4481 - Undetectable RAS mutant clones in plasma: possible implication for therapy and prognosis in the patient with RAS mutant metastatic colorectal cancer?

Background

Combining Cetuximab with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with RAS wild type (RAS-wt) locally advanced or metastatic colorectal cancer (mCRC). Therefore, this active treatment excludes 60% of patients (pts) with muted primary tumor. We tested in this pilot study Cetuximab-based therapy in pts with RAS-wt in plasma whose primaries were RAS muted (RAS-mt).

Methods

We analysed KRAS, NRAS, BRAF and PI3KCA mutations in plasma using a new and ultra-sensitive analysis based on mass spectrometry detection (MassARRAY System with Ultra SEEK technology; detection of 0.1% muted alleles) in pts with histological confirmed RAS-mt mCRC after consent. Pts with plasma RAS-wt whose diseases were progressive received Cetuximab-FOLFIRI while plasma RAS-mt pts received investigator’s proposal therapies.

Results

Sixteen pts were registered in three centers. There were 11 males (69%) and 5 females (31%) aged 48 to 81 years (median, 69) with unresectable metastatic adenocarcinoma from colon cancer (9 pts, 56%) and rectum cancer (7 pts, 44%). They had a median of 2 metastatic sites (1 to 4) and had previously received 1 to 4 chemotherapy lines (median, 3). Plasma genotyping showed RAS-mt in 7 patients (44%) and RAS-wt in 9 patients (56%). The 9 pts with plasma RAS-wt received 1 to 16 courses of Cetuximab-FOLFIRI (median, 6). We observed as best response, 1 complete response, 3 partial responses, and 1 progressive disease. Three pts were not assessed yet for efficacy. No grade 3-4 toxicity was encountered. At the cut-off time on 2019.04.23, median follow-up was 5.3 months (0.3 to 19.5). Survival rate were 77.8% (7/9) and 28.6% (2/7) for pts with RAS-wt and RAS-mt respectively. Median overall survival was not reached for pts with RAS-wt whereas it was 4.7 months [95%CL, 0.0-9.6] for RAS-mt pts, p (Log Rank)=0.001.

Conclusions

Our finding suggests that pts with RAS-mt mCRC whose plasma biopsies are RAS-wt could benefit from cetuximab-based therapy. As a result to these preliminary data, we have planned a phase II study targeting the plasma RAS-wt with EGFR inhibitors in first line mCRC.

Clinical trial identification

Editorial acknowledgement

AK-SCIENCE, Vitry-Sur-Seine, France.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.