199 Background: Fruquintinib is a highly selective, oral inhibitor of all 3 vascular endothelial growth factor receptors. The phase 3 FRESCO-2 (NCT04322539) study demonstrated a significant survival benefit with fruquintinib + best supportive care (BSC) vs placebo + BSC as third or later line of therapy for patients (pts) with metastatic colorectal cancer (mCRC). Based on FRESCO-2, fruquintinib is approved, including in the US and EU, for previously treated mCRC, irrespective of biomarker status. This analysis aimed to evaluate baseline (BL) circulating tumor DNA (ctDNA) and mutation profiles, as well as post-treatment (tx) changes in ctDNA and their potential correlation with clinical outcomes. Methods: Plasma samples collected at BL (n=26) and Cycle 3 Day 1 (C3D1) post-tx (n=7) from pts in FRESCO-2 were analyzed using the Guardant Infinity tissue-free ctDNA detection and quantification platform. BL assessments included genomic profiling, tumor mutational burden (TMB), and tumor fraction (TF) measured by methylation. For pts in the fruquintinib arm with paired BL and post-tx (C3D1) samples, genomic and methylation molecular response (MR) scores were calculated using Guardant’s validated MR algorithm. Associations with overall survival (OS) and progression-free survival (PFS) were evaluated. Results: All plasma samples tested had detectable ctDNA levels at BL and 52% of pts were identified as TMB-high (≥20 mutations/Mb). The most frequently mutated genes included APC , KRAS , and TP53 , across both tx arms. BL TF was comparable between pts in the fruquintinib (n=17) and placebo (n=9) arms, and was observed to be higher in TMB-high pts. Overall, baseline TF levels above the cohort median were associated with shorter OS, regardless of tx arm, although the sample numbers were low (n=26). No significant associations were observed between BL mutation status of TP53 , KRAS , or PIK3CA and OS/PFS. Of the 6 pts in the fruquintinib arm who achieved a best overall response of stable disease, 5 demonstrated a reduction in ctDNA levels with a concordant decrease in both genomic and methylation MR scores at C3D1 compared to BL. Of these 5 pts, 3 met the criteria for molecular responders, defined as ≥50% decrease in ctDNA. Conclusions: This preliminary analysis suggests that ctDNA-based biomarkers, including TMB and methylation TF, may offer prognostic insights in pts with mCRC and support MR evaluation. The concordance between genomic and methylation MR and the observed associations with clinical outcomes underscores the utility of methylation-based ctDNA assessments as a potential tool for predicting the therapeutic benefit of fruquintinib. Due to limited sample numbers, this analysis warrants further investigation in larger cohorts to better understand the relationship between BL ctDNA parameters, early changes following fruquintinib tx, and clinical outcomes. Clinical trial information: NCT04322539 .
Dasari et al. (Sat,) studied this question.