Colorectal cancer, BRAF-mutated

Note: the page has regimens specific to BRAF-mutated colon cancer.

Section editor
Travis Zack, MD, PhD
University of California San Francisco
San Francisco, CA, USA

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Last updated on 2024-07-23:
6 regimens on this page
7 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.



NCCN



Advanced or metastatic disease, second or third-line therapy

Binimetinib, Encorafenib, Cetuximab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kopetz et al. 2019 (BEACON CRC) 2017-2019 Phase 3 (E-RT-switch-ooc) 1a. Irinotecan & Cetuximab
1b. FOLFIRI & Cetuximab
Superior OS (co-primary endpoint)
Median OS: 9 vs 5.4 mo
(HR 0.52, 95% CI 0.39-0.70)
2. Encorafenib & Cetuximab Not reported

Note: the manuscript refers to 28-day cycles; this dosing is equivalent.

Biomarker eligibility criteria

  • BRAF p.V600E

Targeted therapy

7-day cycles

References

  1. BEACON CRC: Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, Wasan H, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Pfeiffer P, Orlov S, Lonardi S, Elez E, Kim TW, Schellens JHM, Guo C, Krishnan A, Dekervel J, Morris V, Calvo Ferrandiz A, Schmidt Tarpgaard L, Braun M, Gollerkeri A, Keir C, Maharry K, Pickard M, Christy-Bittel J, Anderson L, Sandor V, Tabernero J. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. N Engl J Med. 2019 Oct 24;381(17):1632-1643. Epub 2019 Sep 30. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02928224
    1. Update: Tabernero J, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Elez E, Gollerkeri A, Maharry K, Christy-Bittel J, Kopetz S. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol. 2021 Feb 1;39(4):273-284. link to original article link to PMC article PubMed
    2. PRO analysis: Kopetz S, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Belani A, Zhang X, Tabernero J. Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC. ESMO Open. 2022 Jun;7(3):100477. Epub 2022 May 30. link to original article link to PMC article PubMed


Encorafenib & Cetuximab

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kopetz et al. 2019 (BEACON CRC) 2017-2019 Phase 3 (E-RT-switch-ooc) 1a. Irinotecan & Cetuximab
1b. FOLFIRI & Cetuximab
Superior OS (co-primary endpoint)
Median OS: 8.4 vs 5.4 mo
(HR 0.60, 95% CI 0.45-0.79)
2. Binimetinib, Encorafenib, Cetuximab Not reported

Note: the manuscript refers to 28-day cycles; this dosing is equivalent.

Biomarker eligibility criteria

  • BRAF V600E

Targeted therapy

  • Encorafenib (Braftovi) 300 mg PO once per day on days 1 to 7
  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 120 minutes once on day 1
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once on day 1

7-day cycles

References

  1. BEACON CRC: Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, Wasan H, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Pfeiffer P, Orlov S, Lonardi S, Elez E, Kim TW, Schellens JHM, Guo C, Krishnan A, Dekervel J, Morris V, Calvo Ferrandiz A, Schmidt Tarpgaard L, Braun M, Gollerkeri A, Keir C, Maharry K, Pickard M, Christy-Bittel J, Anderson L, Sandor V, Tabernero J. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. N Engl J Med. 2019 Oct 24;381(17):1632-1643. Epub 2019 Sep 30. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02928224
    1. Update: Tabernero J, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Elez E, Gollerkeri A, Maharry K, Christy-Bittel J, Kopetz S. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol. 2021 Feb 1;39(4):273-284. link to original article link to PMC article PubMed
    2. PRO analysis: Kopetz S, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Belani A, Zhang X, Tabernero J. Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC. ESMO Open. 2022 Jun;7(3):100477. Epub 2022 May 30. link to original article link to PMC article PubMed
  2. BREAKWATER: NCT04607421


FOLFIRI & Cetuximab

FOLFIRI & Cetuximab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Cetuximab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kopetz et al. 2019 (BEACON CRC) 2017-2019 Phase 3 (C) 1. Encorafenib & Cetuximab
2. Binimetinib, Encorafenib, Cetuximab
Inferior OS

Note: the manuscript refers to 28-day cycles; this dosing is equivalent. There is an error in the folinic acid dosing in the manuscript; the dose here is the one that is listed in the supplemental protocol.

Biomarker eligibility criteria

  • BRAF p.V600E

Chemotherapy

Targeted therapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 120 minutes once on day 1, then 250 mg/m2 IV over 60 minutes once on day 8
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1 & 8

14-day cycles

References

  1. BEACON CRC: Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, Wasan H, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Pfeiffer P, Orlov S, Lonardi S, Elez E, Kim TW, Schellens JHM, Guo C, Krishnan A, Dekervel J, Morris V, Calvo Ferrandiz A, Schmidt Tarpgaard L, Braun M, Gollerkeri A, Keir C, Maharry K, Pickard M, Christy-Bittel J, Anderson L, Sandor V, Tabernero J. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. N Engl J Med. 2019 Oct 24;381(17):1632-1643. Epub 2019 Sep 30. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02928224
    1. Update: Tabernero J, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Elez E, Gollerkeri A, Maharry K, Christy-Bittel J, Kopetz S. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol. 2021 Feb 1;39(4):273-284. link to original article link to PMC article PubMed
    2. PRO analysis: Kopetz S, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Belani A, Zhang X, Tabernero J. Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC. ESMO Open. 2022 Jun;7(3):100477. Epub 2022 May 30. link to original article link to PMC article PubMed


Irinotecan & Cetuximab

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kopetz et al. 2019 (BEACON CRC) 2017-2019 Phase 3 (C) 1. Encorafenib & Cetuximab
2. Binimetinib, Encorafenib, Cetuximab
Inferior OS

Note: the manuscript refers to 28-day cycles; this dosing is equivalent.

Biomarker eligibility criteria

  • BRAF p.V600E

Chemotherapy

Targeted therapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 120 minutes once on day 1, then 250 mg/m2 IV over 60 minutes once on day 8
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1 & 8

14-day cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kopetz et al. 2020 (SWOG 1406) 2014 to not reported Randomized Phase 2 (C) Irinotecan, Vemurafenib, Cetuximab Inferior PFS

Biomarker eligibility criteria

  • BRAF p.V600E, absence of NRAS and KRAS mutations

Chemotherapy

Targeted therapy

14-day cycles

References

  1. BEACON CRC: Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, Wasan H, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Pfeiffer P, Orlov S, Lonardi S, Elez E, Kim TW, Schellens JHM, Guo C, Krishnan A, Dekervel J, Morris V, Calvo Ferrandiz A, Schmidt Tarpgaard L, Braun M, Gollerkeri A, Keir C, Maharry K, Pickard M, Christy-Bittel J, Anderson L, Sandor V, Tabernero J. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. N Engl J Med. 2019 Oct 24;381(17):1632-1643. Epub 2019 Sep 30. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02928224
    1. Update: Tabernero J, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Elez E, Gollerkeri A, Maharry K, Christy-Bittel J, Kopetz S. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol. 2021 Feb 1;39(4):273-284. link to original article link to PMC article PubMed
    2. PRO analysis: Kopetz S, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Belani A, Zhang X, Tabernero J. Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC. ESMO Open. 2022 Jun;7(3):100477. Epub 2022 May 30. link to original article link to PMC article PubMed
  2. SWOG S1406: Kopetz S, Guthrie KA, Morris VK, Lenz HJ, Magliocco AM, Maru D, Yan Y, Lanman R, Manyam G, Hong DS, Sorokin A, Atreya CE, Diaz LA, Allegra C, Raghav KP, Wang SE, Lieu CH, McDonough SL, Philip PA, Hochster HS. Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406). J Clin Oncol. 2021 Feb 1;39(4):285-294. Epub 2020 Dec 23. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02164916


Irinotecan, Vemurafenib, Cetuximab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kopetz et al. 2020 (SWOG 1406) 2014 to not reported Randomized Phase 2 (E-esc) Irinotecan & Cetuximab Superior PFS (primary endpoint)

Biomarker eligibility criteria

  • BRAF p.V600E, absence of NRAS and KRAS mutations

Chemotherapy

Targeted therapy

14-day cycles

References

  1. SWOG S1406: Kopetz S, Guthrie KA, Morris VK, Lenz HJ, Magliocco AM, Maru D, Yan Y, Lanman R, Manyam G, Hong DS, Sorokin A, Atreya CE, Diaz LA, Allegra C, Raghav KP, Wang SE, Lieu CH, McDonough SL, Philip PA, Hochster HS. Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406). J Clin Oncol. 2021 Feb 1;39(4):285-294. Epub 2020 Dec 23. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02164916


Dabrafenib, Trametinib, Panitumumab

Regimen

Study Evidence Efficacy
Awaiting publication (Study 116833) Phase 1/2 ORR: 26%

Note: efficacy and dosing details are from a 2017 ASCO abstract.

Biomarker eligibility criteria

  • BRAF V600E

Targeted therapy

14-day cycles

References

  1. Study 116833: NCT01750918