Abstract 66P
Background
BRAFm and dMMR/MSI-H mCRC represent a distinct subtype with multiple therapeutic options. According to ESMO guidelines, ICIs are the first treatment choice for all patients (pts) with dMMR/MSI-H mCRC. However, a significant proportion experience primary or secondary resistance and can be treated with TT. Data on the efficacy of TT after progression under ICIs in this population are missing.
Methods
We collected all consecutive pts with dMMR/MSI-H and BRAFm mCRC treated from 2017 to 2024 with a combination of BRAF + EGFR ± MEK inhibitors, after disease progression on ICIs at 16 international centers. Clinico-pathologic characteristics and outcomes were compared with an international cohort of BRAFm and pMMR/MSS mCRC pts treated with TT from 2nd line and beyond.
Results
As compared to pMMR/MSS (n=170), dMMR/MSI-H (n=50) BRAFm mCRC pts were more often >70-year-old, with a right sided primary tumor, a metachronous mCRC, without liver but more lymph nodes metastases. dMMR/MSI-H mCRC pts received more frequently TT beyond 2nd line (70% vs 37%) and 45% had primary resistance to ICIs. A trend towards a lower ORR (18% vs 32%, OR 0.46, 95% CI 0.18-1.06, p = 0.09) and DCR (60% vs 73%, OR 0.55, 95% CI 0.27-1.16, p = 0.11) was seen without reaching significance in dMMR/MSI-H as compared to pMMR/MSS pts. Conversely, after a median follow-up of 14.04 months (IQR 7.59-21.34), no differences in PFS (median 5.13 vs 4.50 months, HR 0.83, 95%CI 0.57-1.20, p = 0.31) and OS (median 10.75 vs 9.11 months, HR 0.89, 95%CI 0.59-1.32, p = 0.55) were observed between dMMR/MSI-H and pMMR/MSS pts. In uni- and multi-variable analyses, age <50 years was associated with shorter PFS and OS in dMMR/MSI-H pts.
Conclusions
This is to our knowledge the first report of efficacy of TT in dMMR/MSI-H BRAFm mCRC patients pre-treated with ICIs. Our results show that BRAFm and dMMR/MSI-H mCRC pts benefit from TT after progression under ICIs. Though a numerically lower ORR and DCR, the outcome is not different in these pts from that observed in pMMR/MSS BRAFm mCRC and is in line with the results of the BEACON registration trial for encorafenib and cetuximab.
Legal entity responsible for the study
AGEO.
Funding
Has not received any funding.
Disclosure
D. Tougeron: Financial Interests, Personal, Advisory Board: AstraZeneca, Sanofi, Amgen, MSD, Roche, Servier, Pierre Fabre, BMS, Bayer; Non-Financial Interests, Member of Board of Directors: Federation Francophone de Cancerologie Digestive. D.P. Modest: Financial Interests, Personal, Invited Speaker: Takeda, Taiho, Amgen, Servier, Merck, Onkowissen, MSD, AstraZeneca, Pierre Fabre, GSK, Medison, COR2ED, JE, 21up, Seagen; Financial Interests, Personal, Advisory Board: Amgen, Servier, Merck, MSD, Takeda, G1, Onkowissen, Pierre Fabre, AstraZeneca, Regeneron; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Invited Speaker: Servier. R. Guimbaud: Financial Interests, Personal, Advisory Board: Adacap, BMS; Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, Bayer, Esteve, Pierre Fabre, Merck. S. Kopetz: Financial Interests, Personal, Advisory Board: Roche, EMD Serono, Merck, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca, Bayer, Pierre Fabre, Redx Pharma, Ipsen, Daiichi Sankyo, Natera, HalioDx, Jacobio, Pfizer, Repare Therapeutics, GSK, Jazz, Xilis, AbbVie, Gilead, Mirati, Flame, Servier, Carina, Bicara, Endeavor BioMedicines, Numab Pharma, Janssen; Financial Interests, Personal, Other, Research: Inivata, Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis; Financial Interests, Personal, Other, Consultant: Genomic Health, Frontier Medicines, Replimune, Taiho Pharmaceutical, Cardiff Oncology, Ono Pharmaceutical, Bristol Myers Squibb-Medarex, Amgen, Tempus, Foundation Medicine, Harbinger Oncology, Takeda, CureTeq, Zentalis, Black Stone Therapeutics, NeoGenomics Laboratories, Accademia Nazionale di Medicina; Financial Interests, Personal, Stocks/Shares: Lutris, Iylon, Navire, Xilis; Financial Interests, Personal, Ownership Interest: Frontier Medicines. F. Sclafani: Financial Interests, Advisory Role, Consultancy, advisory roles, honoraria: AMAL Therapeutics, Amgen, Bayer, BMS, Dragonfly Therapeutics, GSK, Merck, Nordic Pharma, Roche, Servier; Financial Interests, Institutional, Funding: Amgen, Astellas, AstraZeneca, Bayer, BMS, Merck, MSD, Pierre Fabre, Roche, Sanofi; Financial Interests, Personal, Other, Travel grant: Amgen, Bayer, Lilly, Merck, Roche, Servier; Non-Financial Interests, Leadership Role, Secretary EORTC Gastrointestinal Tract Cancer Group: EORTC Gastrointestinal Tract Cancer Group. C. Coutzac: Financial Interests, Personal, Advisory Board: BMS, Servier, Pierre Fabre, Merck Serono; Financial Interests, Institutional, Advisory Board: BMS, Amgen; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca, MSD, ImCore Roche Genentech. A. Lievre: Financial Interests, Personal, Invited Speaker: Amgen, Astellas, AstraZeneca, BMS, Esteve, Pierre Fabre Oncologie, Servier, Viatris; Financial Interests, Personal, Advisory Board: Astellas, BMS, Bayer, Servier; Financial Interests, Institutional, Research Grant, RePERSO trial: Bayer; Financial Interests, Institutional, Invited Speaker, SOCRATE trial (FFCD promotion): Lilly; Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Bayer, Incyte, Lilly; Non-Financial Interests, Other, Travel and meeting registration: Bayer, Pierre Fabre, Servier, Viatris. E.L. Alouani: Financial Interests, Personal, Expert Testimony: Merck; Financial Interests, Personal, Advisory Board: Servier. S. Pernot: Financial Interests, Personal, Invited Speaker: Bayer, Amgen, Pierre Fabre, AstraZeneca; Financial Interests, Personal, Advisory Board: MSD, BMS, Servier, Merck, Takeda. F.A. Sinicrope: Financial Interests, Personal, Advisory Board: Roche, Eisai, Guardant Health; Financial Interests, Institutional, Royalties: Roche/Ventana Medical Systems. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: F. 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. F. Pietrantonio: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, MSD, Bayer, Astellas, Takeda, GSK, Johnson&Johnson, Rottapharm; Financial Interests, Personal, Invited Speaker: Amgen, Merck Serono, BMS, Lilly, Servier, Bayer, Pierre Fabre, AstraZeneca, Astellas, Daiichi Sankyo, Takeda; Financial Interests, Personal, Expert Testimony: Ipsen; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Incyte, Agenus; Financial Interests, Institutional, Invited Speaker: Lilly, Amgen. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Astellas, GSK, Takeda, Bayer; Financial Interests, Personal, Invited Speaker: Pierre Fabre, GSK, Roche, Servier, Amgen, Bristol Myers Squibb, Incyte, Lilly, Merck Serono, MSD; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb; Non-Financial Interests, Member of Board of Directors, Italian No-Profit Oncology Research Foundation supporting academic Clinical trials: GONO Foundation. C. Gallois: Financial Interests, Institutional, Invited Speaker: Sanofi Genzyme; Financial Interests, Institutional, Advisory Board: Servier, Pierre Fabre, Merck; Financial Interests, Institutional, Other, french congress invitation: MSD; Financial Interests, Institutional, Other, Congress invitation: Amgen. J. Taieb: Financial Interests, Personal, Advisory Board: MSD, Merck, Servier, Pierre Fabre, Amgen, BMS, Novartis, Pfizer, Sanofi, Rottapharm, Takeda; Financial Interests, Personal, Expert Testimony: Astellas, Takeda; Financial Interests, Personal, Invited Speaker: Amgen, BMS, Merck, MSD, Novartis; Financial Interests, Personal, Invited Speaker, symposia: Astellas; Financial Interests, Personal, Other, steering committee of clinical trial: Novartis; Non-Financial Interests, Leadership Role, President of the scientific committee of the ARCAD foundation until end 2022: ARCAD Foundation; Non-Financial Interests, Leadership Role, Chair of the ARCAD pancreas research group: ARCAD Foundation; Non-Financial Interests, Leadership Role, Member of the administrative council, the scientific committee, the executive board and responsible for the international relationships /partnership for FFCD in the prodige intergroup: Federation Francophone de Cancerologie Digestive (FFCD); Non-Financial Interests, Other, steering committee of clinical trials: Pfizer, Servier. All other authors have declared no conflicts of interest.