Abstract 108P
Background
Anti-EGFRs plus doublets are the standard first-line treatment for pts with left-sided RAS/BRAF wt mCRC. According to PRESSING1/2 panels, anti-EGFR sensitivity seems restricted to negatively hyperselected RAS/BRAF wt cases. Analysing of ctDNA is a promising strategy to optimize upfront therapy and to identify mechanisms of acquired resistance. TRIPLETE is a phase III trial where 435 pts with RAS/BRAF wt mCRC were randomized to receive first-line FOLFOX/panitumumab (pan) or mFOLFOXIRI/pan.
Methods
Pts enrolled in the TRIPLETE trial with available tissue and plasma at baseline (BP), and plasma at the time of disease progression (PDP) were included. Tissue samples were profiled using FoundationOne CDx and Oncomine™Focus Assay, and plasma samples were analyzed by means of Oncomine™Pan-CancerCell-Free Assay. Pts with pMMR tumors were grouped as PRESSING-positive (+) or negative (-) based on the detection of aof PRESSING panel alterations.
Results
134 (31%) pts were included. Tissue analysis revealed locally unknown RAS mutations in 6 (4%) cases. After excluding RAS mutated and dMMR/unknown cases (N=26), RAS was found to be mutated in 2 BP out of 102 pts (2%) with RAS/BRAF wt and pMMR tumors. PRESSING alterations were found in 15 (15%) tissue cases (HER2ampl: 9, HER2mut: 3, AKT1mut: 1, PIK3CAex20: 2). Matching results were achieved in 8 BP, and 2 additional alterations were found (AKT1mut and PTENmut). No differences between PRESSING+ and - pts were reported in terms of ORR, PFS or OS, regardless of primary tumor location. In PDP, RAS mut were detected in 9 pts (9%), and BRAF V600E mut co-occurred in 2 cases. Pts with RAS mut ctDNA at PDP showed a significative shorter OS compared to RAS wt [HR 0.3 95% CI 0.13-0.9, p=.03]. MAP2K1 mut were found at PD in 2 cases, while no other PRESSING alteration was found.
Conclusions
In contrast to previous data, negative hyperselection both through tissue and plasma analysis failed to demonstrate a prognostic role among pMMR RAS/BRAF wt mCRC pts treated with first-line chemotherapy plus pan. The confounding effect of the associated chemotherapy is a potential explanation for this finding.
Clinical trial identification
NCT03231722.
Legal entity responsible for the study
University of Pisa.
Funding
University of Pisa, Regione Toscana "Bando Ricerca Salute 2018"
Disclosure
D. Rossini: Financial Interests, Personal, Speaker’s Bureau: Amgen, MSD Oncology. F. Bergamo: Financial Interests, Speaker’s Bureau: Lilly, MSD Oncology, Eisai, Bayer, Bristol Myers Squibb; Financial Interests, Advisory Role, Travel, Accommodation, Expenses: Advanced Accelerator Applications/Novartis; Financial Interests, Advisory Role: Servier, Pierre Fabre. F. Pietrantonio: Financial Interests, Personal and Institutional, Funding, Honoraria, Consulting or Advisory Role: Amgen; Financial Interests, Personal, Advisory Role, Honoraria: Servier, Bayer, MSD Oncology, Takeda, Rottapharm Biotech; Financial Interests, Personal, Funding, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: Astellas Pharma, Ipsen, Johnson & Johnson, Daiichi Sankyo, Seagen; Financial Interests, Personal and Institutional, Funding, Honoraria: AstraZeneca; Financial Interests, Institutional, Funding: Incyte, Agenus, Lilly; Financial Interests, Personal, Other, Honoraria, Travel, Accommodation, Expenses: Pierre Fabre; Financial Interests, Personal, Advisory Role, Honoraria, Travel, Accommodation, Expenses: Merck Serono; Financial Interests, Personal, Advisory Role: GSK, Janssen. A. Zaniboni: Financial Interests, Personal, Advisory Role: Amgen, Bayer, Merck Serono, Merck; Financial Interests, Personal, Advisory Role, Speakers' Bureau: Servier; Financial Interests, Institutional, Speaker’s Bureau: Astellas Pharma. L. Antonuzzo: Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Other, Honoraria: Amgen, Roche, AstraZeneca, Novartis. G. Masi: Financial Interests, Personal, Advisory Role: AstraZeneca, Eisai, Roche, MSD Oncology; Financial Interests, Institutional, Funding, Patents, Royalties, Other Intellectual Property: Terumo. C. Cremolini: Financial Interests, Personal, Advisory Role, Honoraria, Research Funding: Roche, Bayer; Financial Interests, Personal, Speaker’s Bureau, Honoraria, Consulting or Advisory Role, Research Funding: Servier; Financial Interests, Personal, Speaker’s Bureau, Honoraria, Consulting or Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role, Honoraria: MSD, Amgen; Financial Interests, Personal, Advisory Role: Nordic Bioscience; Financial Interests, Personal, Speaker’s Bureau, Honoraria, Research Funding: Merck. All other authors have declared no conflicts of interest.