6MO - Evaluation of plasma assessed comprehensive genomic profiling before first-line treatment with FOLFIRI plus cetuximab in RAS/BRAFV600E wild type metastatic colorectal cancer patients in the CAPRI 2-GOIM trial

Background

Liquid biopsy provides a dynamic molecular assessment of metastatic colorectal cancer (mCRC) allowing an optimal use of anti-epidermal growth factor receptor (EGFR) drugs.

Methods

The phase II CAPRI 2-GOIM trial investigates the efficacy and safety of biomarker-driven, cetuximab-based, three treatment lines in patients (pts) with RAS/BRAF ^V600E wild type (WT) mCRC, determined by local laboratory. Baseline comprehensive next generation sequencing (NGS) genomic profiling was done with FoundationOneCDx on tumor tissue and FoundationOneLiquidCDx (324 genes) on plasma circulating tumor DNA (ctDNA). Treatments are: FOLFIRI cetuximab (1^st line), FOLFOX cetuximab (2^nd line); irinotecan cetuximab (3^rd line) in pts with ctDNA RAS/BRAF ^V600E WT mCRC and FOLFOX bevacizumab (2^nd line), regorafenib or trifluridine/tipiracil +/- bevacizumab (3^rd line) in pts with ctDNA RAS/BRAF ^V600E mutant mCRC.

Results

240 pts were screened and 202 enrolled. Baseline plasma ctDNA results were available for all 202 pts. For two pts, no ctDNA was detected by the test (2/202, 1%). One pt showed microsatellite instability high (MSI-H) profile and received immunotherapy 1^st line. 175/199 pts (88%) had RAS/BRAF WT mCRC. 16 pts presented gene alteration in RAS (13 KRAS /NRAS mutations (muts), 3 KRAS amplifications (ampls)), while 8 pts in BRAF (1 BRAF ^V600E mut, 7 non-V600E muts or rearrangements). Other alterations were muts in APC (161/199), TP53 (170/199), PI3KCA (31/199), SMAD4 (24/199), ATM (23/199), MAP2K1 (17/199), SOX9 (15/199), FBXW7 (15/199), NF1 (13/199), ERBB2 (13/199), PTEN (12/199), BRCA1 (11/199), ARID1A (11/199), EGFR (8/199), RNF43 (3/199); ampls in EGFR (3/199) and ERBB2 (6/199); rearrangements in ALK (2/199) and ROS (1/199). 142 pts had both tumor tissue and ctDNA results available. Among RAS mutated tumors, there was concordance between tissue and ctDNA, except for five cases of muts found only in tissue and four cases only in ctDNA.

Conclusions

Baseline plasma based NGS profiling is feasible and re-classifies 24/199 (12%) pts enrolled in CAPRI 2-GOIM trial with molecular alterations that could be involved in anti-EGFR drugs resistance in mCRC.

Clinical trial identification

EudraCT 2020-003008-15; NCT05312398.

Legal entity responsible for the study

GOIM.

Funding

This is an academic study, partially funded by Merck.

Disclosure

G. Martini: Financial Interests, Personal, Invited Speaker: Servier, Incyte, Takeda. E. Martinelli: Financial Interests, Personal, Invited Speaker: Amgen, Merck, Pierre Fabre, Servier, Roche, AstraZeneca. T. Troiani: Financial Interests, Personal, Invited Speaker: Amgen, Merck, AstraZeneca. S. Napolitano: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Other, travel grant: Amgen. E. Tamburini: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, MSD, AstraZeneca, Servier, Roche, Daiichi Sankyo. A. Avallone: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, AstraZeneca, Eisai, Amgen; Financial Interests, Personal, Advisory Role: MSD, Eisai, Bayer, Amgen, Santanova. S. Lonardi: Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, AstraZeneca, Bayer, Astellas, Merck Serono, Pierre Fabre, Bristol, Servier, Takeda, Roche, Lilly, Incyte. F. Ciardiello: Financial Interests, Personal, Invited Speaker: Roche, Servier, Amgen, Pierre Fabre, Merck, Pfizer. D. Ciardiello: Financial Interests, Personal, Other, travel support: Merck KGaA, Sanofi, Bristol Myers Squibb. All other authors have declared no conflicts of interest.