Colorectal cancer, BRAF-mutated

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

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

• See the main colorectal cancer page for general regimens.

3 regimens on this page 3 variants on this page

Guidelines

ESMO

• 2016: Van Cutsem et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. PubMed

Older

• 2013: Labianca et al. Early Colon Cancer: ESMO Clinical Practice Guidelines PubMed
• 2013: Balmaña et al. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. PubMed

Japanese Society for Cancer of the Colon and Rectum

• 2016: Watanabe et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer PubMed

NCCN

• NCCN does not have guidelines at this granular level; please see NCCN Guidelines - Colon Cancer.

SIOG

• 2014: Papamichael et al. Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013 PubMed

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)	1. Irinotecan & Cetuximab 2. FOLFIRI & Cetuximab	Superior OS (co-primary endpoint) Median OS: 9.3 vs 5.9 mo (HR 0.60, 95% CI 0.47-0.75)

Biomarker eligibility criteria

• BRAF p.V600E

Targeted therapy

• Binimetinib (Mektovi) 45 mg PO twice per day
• Encorafenib (Braftovi) 300 mg PO once per day
• 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 per day on days 8, 15, 22
  • Cycle 2 onwards: 250 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22

28-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 contains dosing details in manuscript 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) ESMO-MCBS (4)	2017-2019	Phase 3 (E-RT-switch-ooc)	1. Irinotecan & Cetuximab 2. FOLFIRI & Cetuximab	Superior OS (co-primary endpoint) Median OS: 9.3 vs 5.9 mo (HR 0.60, 95% CI 0.47-0.75)

Biomarker eligibility criteria

• BRAF V600E

Targeted therapy

• Encorafenib (Braftovi) 300 mg PO once per day
• 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 per day on days 8, 15, 22
  • Cycle 2 onwards: 250 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22

28-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 contains dosing details in manuscript 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

Irinotecan, Vemurafenib, Cetuximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kopetz et al. 2020 (SWOG 1406)	2014-NR	Randomized Phase 2 (E-esc)	Irinotecan & Cetuximab	Superior PFS (primary endpoint)

Biomarker eligibility criteria

• BRAF V600E, absence of NRAS and KRAS mutations

Chemotherapy

• Irinotecan (Camptosar) 180 mg/m² IV once on day 1

Targeted therapy

• Vemurafenib (Zelboraf) 960 mg PO twice per day
• Cetuximab (Erbitux) 500 mg/m² IV once on day 1

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 contains dosing details in manuscript 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

• Dabrafenib (Tafinlar) 150 mg PO twice per day
• Trametinib (Mekinist) 2 mg PO once per day
• Panitumumab (Vectibix) 6 mg/kg IV once on day 1

14-day cycles

References

1. Study 116833: NCT01750918