Eric Van Cutsem

Background: Synthetic control arms (SCAs) derived from historical trial data can complement randomized controlled trials (RCTs), particularly in oncology, where feasibility, ethical, and cost constraints may limit conventional trial designs. However, their validity for overall survival (OS) remains uncertain. We evaluated the feasibility and limitations of constructing SCAs from the ARCAD metastatic colorectal cancer (mCRC) database across multiple treatment lines. Methods: Seven landmark RCTs representing first-, second-, and third-line settings were selected. External control arms were constructed from Aide et Recherche en Cancérologie Digestive (ARCAD) individual patient-level data using propensity score matching based on key clinical and biological variables from a validated ARCAD prognostic score, with adjustment for geographic region and time era when needed. A prespecified 2-step benchmarking framework assessed: (1) control-arm OS reproducibility and (2) virtual trial comparisons between matched synthetic controls and original RCT experimental arms. Agreement was evaluated using hazard ratios (HRs) and Z-tests. Results: A total of 28 022 patients met the inclusion criteria. ARCAD-derived SCAs were successfully constructed for all selected RCTs and closely reproduced control-arm OS. After matching, baseline characteristics were well balanced, with minimal differences between included and excluded patients. Virtual trials showed concordant treatment-effect estimates with the original RCTs, with a median absolute HR deviation of 0.05 and no significant differences by Z-tests (P > .05). Survival outcomes were consistently reproduced across treatment lines. Conclusion: ARCAD-derived SCAs reliably reproduced control-arm OS and benchmark treatment-effect estimates from landmark RCTs in mCRC. Despite limitations related to residual confounding and missing data, this framework supports benchmarking, trial design, and exploratory analyses when conventional control arms are impractical.

Pharmacokinetic parameters for BI 905711 as monotherapy (NCT04137289)a.

Summary of the most frequently reported adverse events by CTCAE preferred term for BI 905711 as monotherapy (>10% of patients) or combination therapy (≥25% of patients).

Representativeness of study participants with advanced CRC.

Baseline demographics and disease characteristics.

Pharmacokinetic parameters (AUC0–336 and Cmax) after infusion of BI 905711 (0.02–4.8 mg/kg) during cycles 1 and 3 of (A) monotherapy study (NCT04137289) and (B) combination study (NCT05087992). Ia, study phase Ia; Ib, study phase Ib; Q2W, every 2 weeks. For numbers of evaluable patients in cycles 1 and 3, refer to Table 4.

Effect of BI 905711 monotherapy on plasma caspase 3/7 activity in patients with advanced GI cancers (n = 104)a. N/A, not applicable; Q1W, every 1 week; Q2W, every 2 weeks. aThe figures show caspase 3/7 activity levels in cycles 1 and 3 for the BI 905711 monotherapy study (NCT04137289). Baseline correction was done to the predose of cycle 1. The blue lines represent patients who showed a ≥2-fold increase in caspase 3/7 activity in either one or both cycles, whereas the orange lines represent patients who did not show a ≥2-fold increase in caspase 3/7 activity. A filled square indicates that the patient successfully achieved PFS of at least 4 months, whereas the open circle indicates a shorter PFS. A lack of symbol indicates missing PFS data.