LBA26 - BREAKWATER safety lead-in (SLI): Encorafenib (E) + cetuximab (C) + chemotherapy (chemo) for BRAFV600E metastatic colorectal cancer (mCRC)

Background

Based on the Ph 3 BEACON study (NCT02928224), BRAF inhibitor (i) encorafenib (E) + EGFRi cetuximab (C) was approved for treatment (tx) of previously treated patients (pts) with BRAF ^V600E mCRC, with mPFS of 4.3 months (mo) and ORR of 19.5%. In the Ph 2 ANCHOR study (NCT03693170), mPFS was 5.8 mo and ORR was 48% with 1L EC + binimetinib in BRAF ^V600E mCRC. To further assess 1L approaches, the ongoing Ph 3 BREAKWATER study (NCT04607421) is evaluating EC ± chemo vs standard-of-care chemo in BRAF ^V600E mCRC. We present updated safety and PK data, and new antitumor activity data from BREAKWATER SLI.

Methods

Inclusion criteria for the SLI were BRAF ^V600E mCRC (blood or tumor tissue), ≤1 prior systemic tx for mCRC, and ECOG PS 0/1. Pts previously treated with BRAFi/EGFRi or both oxaliplatin and irinotecan were excluded. Pts received E 300 mg daily + C 500 mg/m² every 2 weeks (Q2W) + either mFOLFOX6 Q2W (n=27) or FOLFIRI Q2W (n=30) in 28-day cycles until disease progression or unacceptable toxicity. Primary endpoint was frequency of dose-limiting toxicities (DLTs). Secondary endpoints included safety, PK, and antitumor activity.

Results

In this updated analysis (May 16, 2022 cutoff), SAEs occurred in 48.1% and 33.3%, and tx-related SAEs (any drug) in 25.9% and 13.3% of pts, in EC + mFOLFOX6 and EC + FOLFIRI, respectively. One DLT (grade ≥3 neutropenia) was seen in EC + FOLFIRI. In EC + FOLFIRI, in the presence of steady-state E, AUC_last of irinotecan and its active metabolite, SN-38, decreased by 24.9% and 26.8%, respectively, consistent with a predicted CYP3A-mediated drug interaction. In EC + mFOLFOX6, in the presence of steady state E, AUC_last of platinum in plasma and plasma ultrafiltrate, increased by 15% and 6%, respectively. Antitumor activity data are in the table.

Conclusions

EC + chemo was generally tolerable. Preliminary promising antitumor activity was seen in 1L and 2L BRAF ^V600E mCRC, supporting the ongoing study. Table: 000LBA26

NE, not estimable.

Clinical trial identification

NCT04607421.

Editorial acknowledgement

Medical writing support was provided by Asu Erden, PhD, of Health Interactions, Nucleus Global, and was funded by Pfizer.

Legal entity responsible for the study

The BREAKWATER trial is sponsored by Pfizer in collaboration with Merck KGaA, Ono Pharmaceutical, and Eli Lilly and Company.

Funding

Pfizer.

Disclosure

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, Hutchinson MediPharma International, Avvinity, Scandion Oncology, Ona Therapeutics, 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, 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, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, 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, 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; 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; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., Hutchinson Medipharma, HalioDX SAS; Non-Financial Interests: Hutchinson Medipharma. 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. T.W. Kim: Financial Interests, Institutional, Research Grant: AstraZeneca, SanofiAventis. R. Yaeger: Financial Interests, Personal, Advisory Board, Consulting or Advisory Role: Array BioPharma, Mirati Therapeutics, Natera; Financial Interests, Institutional, Funding, Research Funding: Array BioPharma, Boehringer Ingelheim, Mirati Therapeutics, Pfizer. J. Desai: Financial Interests, Institutional, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Bayer, BeiGene, Daiichi Sankyo, Eisai, GlaxoSmithKline, Merck KGaA, Pierre Fabre; Financial Interests, Institutional, Funding, Research Funding: AstraZeneca/MedImmune, BeiGene, Bionomics, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Roche. 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. 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. 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. T. Maughan: Financial Interests, Personal, Advisory Role: Pierre Fabre, Vertex, AstraZeneca; Financial Interests, Institutional, Funding, Research Funding: Almac Diagnostics, AstraZeneca, Merck KgAA, PsiOxus Therapeutics . C. Eng: Financial Interests, Personal, Other, Consulting: Bayer, Boston Scientific, GSK, Halio Dx, Merck, Mirati, Hookipa, J&J, Merck, Natera, Roche, Seagen, Taiho, Veloxis; Financial Interests, Personal, Funding, Research Funding: VUMC, Elevar, Hutchinson, Merck, Pfizer. J. Tie: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Pierre Fabre, Inivata; Financial Interests, Personal, Invited Speaker: Servier, Merck Serono; Financial Interests, Personal, Other, Consultancy: Haystack Oncology. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi, Bayer; Financial Interests, Institutional, Research Grant: Hoffman La-Roche, Sanofi Aventis, Amgen, Merck Serono, MSD, Boehringer Ingelheim, AbbVie, Pierre-Fabre, Novartis, Bristol-Myers Squibb, GlaxoSmithKline, Medimmune, Array Pharmaceuticals, AstraZeneca. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi-Sankyo, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GlaxoSmithKline; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb. X. Zhang: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Royalties: Johns Hopkins University. R. Chavira: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. T. Usari: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer, Viatris. E. Hahn: Financial Interests, Personal, Full or part-time Employment: Pfizer. 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.