Exploratory analysis of baseline microsatellite instability (MSI) status in patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) or placebo in the phase 3 CORRECT trial

Abstract

Background: A high degree of MSI (MSI‐H) has been associated with a good prognosis in early‐stage CRC. However, emerging evidence suggests that MSI‐H patients may have a worse response to chemotherapy in the metastatic setting. Here, we evaluate survival outcomes by baseline MSI status in patients with mCRC in the CORRECT phase 3 trial. Methods: CORRECT was an international, multicenter, placebo‐controlled trial of 760 patients with treatment‐refractory mCRC. Patients were randomized 2:1 to receive oral REG 160 mg or placebo once daily for Weeks 1‐3 of each 4‐week cycle. Subgroup analysis included patients in the safety population (≥1 dose of study drug) who consented to genetic biomarker studies and from whom archival tissue was available. Nextgeneration sequencing of archival tumor was performed using the FoundationONE gene panel (Foundation Medicine, Cambridge, MA). Overall survival (OS) and progression‐free survival (PFS) by MSI status and its potential interaction with treatment were assessed by a Cox proportional hazards model and Kaplan‐Meier analysis. Results: Archival tumor tissue was available for 229 of the 760 randomized patients (Table). Of the 229 patients, 42 (18%) were MSI‐H and 187 (82%) were non‐MSI‐H, 62% were male, 57%/43% were ECOG performance status 0/1, 58% had a KRAS mutation, and 3% had a BRAF mutation. Although there was less clinical benefit in patients in the MSI‐H subgroup, no significant association was detected between MSI status and treatment interaction with OS or PFS in the multivariate analysis (P=0.15). Conclusions: This retrospective exploratory analysis of a small subgroup of patients with mCRC from CORRECT shows a prevalence of MSI‐H at ∼15‐20% and no interaction between MSI status and REG treatment benefit. Due to small sample sizes in the subgroups no firm conclusions can be drawn and further studies are necessary to assess the correlation of MSI status with REG clinical benefit. (Table Presented).