1938P Profiling of circulating tumour DNA for treatment selection in patients with advanced and refractory carcinoma: A prospective, two-stage phase II individualized cancer treatment trial

Abstract

Precision oncology trials have typically been based on molecular profiling (MP) of tissue biopsy-derived DNA. In this trial we aimed to evaluate the success of a targeted therapy selected by MP of circulating tumor DNA (ctDNA) in patients with advanced and refractory carcinoma in a prospective setting. Molecular profiles, which were established on ctDNA and an optional tissue biopsy were reviewed at a molecular tumor board in order to identify and match a MP-based treatment. The primary endpoint was the progression-free survival (PFS) ratio (PFS on MP-guided therapy / PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ≥ 1.2. Secondary endpoints were the number of patients for whom an anti-tumor drug could be defined based on the MP, the overall survival and the overall radiographic response rate. In order to test the impact of MP-treatment matching strategies, we retrospectively analyzed selected cases via the CureMatch PreciGENE™ decision support algorithm. After inclusion of 24 patients, an interim analysis was performed and the study was terminated due to slow patient accrual and lack of clinical benefit. MP yielded informative results from 20 patients (83%), a potential tumor-specific drug could be matched in 11 out of 24 patients (46%) and eight patients (33%) received a matched treatment. Median PFS in the matched treatment group was 61.5 days (IQR 49.8-71.0) compared to 81.5 days (IQR 68.5-117.8) for the last evidence-based treatment, resulting in a median PFS ratio of 0.7 (IQR 0.6-0.9). Whereas database-based molecular profiling matching suggested mainly single drugs, the retrospective CureMatch analysis identified either a 2-drug or 3-drug combination option in each of the tested cases, including a case for which no therapy was previously identified. This study is first to report prospective outcome results on the efficacy of plasma DNA profiling-based treatment, but it challenges the routine use of this procedure for treatment selection in advanced cancer patients outside of clinical trials.