Clinical characteristics, efficacy, and safety in patients receiving second- or third-line encorafenib plus cetuximab (E+C) vs control for metastatic colorectal cancer (mCRC): BEACON CRC post hoc analysis

BRAF mutations occur in 8% to 12% of patients with mCRC and are associated with clinically poor prognosis. E+C was approved by the FDA and EMA for patients with BRAF V600E-mutant mCRC who have received prior systemic therapy based on the results of the BEACON study (NCT02928224), which combined patients treated in the second- (2L) and third-line (3L) setting. Here we evaluate the characteristics and outcomes separately for patients who received 2L and 3L E+C or control.

BEACON was a phase 3, open label study evaluating E (300 mg QD) plus C (400 mg/m 2 initial dose followed by 250 mg/m 2 weekly) with or without binimetinib (45 mg BID) vs control (C plus irinotecan or FOLFIRI). The primary study endpoint was OS. For this post hoc analysis (data cutoff: November 10, 2022), patients receiving E+C or control were grouped by line of therapy (2L and 3L).

A total of 291 patients received 2L treatment (n=146 E+C; n=145 control); median age was 60 and 59 years, 45.9% and 49.0% had ECOG PS 1, and 45.2% and 44.1% had ≥3 organs involved at baseline. Of those who received 3L treatment (n=74 E+C; n=76), median age was 62 and 61 years, 50.0% and 55.3% had ECOG PS 1, and 50.0% and 44.7% had ≥3 organs involved at baseline. For 2L, the OS HR [95% CI] was 0.60 [0.46, 0.78]; P P P =0.0057 (median OS: 7.9 and 4.8 months for E+C and control); the PFS HR [95% CI] was 0.43 [0.29, 0.66]; P < 0.0001 (median PFS: 4.2 and 1.5 months). In 2L, 31 (21.2%) vs 3 (2.1%) patients for E+C vs control were confirmed responders. For 3L, 14 (18.9%) vs 1 (1.3%) patients for E+C vs control were confirmed responders. Of patients who received 2L treatment, 91 patients (62.3%) in the E+C group, and 77 patients (53.1%) in the control group received subsequent therapy. Of those who received 3L treatment, 35 patients (47.3%) in the E+C group and 34 patients (44.7%) in the control group received subsequent therapy. The most common all-causality AEs (≥30% in the E+C arm) in the 2L (E+C vs control) were diarrhea, nausea, dermatitis acneiform, abdominal pain, and fatigue. In the 3L, these were fatigue, diarrhea, nausea, decreased appetite, and anemia.

E+C is an effective treatment regimen for patients with BRAF V600E-mutant mCRC in the 2L and 3L setting. In the BEACON CRC study, patient characteristics and outcomes were generally similar between those who received E+C in 2L and those who received it in 3L. First-line E+C with or without chemotherapy is currently under investigation in the BREAKWATER study (NCT04607421).

NCT02928224.

Editorial/medical writing support was provided by Amber Wood, PhD, at Meditech Media, Nucleus Global, and was funded by Pfizer.

Pfizer, Inc.

The BEACON trial was sponsored by Array BioPharma Inc. (acquired by Pfizer in July 2019), with support from Merck Healthcare KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) (for sites outside of North America), ONO Pharmaceutical, and Pierre Fabre.

J. Tabernero: Honoraria (self): educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER); Advisory / Consultancy: scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc and Tolremo Therapeutics; Research grant / Funding (institution): institutional financial support for clinical trials or contracted research for Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA , MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK.; Shareholder / Stockholder / Stock options: Oniria Therapeutics . E. Van Cutsem: Advisory / Consultancy: Array BioPharma, Astellas Pharma, Astrazeneca, Bayer, Biocartis, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, GSK, Halozyme, Incyte, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis,Pierre Fabre, Roche, SERVIER, Sirtex Medical, Taiho Pharmaceutical; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier . T. Yoshino: Honoraria (self): Bayer Yakuhin, Chugai Pharmaceutical, Merck Biopharma, MSD K.K., Ono Pharmaceutical, Takeda Pharmaceutical; Advisory / Consultancy: Sumitomo Corp.; Research grant / Funding (institution): Amgen, Chugai, Daiichi Sankyo, Esai, FALCO Biosystems, Molecular Health GmbH, MSD, Ono, Pfizer, Roche Diagnostics, Sanofi, Taiho. R. Yaeger: Honoraria (Institution): Zai Lab; Advisory / Consultancy: Mirati Therapeutics, Pfizer; Research grant / Funding (institution): Pfizer, Mirati Therapeutics, Boehringer Ingelheim. H. Wasan: Honoraria (self): Servier, Incyte, Pierre Farbre; Advisory / Consultancy: Servier, Incyte, Pierre Farbre; Speaker Bureau / Expert testimony: Servier, Incyte, Pierre Farbre; Research grant / Funding (institution): Pfizer, Sirtex; Travel / Accommodation / Expenses: Servier, Incyte , Pierre Farbre. J. Desai: Advisory / Consultancy: Amgen, Pierre Fabre, Beigene, Bayer, GlaxoSmithKline, Merck KGaA, Boehringer Ingelheim, Roche/Genentech, IQVIA, Novartis, Pfizer, Daiichi-Sankyo; Research grant / Funding (institution): Amgen, Astra Zeneca, Beigene, BMS, GSK, Roche/Genentech, Novartis ; Travel / Accommodation / Expenses: Pierre Fabre. B. Alkuzweny: Full / Part-time employment: Pfizer. X. Zhang: Shareholder / Stockholder / Stock options: Pfizer; Full / Part-time employment: Pfizer; Spouse / Financial dependant: Pfizer. C. Guenzil: Shareholder / Stockholder / Stock options: Pfizer Pharma GmbH; Full / Part-time employment: Pfizer Pharma GmbH. S. Kopetz: Advisory / Consultancy: Genentech, EMD Serono, Merck, Holy Stone Healthcare, Novartis, Lilly, Boehringer Ingelheim, AstraZeneca/MedImmune, Bayer Health, Redx Pharma, Ipsen, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, GlaxoSmithKline, Jazz Pharmaceuticals, Iylon, Xilis, Abbvie, Amal Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotech, Bicara Therapeutics, Endeavor BioMedicines, Numab, Johnson & Johnson/Janssen, Genomic Health, Frontier Medicines, Replimune, Taiho Pharmaceutical, Cardiff Oncology, Ono Pharmaceutical, Bristol-Myers Squibb-Medarex, Amgen, Tempus, Foundation Medicine, Harbinger Oncology, Inc, Takeda, CureTeq, Zentalis, Black Stone Therapeutics, NeoGenomics Laboratories, Accademia Nazionale Di Medicina,; Research grant / Funding (self): Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, Daiichi Sankyo. The author has declared no conflicts of interest.