600-mutant melanoma treated with encorafenib plus binimetinib (ENCO+BINI) drawn from the phase 3 COLUMBUS trial and from Flatiron Health, an electronic medical records-derived database of primarily community oncology clinics in the US.

RESULTS: After applying key trial inclusion/exclusion criteria to the RWD, imputing missing baseline prognostic factors using multiple imputation, and adjusting for baseline prognostic factors, OS was similar in ENCO+BINI-initiating patients across trial (n=192) and RWD (n=83; hazard ratio (HR): 1.03; 95% CI: 0.53, 1.54) settings. Similar OS between trials (n=241) and RWD (n=816) from Flatiron was also reported in a previous analysis of patients with metastatic melanoma, regardless of molecular testing status, treated with ipilimumab (HR: 0.98 (0.75, 1.26)).

CONCLUSIONS: These findings of consistent OS with clinical trials after applying equivalent I/E criteria, and adjusting for differences in patient profiles and missing data are encouraging for the use of RWD from Flatiron to construct external controls for OS in BRAF+ metastatic melanoma. RWD may augment randomized control arms, provide a reference arm in long-term extension periods, contextualize trial outcomes, or be pooled with trial data to facilitate analyses based on more comprehensive evidence.