316O - Genomic mechanisms of acquired resistance of patients (pts) with BRAF V600E-mutant (mt) metastatic colorectal cancer (mCRC) treated in the BEACON study

Background

In the randomized phase III BEACON study (NCT02928224), encorafenib + cetuximab ± binimetinib regimens improved overall survival and objective response rate vs standard of care (control) in pts with previously treated BRAF V600E-mt mCRC. To assess the genomic landscape of resistance, we profiled circulating tumor DNA (ctDNA) in the BEACON pt population.

Methods

Plasma samples were collected at baseline and end of treatment (EOT) and were analyzed using GuardantOMNI to evaluate somatic alterations, including nonsynonymous mutations, amplification (focal/amplified), and rearrangements. Genomic changes were evaluated at individual pt level to characterize acquired alterations.

Results

To explore mechanisms of resistance, paired baseline and EOT samples were evaluated from 320/665 (48.1%) pts in this analysis. BRAF V600E mutations were detectable in ctDNA at baseline and at progression (89.0% and 88.7% of pts, respectively). The most commonly acquired resistance alterations consisted of KRAS and NRAS mutations and MET amplification in both the doublet (44.6%, 36.6%, and 17.0%, respectively; n=112) and triplet (40.2%, 25.0%, and 19.6%, respectively; n=112) arms, compared with the control arm (0%, 3.2%, 0%, respectively; n=94). At least one of these resistance alterations was identified in 59.8% of doublet-, 56.3% of triplet-, and 3.2% of control-treated pts and was frequently observed concurrently in doublet and triplet arms. MAP2K1 mutations were acquired in 16.1% of doublet-treated pts vs only 3.6% of triplet-treated pts (P<0.01). Amplification of KRAS, BRAF, and IGF1R were acquired in 4.5%, 1.8%, and 0.9% of pts in the doublet arm vs 8.9%, 5.4%, and 4.5% of pts in the triplet arm.

Conclusions

ctDNA analyses revealed that MAPK pathway reactivation is a common mechanism of resistance for BRAF V600E-mt mCRC following inhibition of BRAF and EGFR ± MEK inhibition. Acquired mutations in RAS-MEK signaling were more prevalent in the doublet arm, while enhanced receptor signaling was more prevalent in the triplet arm.

Clinical trial identification

NCT02928224.

Editorial acknowledgement

Medical writing support was provided by Alexus Kolb, PhD, from Caudex and was funded by Pfizer.

Legal entity responsible for the study

BEACON CRC was sponsored by Pfizer in collaboration with Merck KGaA, ONO Pharmaceutical, and Pierre Fabre.

Funding

Pfizer in collaboration with Merck KGaA, ONO Pharmaceutical, and Pierre Fabre.

Disclosure

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, Natera, HalioDx, Jacobio, Pfizer, Repare Therapeutics, GlaxoSmithKline, Jazz, Xilis, Abbvie, Gilead, Mirati, Flame, Servier, Carina, Bicara, Endeavor BioMedicines, Numab Pharma, Janssen; Financial Interests, Personal, Other, Research: Inivata; Financial Interests, Personal, Stocks/Shares: Lutris, Iylon, Navire, Xilis. D.A. Murphy: Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Full or part-time Employment: Pfizer. J. Pu: Non-Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. R. Yaeger: Financial Interests, Personal, Advisory Role: Array BioPharma, Mirati, Natera; Financial Interests, Institutional, Funding, Research Funding: Array BioPharma, Boehringer Ingelheim, Mirati, Pfizer. F. Ciardiello: Financial Interests, Personal, Advisory Board: Roche, Merck Serono, Servier, Pierre Fabre, Pfizer; Financial Interests, Institutional, Research Grant: Merck Serono, Roche, Amgen; Financial Interests, Institutional, Invited Speaker: Pfizer, Pierre Fabre, Servier. J. Desai: Financial Interests, Personal, Advisory Role: Amgen, Bayer, BeiGene, Eisai, GlaxoSmithKline, Pierre Fabre; Financial Interests, Institutional, Funding, Research Funding: AstraZeneca/MedImmune, BeiGene, Bionomics, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Roche. E. Van Cutsem: Financial Interests, Personal, Advisory Board, Advisory board and/or Speaking: AbbVie, Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Helsinn, Incyte, Ipsen, Janssen Research, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabr; Financial Interests, Institutional, Funding, research grant paid to institution: Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. H.S. Wasan: Financial Interests, Personal, Advisory Board, Advisory Boards and Invited Speaker: Incyte, Pierre Fabre, Servier, Bayer, Roche/Genentech/ FM AG, SIRTEX medical ERYTECH, Celgene, Array BioPharma, Merck KGaA: BMS; Financial Interests, Personal, Invited Speaker, Trial steering committee and advisory: Zymeworks; Financial Interests, Personal and Institutional, Invited Speaker, Trial PI steering committee and advisory: Sirtex Medical; Financial Interests, Personal, Other, Consultancy for Submission for UK approval (BSI): ONCOSL; Non-Financial Interests, Advisory Role, Trial steering committee: Pfizer; Non-Financial Interests, Advisory Role, UK NICE submission: Bayer, Pierre Fabre. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Bayer, Ono, MSD; Financial Interests, Institutional, Invited Speaker: Ono, Sanofi, Daiichi Sankyo, Chugai, Pfizer; Financial Interests, Institutional, Research Grant: Taiho, MSD, Ono, Amgen, Genomedia, Sysmex, Daiichi Sankyo, Chugai, Boehringer Ingelheim. B. Alkuzweny: Financial Interests, Personal, Full or part-time Employment: Pfizer. T. Xie: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. X. Zhang: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Royalties: Johns Hopkins University. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daichii Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Ona Therapeutics, Hutchinson MediPharma International, Avvinity, Scandion Oncology, Sotio Biotech, Inspirna Inc; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; 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, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb International Corporation, Genentech Inc, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, 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, HalioDX SAS, Hutchinson Medipharma, Pfizer, MedImmune, Menarini, Merus N V, Mirati; Non-Financial Interests, Invited Speaker, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Invited Speaker, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; 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, 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, 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, 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, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., Hutchinson Medipharma, HalioDX SAS, 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, Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System.