LAUSR

3121 Background: TEXCAN, a prospective phase II GERCOR study of treatment with REGO in chemorefractory metastatic colorectal cancer (mCRC) patients (NCT02699073) included a prospective pharmacokinetic (PK) ancillary study aiming to investigate correlations between OS and concentrations (C) of REGO and its active metabolites M-2 and M-5. Methods: 55 patients were included, with the same inclusion/exclusion criteria as CORRECT (NCT01103323), and treated orally with 160 mg REGO daily for 3 weeks on and 1 week off. 34 patients had PK samples at C1D15 and 26 at C2D15 for Cmin. REGO, M-2 and M-5 Cmin were measured by LC-MS/MS. PK analyses studied the link between OS and PK parameters: Cmin of REGO, M-2 and M-5 at C1 and accumulation of pharmacological active metabolites between C1 and C2, assessed by the C2/C1 ratio of M-2 or M-5 Cmin concentrations. Results: REGO, M-2 and M-5 Cmin [median (Q1-Q3)] were respectively 1.99 (1.03-2.73), 1.44 (0.89-2.49) and 1.61 (0.79-2.37) mg/L at C1D15 and 1.90 (1.10-2.76), 1.29 (0.77-2.24) and 1.17 (0.45-2.42) mg/L at C2D15. C2/C1 M-2 ratio and M-5 ratio medians were 0.82 (0.50-1.78) and 0.75 (0.41-1.93), respectively. Univariate analyses showed a major OS benefit in patients with C2/C1 M-2 ratio ≥median vs < median (12.6 vs 4.0 months respectively, hazard ratio = 0.35, 95% confidence interval 0.14-0.86, p-value = 0.023) but not for C2/C1 M-5 ratio ≥median. Multivariate analyses, including the CORRECT REGOSCORE groups, showedan independent 66% reduction in death risk in the group of patients with C2/C1 M-2 ratio ≥median. The C2/C1 M-2 ratio correlated with C1 REGO+M-2+M-5 (Csum) (0.53, p-value = 0.006). Restricted Cubic spline analysis showed an increased OS benefit as the C2/C1 M-2 ratio rises and when C1 Csum ranged between 2.5 and 5.5 mg/L. PK parameters were not associated with toxicities. Conclusions: M-2 accumulation between C1 and C2 is independently associated with improved OS in mCRC patients treated by REGO. M-2 accumulates and OS is favorable when C1 REGO+M-2+M-5 sum ranged between 2.5 and 5.5 mg/L. These results may lead to develop individual REGO dosage modification strategies based on PK monitoring. Clinical trial information: NCT02699073.