Clinical outcomes and emergent circulating tumor (ct)DNA RAS mutations and allele fraction for patients with metastatic colorectal cancer (mCRC) treated with panitumumab from the ASPECCT study.

Abstract

3584 Background: ASPECCT was a phase III clinical trial performed in the chemotherapy-refractory third-line mCRC setting (N = 1010). This analysis explores the relationship between circulating levels of mutations and clinical outcomes for panitumumab-treated subjects using univariate and multivariate models that treat total mutational load as a continuous measure. Methods: 238 subjects treated with panitumumab had paired plasma samples at baseline and post-treatment (PT). Samples were analyzed for mutations using the Plasma Select-R™ 63-gene panel (0.1% limit of detection). The fraction of mutant RAS reads was evaluated for association with tumor response (by RECIST) and overall survival using univariate and multivariate Cox proportional hazards models. Results: 52% of the subjects who were RAS wild-type by plasma at baseline never developed a RAS mutation. For those with mutant RAS ctDNA ( KRAS+ NRAS) detected at baseline or PT, there was an overall increase in RAS mutant DNA fraction at PT compared to baseline. By non-parametric analysis, there was no difference in the distribution of baseline mutant RAS fraction between those who achieved stable disease (SD) or those with progression ( P = 0.09). There was also no difference in the increase in mutant RAS fraction on therapy between subjects with SD or progressive disease (PD). In addition, RAS mutation was not required for progression: 48% of subjects with PD had no RAS mutant DNA detected. Conclusions: In this exploratory analysis, baseline plasma mutant RAS fraction is an unreliable predictor of subsequent tumor response. Subjects with objective response or SD may have stable or rising levels of mutant RAS DNA. Subjects without any detectable RAS mutation still experience PD. These findings suggest that detectable plasma ctDNA RAS mutations do not necessarily predict response to panitumumab and should be interpreted with caution. Further work is needed to establish clinically relevant and validated thresholds. Clinical trial information: NCT01001377.