Circulating Tumor Dna (Ctdna) Heterogeneity As First- And Third-Line Treatment In Patients (Pts) With Metastatic Colorectal Cancer (Mcrc) Treated With Panitumumab

238 Background: RAS mutations are negative predictors of response to anti-EGFR therapies such as panitumumab in mCRC. Mutations at baseline (BL) and follow-up (FU) during randomized phase 3 studies of first line treatment (1L; study 20050203 [‘203]; panitumumab + fluorouracil, leucovorin and oxaliplatin [FOLFOX4] vs FOLFOX4) were compared with those in third line treatment (3L; study 20100007 [‘0007]; panitumumab + best supportive care [BSC] vs BSC) to assess tumor heterogeneity via ctDNA analysis. Methods: Biomarker analysis was conducted for pts with plasma samples at BL and FU. Samples were analyzed using the Plasma Select-R 63-gene panel (Personal Genome Diagnostics, Inc.), with a limit of detection of 0.1%. Mutations were defined at the amino acid level. The Cox hazard ratio (HR) by sum of RAS mutant allele frequency (MAF) was determined, as were event-free survival (EFS) and best response by RAS mutation status. Results: For all pts with available samples (‘203, n = 120; ‘0007, n = 90), fewer mutations and fewer mutations/gene were observed in the 1L vs 3L setting at BL ( KRAS 2 vs 3 maximum mutations/gene; EGFR 1 vs 4 maximum mutations/gene). In 3L the Cox HR increased continuously with RAS MAF; while this was not found in 1L. In the 1L setting, emergent RAS mutations were not predictive of EFS for FOLFOX4, but were predictive of shorter EFS for panitumumab + FOLFOX4. More panitumumab-treated pts in the 3L setting had detectable RAS mutations emerging from BL to FU (28.6%, 57.1%) vs pts treated in 1L (24.5%, 26.5%). For pts who achieved a partial response, more treated in 1L maintained a higher frequency of wild-type RAS from BL to FU (84.4%, 78.1%) vs pts treated in 3L (95.7%, 43.5%). Conclusions: The overall mutational landscape differs between the 1L vs 3L setting in anti-EGFR–treated mCRC pts. Panitumumab monotherapy in the 3L setting appears to induce greater RAS-specific selective pressure than panitumumab FOLFOX4 combination therapy in 1L, resulting in increased RAS mutations at FU in the 3L setting. The combination of panitumumab + FOLFOX in 1L is associated with delayed emergence of expansion of RAS mutations compared to later line single agent panitumumab.