367P - Prospective evaluation of emergent RAS and BRAF mutations in pre-treated metastatic colorectal cancer patients candidate to anti-EGFR re-treatment: Preliminary findings from the PARERE study

Background

Retreatment (re-tx) with anti-EGFRs is a promising strategy in RAS/BRAF wild-type (wt) anti-EGFR pre-treated metastatic colorectal cancer patients (mCRC pts), provided that no mechanisms of acquired resistance to anti-EGFRs are found in circulating tumor DNA (ctDNA). The phase II single arm CHRONOS study showed a 31% prevalence of RAS/BRAF mutations (mut) in ctDNA of pts candidate to anti-EGFR re-tx. We are now conducting a phase II randomized study, PARERE, to compare panitumumab followed by regorafenib versus the reverse sequence as treatment strategy in anti-EGFR pre-treated chemorefractory pts with RAS/BRAF wt ctDNA. Here we show initial results from the molecular screening.

Methods

RAS/BRAF wt mCRC pts who achieved ≥6 months (mo) benefit with a previous anti-EGFR based tx and received ≥1 subsequent anti-EGFR free tx lasting ≥4 mo were eligible. ctDNA was analysed with the Next Generation Sequencing Ion Torrent^TM Oncomine^TM cfDNA Colon assay, enabling parallel profiling of 14 genes.

Results

101 pts were screened and ctDNA was successfully assessed in 91 (90%). Among them, 25 (28%) harboured KRAS/NRAS/BRAF V600E mut, with co-mut of KRAS and BRAFV600E genes in 2 pts (8%). Within the RAS/BRAF wt cohort (n=65), mut in at least another gene were found in 49 pts (75%). In particular, TP53, APC, PIK3CA, FBXW7, GNAS, EGFR, AKT and SMAD4 mut occurred in 39 (60%), 24 (36%), 8 (12%), 7 (11%), 2 (3%), 1 (1%), 1 (1%) and 1 (1%) cases, respectively. No mut in ERBB2, CTNNB1 and MAP2K genes were found. The overall limit of detection was 0.07% [95% CI: 0.06-0.09%] and the median variant allele fraction of RAS/BRAF genes was 0.32% [95% CI: 0.23-1.70%]. The median anti-EGFR free interval did not differ between the group with RAS/BRAF wt and RAS/BRAF mut ctDNA (13.8 [95% CI: 12-18.3] and 16.9 mo [95% CI: 10.6-24.6], respectively, p=0.70).

Conclusions

This is the largest series of pts prospectively screened for anti-EGFR re-tx. About 1 out of 3 pts bear RAS or BRAF mut in their ctDNA. Anti-EGFR free interval is not a valuable surrogate of ctDNA mut status, thus supporting liquid biopsy as a selection tool for clinical trials in this setting and for the use of anti-EGFR re-tx in the real life.

Clinical trial identification

NCT04787341.

Editorial acknowledgement

Legal entity responsible for the study

GONO (Gruppo Oncologico del Nord Ovest).

Funding

GONO, Amgen, Bayer.

Disclosure

D. Rossini: Financial Interests, Personal, Invited Speaker: Takeda. C. Cremolini: Financial Interests, Personal, Advisory Board: Roche, MSD; Financial Interests, Personal, Invited Speaker: Bayer, Servier; Financial Interests, Personal, Expert Testimony: Amgen; Financial Interests, Institutional, Invited Speaker: Roche, Bayer, Servier, Merck. All other authors have declared no conflicts of interest.