STRATEGIC-1: Multi-line therapy trial in unresectable wild-type KRAS/NRAS/BRAF metastatic colorectal cancer—A GERCOR-PRODIGE randomized open-label phase III study.

3504 Background: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic and anti-epidermal growth factor receptor (EGFR) agents have become available. Ultimately, strategy trials are needed to define the optimal use and the best sequencing of these agents. Methods: Patients with previously untreated RAS/BRAF wild-type unresectable mCRC were randomly assigned (1:1 ratio) to receive either FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab (arm A) or OPTIMOX-bevacizumab followed by FOLFIRI-bevacizumab followed by EGFR mab +/- irinotecan (arm B). This trial was designed as a superiority study (hypothesis arm B > arm A) with Duration of Disease Control (DDC) as primary endpoint, defined as the sum of PFS of each active sequence of treatment (Chibaudel B, J Clin Oncol, 2011). Secondary endpoints were overall survival (OS), Time to Failure of Strategy (TFS), Progression-free survival (PFS) and response rate (RECIST version 1.1) per sequence, salvage surgery rate, safety, and Quality of life (QoL). Results: Between October 2013 and May 2019, 263 eligible patients were randomized (arm A, n = 131; arm B, N = 132). After a median follow-up of 51.2 months (95% CI 43.3-57.4), 188 events for DDC were observed. Efficacy outcomes are presented in table. Median DDC was similar in both arms (HR 0.97, 95% CI 0.72-1.29; P = 0.805). Salvage surgery for metastasis (+/- radiofrequency ablation) was done in 36 (27.5%) patients in arm A and 28 (21.2%) in arm B. Median time until definitive deterioration of QoL (global health status) were 18.3 and 18.0 months (P = 0.628). The safety profiles were consistent with the established safety profiles of each treatment regimen. Conclusions: STRATEGIC-1 is the first randomized phase III study comparing multi-line standard treatment strategies in patients with KRAS/NRAS/BRAF wild-type mCRC. This study did not meet its primary endpoint of DDC. The treatment strategy starting with FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab led to higher response rates and to a trend for better median OS exceeding 3 years. These findings may add to our understanding of treatment sequencing in mCRC. Clinical trial information: NCT01910610. [Table: see text]