Abstract 110P
Background
Doublet chemotherapy (CT) + anti-EGFR monoclonal antibody (moAb) is the standard 1L for RAS WT mCRC. While acquired resistance (AR) to anti-EGFR monotherapy in refractory mCRC has been extensively characterized, little is known on AR to 1L anti-EGFR moAb + CT. ctDNA is a non-invasive, reproducible approach to explore real-time tumor molecular biology. The multicentric prospective PLATFORM-B study enrolled 1L mCRC patients (pts) undergoing longitudinal ctDNA analysis. Data on the role of ctDNA at C3 has been previously published. Here we report results on ctDNA at progressive disease (PD) to unveil mechanisms of AR in 1L.
Methods
Baseline (BL) and PD blood samples were analysed from all patients included in the PLATFORM-B study [cohort A: 100 RAS WT mCRC treated with CT + anti-EGFR moAb; cohort B (control): 30 RAS MUT mCRC treated with CT + bevacizumab], by a targeted NGS-based approach (Ion S5 system). RAS/BRAF/MEK/EGFR-ECD/MAP2K1 were considered mutations of AR, if detected at PD but not at BL. Molecular results were correlated to clinical-pathological features and outcomes.
Results
Overall, 126 pts were included: 97 in cohort A and 29 in cohort B. ctDNA was undetectable at BL and PD in N = 26 (26.8%) pts in cohort A and N = 9 (31%) in cohort B. TP53 (44%) and APC(33%) were the most frequently mutated genes at BL and PD in the study population. In cohort A, only 10.3% pts developed ≥ 1 mutations of AR: MAP2K1 was the most detected (N = 5; 5.2%), while KRAS, BRAF, EGFR-ECD, and NRAS mutations emerged in < 5% pts. Co-existence of multiple mutations occurred in N = 4 (4.1%) pts. In cohort B, the most frequently detected gene was KRAS, mutated both at BL and PD in N = 15 (51.7%) and at BL-only in N = 4 (13.7%) pts. BRAF was found in 1 pt (BL and PD). No mutations of AR were detected. Uni- and multivariate analysis did not show significant correlations between emergence of AR, clinical-pathological features and overall survival.
Conclusions
AR mutations emerged in only 10% of RAS WT mCRC pts treated with CT + anti-EGFR moAb, and in none of RAS MUT mCRC pts treated with CT + bevacizumab, in 1L within the PLATFORM-B study. Additional analyses in ctDNA and tissue are ongoing to explore other mechanisms of AR.
Legal entity responsible for the study
Grupo de Tratamiento de los Tumores Digestivos (TTD).
Funding
Instituto de Salud Carlos III - FEDER Grant PI18/00031; Fundacion CRIS Excellence 19-30 Grant.
Disclosure
J. Vidal Barrull: Financial Interests, Personal, Invited Speaker: Merck Serono, Amgen, Pierre Fabre, Novartis; Financial Interests, Personal, Advisory Board: Merck Serono, Amgen, BMS. C. Fernandez Rodriguez: Financial Interests, Personal, Speaker’s Bureau: Roche, AstraZeneca, Merck; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Merck, Palex. P. García Alfonso: Financial Interests, Personal, Advisory Board: Amgen. J. Gibert: Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Roche. C. Santos Vivas: Financial Interests, Personal, Advisory Board: Sanofi, Amgen, Pierre Fabre; Financial Interests, Personal, Other, Travel and accommodation: Merck KGaA, Merck. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffmann-La Roche, Servier, Amgen, Merck Serono, Sanofi, Bayer, Pierre Fabre, MSD, Takeda, Boehringer Ingelheim, Cure Teq AG, Repare Therapeutics Inc., RIN Institute Inc., Janssen; Financial Interests, Personal, Invited Speaker: Organon, Novartis, Pfizer, BMS, Lilly, Medscape; Financial Interests, Personal, Other, Educational training: Seagen International GmbH; Financial Interests, Institutional, Funding: F. Hoffmann-La Roche Ltd., Sanofi Aventis Recherche & Développement, Amgen Inc., Boehringer Ingelheim, Novartis Farmacéutica SA, Bristol Myers Squibb International Corporation, BeiGene, HalioDX SAS, Janssen-Cilag SA, Merck Health KGaA, Merck Sharp & Dohme de España SA, PharmaMar SA, Servier, Taiho Pharma USA Inc, Hutchison MediPharma International, Menarini, Merus NV, Pfizer, Mirati, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Celgene International SARL, Debiopharm International SA, Genentech Inc, MedImmune, AbbVie Deutschland GmbH & Co KG, Bayer Pharma AG, Bioncotech Therapeutics, S.L., BioNTech Rna Pharmaceuticals GmbH, BioNTech Small Molecules GmbH, Boehringer Ingelheim de España S.A., Daiichi Sankyo, Inc, Gercor, Hutchinson Medipharma Limited, Iovance Biotherapeutics, Inc., Janssen Research & Development, Menarini Ricerche SPA, Merck, Sharp & Dohme De España S.A., Nouscom SRL., Pledpharma AB, Redx Pharma PLC, Scandion Oncology, Seattle Genetics Inc., Sotio A.S., Wntresearch AB; Non-Financial Interests, Other, Coordinator of the SEOM +MIR Section of Residents and Young Assistants: Sociedad Española de Oncología Médica (SEOM); Non-Financial Interests, Other, Speaker of the ESMO Academy: European Society for Medical Oncology (ESMO); Non-Financial Interests, Other, Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy: American Society of Clinical Oncology (ASCO); Non-Financial Interests, Leadership Role, Member of the Scientific Program Committee and Developmental Therapeutics-Immunotherapy Track Leader, 2023-2024 term: American Society for Clinical Oncology (ASCO); Non-Financial Interests, Other, Member of the Scientific Committee 2024: European Society for Medical Oncology (ESMO); Other, Travel, accommodation, expenses: Roche, Merck Serono, Sanofi, Amgen, Array BioPharma, Servier, Bristol Myers Squibb. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Astellas, Bayer, BMS, Boehringer Ingelheim, Esteve, Hutchmed, Ipsen, Midatech Pharma, MSD, Novartis, PharmaMar, Servier, Takeda; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Global PI of investigator-initiated clinical trials (AXINET, NICENEC, PEMBROLA): BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Chair elect: European Neuroendocrine Tumor Society (ENETS); Non-Financial Interests, Leadership Role, Past president, Member of the Executive Committee: Grupo Español de Tumores Neuroendocrinos (GETNE); Other, Honoraria received by spouse for advisory board or invited speaker roles: Abbie, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. B. Bellosillo Paricio: Financial Interests, Personal, Research Grant: Thermo Fisher, AstraZeneca, Roche; Financial Interests, Personal, Royalties: Biocartis. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Genentech Inc., Ikena Oncology, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics, CARSgen Therapeutics, hC Bioscience Inc, Takeda Pharmaceuticals International AG, Alentis Therapeutics, Immodulon Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex/HMP; Financial Interests, Personal, Advisory Board: Cardiff Oncology, Aveo Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeutics, 1TRIALSP, Alentis Therapeutics, Pangaea Oncology; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd., Genentech Inc, Janssen-Cilag International NV, Merck Health KGaA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA-Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGaA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd., Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, MedImmune, Menarini, Merck Healthcare KGaA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd., Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. R. Salazar Soler: Financial Interests, Personal, Advisory Board: GSK, Sanofi Genzyme; Financial Interests, Personal, Expert Testimony: Laboratorios Servier, Esteve; Financial Interests, Personal, Other, Commercial Medical Education Company owned by wife until ,2023: SACE Medhealth; Financial Interests, Personal, Other, Co-administrator and co-owner of this commercial medical education company until April 2022: SACE Medhealth; Financial Interests, Personal, Other, Member of executive committee: TTD; Financial Interests, Personal and Institutional, Invited Speaker: WNT Pharma. E. Aranda Aguilar: Financial Interests, Personal, Advisory Board: Amgen, Bayer, Sanofi, Incyte, Pierre Fabre. C. Montagut Viladot: Financial Interests, Personal, Advisory Board: Merck Serono, Roche; Financial Interests, Personal, Invited Speaker: Merck Serono, Pierre Fabre, Guardant Health, Amgen; Financial Interests, Institutional, Royalties: Biocartis; Financial Interests, Institutional, Invited Speaker: Merck Serono; Non-Financial Interests, Member: TTD (Grupo Tratamiento Tumores Digestivos). All other authors have declared no conflicts of interest.