588P - Genomic landscape of acquired resistance to first-line (1L) anti-EGFR treatment in metastatic colorectal cancer (mCRC) beyond the classical EGFR pathway: Findings from the PLATFORM-B study

Background

Acquired resistance (AR) poses a major limitation to first-line (1L) chemotherapy plus anti-EGFR in RAS ^WT mCRC patients (pts), and mutations (mut) in EGFR pathway can explain < 10% of the cases. Tumor molecular biology can be studied real-time with circulating tumor DNA (ctDNA), a minimally-invasive and highly reproducible technique. The PLATFORM-B study enrolled 1L mCRC pts undergoing sequential ctDNA analysis. Data on ctDNA role at Progression Disease (PD) has been already presented, confirming the low rate of AR mut emergence in 1L. Here we aim to unveil possible uncommon mechanisms of resistance.

Methods

We analyzed baseline (BL) and PD blood samples from all pts of the PLATFORM-B study [cohort A: 100 RAS ^WT mCRC treated with CT + anti-EGFR; cohort B (control): 30 RAS ^MUT mCRC treated with CT + anti-VEGF] with a NGS-based method (Ion S5 system), covering 14 hotspot regions. Emerging RAS/BRAF/MEK/EGFR-ECD/MAP2K1 were considered classical mut of AR (CAR) to anti-EGFR, compared to mut in AKT1/CTNNB1/FBXW7/GNAS/PIK3CA/SMAD4/TP53/APC (non-CAR). Molecular data were correlated to clinical-pathological features and outcomes.

Results

Overall, 97 pts were included in cohort A and 29 in cohort B. ctDNA was detected at BL and PD in N=71 (73.2%) pts in cohort A and N=20 (69%) in cohort B. FBXW7 (N=9) and PIK3CA (N=6) were the most frequently mutated genes at BL and PD in the entire population. In RAS^WT group, only 5% of pts developed ≥1 non-CAR mut: FBXW7 emerged in N=2 (2%), CTNNB1/GNAS/SMAD4 mut in 1 pt, respectively, while AKT1 and PIK3CA mut did not appear de novo. Co-existence of non-CAR and CAR mut was not detected. In cohort B, PIK3CA was detected both at BL and PD in N=1 (3%) and at BL-only in N=5 (17%) pts; FBXW7 and SMAD4 mut occurred at BL and PD in N = 2 (7%), respectively. Uni- and multivariate analysis did not show significant correlations between the non-CAR mut, clinical-pathological features, and survival outcomes.

Conclusions

The emergence of non-CAR mut in ctDNA failed to explain PD in RAS ^WT mCRC pts treated with CT + anti-EGFR in the PLATFORM-B study. Additional analyses in blood and tissue samples by whole-exome sequencing are ongoing to explore other mechanisms of AR.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

TTD - Grupo de Tratamiento de los Tumores Digestivos.

Funding

Instituto de Salud Carlos III – FEDER Grant PI18/00031 and 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, Pierre Fabre. C. Fernandez Rodriguez: Financial Interests, Personal, Speaker’s Bureau: Roche, AstraZeneca, Merck; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Palex, Merck. R.D.A. Toledo: Financial Interests, Institutional, Research Grant, Research Funding: Novartis, AstraZeneca, BeiGene Pharmaceuticals. J. Gibert: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche. P. García Alfonso: Financial Interests, Personal, Advisory Board: Amgen. D. Paez: Financial Interests, Personal, Invited Speaker: MSD, Novartis, BMS; Financial Interests, Personal, Advisory Board: Amgen, Esteve, Ipsen; Financial Interests, Personal and Institutional, Research Grant: Merck. C. Santos Vivas: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Invited Speaker: Amgen; Non-Financial Interests, Leadership Role, Clinical trial coordinator: Merck; Other, Travel grant: Merck, MSD, Amgen. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman 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: 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 Pharmacuticals 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, Accommodations, 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, Boerhringer, 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 presidente, Member of the Executive Committee: Grupo Español de Tumores Neuroendocrinos (GETNE); Other, Honoraria received by spouse for advisory board or invited speaker roles: AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. B. Bellosillo Paricio: Financial Interests, Personal, Advisory Role: AstraZeneca, Merck-Serono, Novartis, Roche, Thermofisher; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Janssen, Merck-Serono, Novartis, Roche, Thermofisher, Pfizer; Financial Interests, Institutional, Research Funding: Thermofisher, AstraZeneca, Roche; Financial Interests, Personal and Institutional, Royalties: Biocartis; Financial Interests, Personal, Other, travel, accomodations, expenses: Pfizer, BMS. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, AstraZeneca, Boehringer Ingelheim, Chugai, Daichii 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 Therapeuics, 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, Laboratorios Servier, Esteve; Financial Interests, Personal, Other, Commercial Medical Education Company owned by wife until december 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, Coordinating PI: 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, Coordinating PI: Merck-Serono; Non-Financial Interests, Member: TTD (Grupo Tratamiento Tumores Digestivos). All other authors have declared no conflicts of interest.