A feasibility analysis to align fit-for-purpose real-world (RW) data to emulate the AZUR-1 single-arm clinical trial in patients (pts) with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (RC).

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70 Background: AZUR-1, a clinical trial (NCT05723562) evaluating dostarlimab for pts with dMMR/MSI-H stage II/III RC, has a single-arm design due to the rarity of dMMR/MSI-H in locally advanced RC, known clinical activity of dostarlimab, 1 and complications of the current multimodal standard of care (SOC). A robust natural history study (NHS) using RW data has been designed to contextualize AZUR-1 efficacy and inform regulatory decisions. Methods: The US-based Flatiron Health research database was confirmed to be fit-for-use for the planned NHS and includes RW data needed to define key study variables to emulate the AZUR-1 trial such as pt baseline clinical characteristics, SOC, tumor response assessments, disease progression, and mortality. A preliminary feasibility assessment sample of 50 pts with dMMR/MSI-H locally advanced RC (data cutoff date: Feb 28, 2023) was conducted to confirm the data quality for these key variables. Results: For the 50 assessed pts, median age (interquartile range [IQR]) was 56 (48, 65) years; 54% were female and 72% were White. Median year of diagnosis was 2018 and median (IQR) duration of follow-up (f/u) was 32.3 (11.2, 63.1) months (mo); over 70% of pts had ≥12 mo of f/u from locally advanced RC diagnosis (n=36). Only 56% of pts had known dMMR/MSI-H status before starting treatment (tx), rising to 71% within 3 mo after tx initiation. All pts had known dMMR/MSI-H status by end of f/u or by metastatic diagnosis. Pts received the following tx at any time in their tx journey: systemic therapy (88%), any radiotherapy (78%), surgery (66%). The majority of pts received chemoradiotherapy (58%). Five (10%) pts received radiotherapy only and 2 (4%) pts received surgery only. The most common systemic therapies were FOLFOX and capecitabine, administered to 52% and 48% of pts, respectively. Few pts were treated with immunotherapies (pembrolizumab 6%; nivolumab 4%). Most pts (92%) had ≥1 radiographic disease assessment and 1 endoscopic disease assessment between diagnosis and first distant recurrence or end of f/u. Median (IQR) time from end of initial treatment to first disease assessment was 1.7 (0.7, 3.4) mo. Conclusions: The pt distributions in the feasibility sample aligned with existing clinical data in this population, indicating representativeness for dMMR/MSI-H locally advanced RC. The sample also highlighted the need for routine biomarker testing in locally advanced RC prior to tx initiation. The common data model will be implemented in the full NHS to ensure the study can emulate the AZUR-1 population and reflect the current RW SOC and treatment outcomes to the extent possible for RW data. 1 Cercek et al. NEJM 2025;392:2297–2308. Funding: GSK (Study 222330). Medical writing support was provided by Avalere Health, funded by GSK. Clinical trial information: NCT05723562 .

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