Abstract 378P
Background
Chemotherapy plus anti-EGFR therapy is the standard first-line treatment in RAS wild-type (wt) metastatic colorectal cancer (mCRC). The utility of ctDNA sequencing (liquid biopsy) to assess early molecular response to chemotherapy plus anti-EGFR therapy before radiological progression is yet to be determined, and should integrate information on changes in total tumor burden and early emergence of resistant sub-clones.
Methods
We conducted a prospective multicentric observational study of patients with tissue RAS wt mCRC treated with first-line chemotherapy plus cetuximab undergoing sequential liquid biopsies. Baseline and early (C3) ctDNA were analyzed by a comprehensive NGS-based approach. Trunk mutations were assessed as a surrogate marker of total tumor burden and RAS/BRAF/MEK/EGFR-ECD/MAP2K1 were considered mutations of resistance.
Results
One hundred patients were included. Decrease in ctDNA trunk mutations between baseline and C3 correlated with progression-free survival (PFS) (HR= 0.23 P=0.001). RAS/BRAF were the only mutations of resistance detected at C3, while other coexisting and sub-clonal mutations of acquired resistance -mainly mutations in EGFR-ECD- emerged later during anti-EGFR therapy. An increase in the relative fraction of RAS/BRAF at C3 was associated with shorter PFS (HR= 10.5, P< 0.001), and predicted clonal expansion of the specific RAS/BRAF mutation in sequential liquid biopsies. Combined analysis of trunk and resistant mutations at C3 showed that patients with “early molecular response” (decrease in trunk and decrease in mutations of resistance at C3) had better response (77.5% vs. 25%, P=0.008) and longer PFS (HR=0.18, P< 0.001) compared to patients with “early molecular progression” (increase in trunk and/or increase in mutations of resistance).
Conclusions
Liquid biopsy detects early molecular response and predicts benefit to chemotherapy plus cetuximab. A comprehensive NGS-based approach is necessary to integrate information on total disease burden and resistance mutations. This sets the rationale for clinical trials to evaluate early ctDNA-guided treatment decisions in first-line mCRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD).
Funding
Instituto de Salud Carlos III – FEDER Grant PI18/00031 and Fundacion CRIS Excellence 19-30 Grant.
Disclosure
V. Alonso-Orduna: Financial Interests, Personal, Speaker’s Bureau: Hoffman La-Roche, Merck-Serono, Sanofi, Amgen; Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Personal, Advisory Board: Amgen, Merck-Serono; Financial Interests, Personal, Other, Support for attending meetings and/or travel: Merck-Serono, Hoffman La-Roche. C. Santos Vivas: Financial Interests, Personal, Speaker’s Bureau, lectures, presentations, speakers bureaus, manuscript writing or educational events: Pierre-Fabre; Financial Interests, Personal, Expert Testimony: Sanofi, Amgen ; Financial Interests, Personal, Other, attending meetings and/or travel: Amgen; Financial Interests, Personal, Invited Speaker, attending meetings and/or travel: Merck. M.E. Elez Fernandez: Financial Interests, Institutional, Research Grant: AbbVie, Amgen, Array Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Hoffman La-Roche, Medimmune, Merck Serono, MSD, Novartis, Pierre-Fabre, Sanofi Aventis; Financial Interests, Personal, Advisory Board: Amgen, Array Biopharma, Bayer, Bristol Myers Squibb, Hoffman La - Roche, Merck Serono, Sanofi, Servier; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Amgen, Servier, Array Biopharma, Merck Serono, Sanofi, Bristol Myers Squibb, Roche. R. Garcia-Carbonero: Financial Interests, Personal, Funding, for continuous medical education: AAA, Advanz Pharma, Amgen, Bayer, BMS, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pierre Fabre, Roche, Servier , Sanofi; Financial Interests, Personal, Other, research support: Pfizer, BMS , MSD. F. Rivera Herrero: Financial Interests, Personal, Research Grant: Sanofi, Roche, MSD, BMS, Bayer, Lilly, Astellas, Servier, Merck-Serono, Amgen, Celgene; Financial Interests, Personal, Speaker’s Bureau: Sanofi, Roche, MSD, BMS, Bayer, Lilly, Astellas, Servier, Merck-Serono, Amgen, Celgene; Financial Interests, Personal, Other, attending meetings and/or travel: Sanofi, Roche, MSD, BMS, Bayer, Lilly, Astellas, Servier, Merck-Serono, Amgen, Celgene ; Financial Interests, Personal, Advisory Board: Sanofi, Roche, MSD, BMS, Bayer, Lilly, Astellas, Servier, Merck-Serono, Amgen, Celgene. E. Aranda Aguilar: Financial Interests, Personal, Advisory Role: Amgen, Bayer, Bristol Myers Squibb, Merck, Roche, Sanofi. All other authors have declared no conflicts of interest.