515MO - Encorafenib + cetuximab (EC) + FOLFIRI for BRAF V600E-mutant metastatic colorectal cancer (mCRC): Updated results from the BREAKWATER safety lead-in (SLI)

Background

BRAF inhibitor encorafenib (E) + anti-EGFR antibody cetuximab (C) was approved for the treatment (tx) of previously treated patients (pts) with BRAF V600E-mutant mCRC based on the phase 3 BEACON study (NCT02928224) (mPFS, 4.3 months [mo]; ORR, 19.5%). Currently, there are no specifically targeted first-line (1L) tx for BRAF V600E-mutant mCRC. BREAKWATER (NCT04607421) is evaluating EC ± chemotherapy (chemo) vs standard-of-care chemo in pts with previously untreated BRAF V600E-mutant mCRC. We report updated results (≈28 mo after the last pt was enrolled) from the EC + FOLFIRI cohort of the SLI, including the final pharmacokinetic (PK) data.

Methods

In the SLI, inclusion criteria were BRAF V600E-mutant mCRC (blood or tumor tissue), ≤1 prior systemic tx for mCRC, and ECOG PS of 0 or 1. Pts had no prior tx with BRAFi/EGFRi or both oxaliplatin and irinotecan (I). Pts received E 300 mg once a day + C 500 mg/m² intravenously (IV) every 2 weeks (Q2W) + FOLFIRI/mFOLFOX6 IV Q2W in 28-day cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Secondary endpoints included safety, PK, and antitumor activity.

Results

As of the data cutoff (Dec 22, 2023), 30 pts (1L, n=12; second-line [2L], n=18) were enrolled in the EC + FOLFIRI cohort of the SLI. One pt had a DLT of grade 4 neutropenia lasting >7 days; no other DLTs were reported. All-causality serious AEs occurred in 46.7% of pts. In the presence of steady-state E, AUC_last of I and its active metabolite, SN-38, decreased by ≈24% and ≈28%, respectively, compared with values in the absence of E. This is consistent with the predicted CYP3A-mediated interaction between E and I. The confirmed ORR by blinded independent central review (BICR) was 83.3% and 44.4% in the 1L and 2L, respectively. mPFS by BICR was not estimable (NE) (95% CI: 13.8, NE) for 1L and 12.6 mo (95% CI: 6.9, 18.0) for 2L. mOS was NE (95% CI: 23.7, NE) for 1L and 19.7 mo (95% CI: 13.9, 25.1) for 2L, respectively. Safety data will be presented.

Conclusions

EC + FOLFIRI was generally tolerable, with no new safety signals identified. The antitumor activity reported is encouraging. These results support the continued evaluation of EC + chemo in cohort 3.

Clinical trial identification

NCT04607421.

Editorial acknowledgement

Medical writing support was provided by Blaise Low, PhD, of Nucleus Global, an Inizio company, and was funded by Pfizer.

Legal entity responsible for the study

Pfizer Inc, with support from Merck KGaA, Darmstadt, Germany, ONO Pharmaceutical, and Eli Lilly and Company.

Funding

Pfizer.

Disclosure

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. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd, Sanofi K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Amgen K.K., Pfizer Japan Inc., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Roche Diagnostics K.K., FALCO Biosystems Ltd., Merus N.V., Bristol-Myers Squibb K.K., Medical & Biological Laboratories Co., LTD., Takeda Pharmaceutical Co., Ltd. T.W. Kim: Financial Interests, Institutional, Research Grant: Genentech, Genome insight. R. Yaeger: Financial Interests, Speaker, Consultant, Advisor: Array BioPharma, Mirati Therapeutics, Naetra, ZaiLab; Financial Interests, Research Funding: Array BioPharma (Inst), Mirati Therapeutics (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst). J. Desai: Financial Interests, Personal, Invited Speaker: Pierre Fabre, Merck KGaA, Novartis; Financial Interests, Personal, Advisory Board: Bayer, Boehringer Ingelheim, Roche/Genentech, Pfizer, Amgen, Pierre Fabre, BeiGene, Axelia, Ellipses; Financial Interests, Coordinating PI: Roche/Genentech, BeiGene; Financial Interests, Local PI: Amgen, AstraZeneca, GSK, Novartis; Financial Interests, Steering Committee Member: Pfizer; Non-Financial Interests, Principal Investigator: BeiGene, Roche/Genentech, Amgen, Pfizer, Novartis, Boehringer, MapCure, Springworks, AstraZeneca, Vivace, Incyte; Non-Financial Interests, Member: ASCO, AACR; Non-Financial Interests, Leadership Role: Australia New Zealand Sarcoma Association; Other, Not-for-profit. Director, uncompensated: Cancer Trials Australia. H.S. Wasan: Financial Interests, Other, Honoraria: Array BioPharma, Celgene, Erytech Pharma, Incyte, Merck KgaA, Roche/Genentech, Servier, Sirtex Medical, Zymeworks; Financial Interests, Speaker, Consultant, Advisor: Bayer, Erytech Pharma, Incyte, Pfizer, Pierre Fabre, Roche Pharma AG, Shire, Sirtex Medical; Financial Interests, Speaker’s Bureau: Celgene, Incyte, Merck KgaA, Servier, Sirtex Medical; Financial Interests, Research Funding: Merck KgaA (Inst), MSD (Inst), Pfizer (Inst), Sirtex Medical (Inst). E. 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Tie: Financial Interests, Personal, Advisory Board: AstraZeneca, Pierre Fabre, BeiGene; Financial Interests, Personal, Invited Speaker: Merck Serono; Financial Interests, Personal, Other, Consultancy: Haystack Oncology; Financial Interests, Institutional, Advisory Board: Daiichi Sankyo, Gilead, Arcus, Takeda, Illumina; Non-Financial Interests, Leadership Role, Working Party Chair: AGITG. 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. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Astellas, GSK, Takeda, Bayer, Rottapharm; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GSK, Roche, Servier, Amgen, Bristol Myers Squibb, Incyte, Lilly, Merck Serono, MSD, AstraZeneca; Financial Interests, Institutional, Coordinating PI: 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. T. Usari: Financial Interests, Other, Employment: Pfizer; Financial Interests, Stocks or ownership: Pfizer, Viatris. E. Hahn: Financial Interests, Other, Employment: Pfizer; Financial Interests, Stocks or ownership: Pfizer. S. Dychter: Financial Interests, Other, Employee: Pfizer; Financial Interests, Stocks or ownership: Pfizer, Fate Therapeutics. 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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, 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.