Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer

Scott Kopetz; Axel Grothey; Rona Yaeger; Eric Van Cutsem; Jayesh Desai; Takayuki Yoshino; Harpreet Wasan; Fortunato Ciardiello; Fotios Loupakis; Yong Sang Hong; Neeltje Steeghs; Tormod K Guren; Hendrik-Tobias Arkenau; Pilar Garcia-Alfonso; Per Pfeiffer; Sergey Orlov; Sara Lonardi; Elena Elez; Tae-Won Kim; Jan H M Schellens; Christina Guo; Asha Krishnan; Jeroen Dekervel; Van Morris; Aitana Calvo Ferrandiz; L S Tarpgaard; Michael Braun; Ashwin Gollerkeri; Christopher Keir; Kati Maharry; Michael Pickard; Janna Christy-Bittel; Lisa Anderson; Victor Sandor; Josep Tabernero

doi:10.1056/NEJMoa1908075

Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer

Scott Kopetz, Axel Grothey, Rona Yaeger, Eric Van Cutsem, Jayesh Desai, Takayuki Yoshino, Harpreet Wasan, Fortunato Ciardiello, Fotios Loupakis, Yong Sang Hong, Neeltje Steeghs, Tormod K Guren, Hendrik-Tobias Arkenau, Pilar Garcia-Alfonso, Per Pfeiffer, Sergey Orlov, Sara Lonardi, Elena Elez, Tae-Won Kim, Jan H M SchellensChristina Guo, Asha Krishnan, Jeroen Dekervel, Van Morris, Aitana Calvo Ferrandiz, L S Tarpgaard, Michael Braun, Ashwin Gollerkeri, Christopher Keir, Kati Maharry, Michael Pickard, Janna Christy-Bittel, Lisa Anderson, Victor Sandor, Josep Tabernero

Istituto Oncologico Veneto

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.

METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.

RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.

CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).

Original language	English
Pages (from-to)	1632-1643
Number of pages	12
Journal	The New England journal of medicine
Volume	381
Issue number	17
DOIs	https://doi.org/10.1056/NEJMoa1908075
Publication status	Published - Oct 24 2019

Keywords

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols/adverse effects
Benzimidazoles/administration & dosage
Carbamates/administration & dosage
Cetuximab/administration & dosage
Colorectal Neoplasms/drug therapy
Disease Progression
Electrocorticography
Female
Humans
Intention to Treat Analysis
Irinotecan/therapeutic use
Kaplan-Meier Estimate
Male
Middle Aged
Mutation
Proto-Oncogene Proteins B-raf/genetics
Sulfonamides/administration & dosage
Survival Analysis

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Kopetz, S., Grothey, A., Yaeger, R., Van Cutsem, E., Desai, J., Yoshino, T., Wasan, H., Ciardiello, F., Loupakis, F., Hong, Y. S., Steeghs, N., Guren, T. K., Arkenau, H-T., Garcia-Alfonso, P., Pfeiffer, P., Orlov, S., Lonardi, S., Elez, E., Kim, T-W., ... Tabernero, J. (2019). Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. The New England journal of medicine, 381(17), 1632-1643. https://doi.org/10.1056/NEJMoa1908075

Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. / Kopetz, Scott; Grothey, Axel; Yaeger, Rona; Van Cutsem, Eric; Desai, Jayesh; Yoshino, Takayuki; Wasan, Harpreet; Ciardiello, Fortunato; Loupakis, Fotios; Hong, Yong Sang; Steeghs, Neeltje; Guren, Tormod K; Arkenau, Hendrik-Tobias; Garcia-Alfonso, Pilar; Pfeiffer, Per; Orlov, Sergey; Lonardi, Sara; Elez, Elena; Kim, Tae-Won; Schellens, Jan H M; Guo, Christina; Krishnan, Asha; Dekervel, Jeroen; Morris, Van; Calvo Ferrandiz, Aitana; Tarpgaard, L S; Braun, Michael; Gollerkeri, Ashwin; Keir, Christopher; Maharry, Kati; Pickard, Michael; Christy-Bittel, Janna; Anderson, Lisa; Sandor, Victor; Tabernero, Josep.

In: The New England journal of medicine, Vol. 381, No. 17, 24.10.2019, p. 1632-1643.

Research output: Contribution to journal › Article › peer-review

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, H-T, Garcia-Alfonso, P, Pfeiffer, P, Orlov, S, Lonardi, S, Elez, E, Kim, T-W, Schellens, JHM, Guo, C, Krishnan, A, Dekervel, J, Morris, V, Calvo Ferrandiz, A, Tarpgaard, LS, Braun, M, Gollerkeri, A, Keir, C, Maharry, K, Pickard, M, Christy-Bittel, J, Anderson, L, Sandor, V & Tabernero, J 2019, 'Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer', The New England journal of medicine, vol. 381, no. 17, pp. 1632-1643. https://doi.org/10.1056/NEJMoa1908075

Kopetz, Scott ; Grothey, Axel ; Yaeger, Rona ; Van Cutsem, Eric ; Desai, Jayesh ; Yoshino, Takayuki ; Wasan, Harpreet ; Ciardiello, Fortunato ; Loupakis, Fotios ; Hong, Yong Sang ; Steeghs, Neeltje ; Guren, Tormod K ; Arkenau, Hendrik-Tobias ; Garcia-Alfonso, Pilar ; Pfeiffer, Per ; Orlov, Sergey ; Lonardi, Sara ; Elez, Elena ; Kim, Tae-Won ; Schellens, Jan H M ; Guo, Christina ; Krishnan, Asha ; Dekervel, Jeroen ; Morris, Van ; Calvo Ferrandiz, Aitana ; Tarpgaard, L S ; Braun, Michael ; Gollerkeri, Ashwin ; Keir, Christopher ; Maharry, Kati ; Pickard, Michael ; Christy-Bittel, Janna ; Anderson, Lisa ; Sandor, Victor ; Tabernero, Josep. / Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. In: The New England journal of medicine. 2019 ; Vol. 381, No. 17. pp. 1632-1643.

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title = "Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer",

abstract = "BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).",

keywords = "Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Benzimidazoles/administration & dosage, Carbamates/administration & dosage, Cetuximab/administration & dosage, Colorectal Neoplasms/drug therapy, Disease Progression, Electrocorticography, Female, Humans, Intention to Treat Analysis, Irinotecan/therapeutic use, Kaplan-Meier Estimate, Male, Middle Aged, Mutation, Proto-Oncogene Proteins B-raf/genetics, Sulfonamides/administration & dosage, Survival Analysis",

author = "Scott Kopetz and Axel Grothey and Rona Yaeger and {Van Cutsem}, Eric and Jayesh Desai and Takayuki Yoshino and Harpreet Wasan and Fortunato Ciardiello and Fotios Loupakis and Hong, {Yong Sang} and Neeltje Steeghs and Guren, {Tormod K} and Hendrik-Tobias Arkenau and Pilar Garcia-Alfonso and Per Pfeiffer and Sergey Orlov and Sara Lonardi and Elena Elez and Tae-Won Kim and Schellens, {Jan H M} and Christina Guo and Asha Krishnan and Jeroen Dekervel and Van Morris and {Calvo Ferrandiz}, Aitana and Tarpgaard, {L S} and Michael Braun and Ashwin Gollerkeri and Christopher Keir and Kati Maharry and Michael Pickard and Janna Christy-Bittel and Lisa Anderson and Victor Sandor and Josep Tabernero",

note = "Copyright {\textcopyright} 2019 Massachusetts Medical Society.",

year = "2019",

month = oct,

day = "24",

doi = "10.1056/NEJMoa1908075",

language = "English",

volume = "381",

pages = "1632--1643",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "17",

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TY - JOUR

T1 - Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer

AU - Kopetz, Scott

AU - Grothey, Axel

AU - Yaeger, Rona

AU - Van Cutsem, Eric

AU - Desai, Jayesh

AU - Yoshino, Takayuki

AU - Wasan, Harpreet

AU - Ciardiello, Fortunato

AU - Loupakis, Fotios

AU - Hong, Yong Sang

AU - Steeghs, Neeltje

AU - Guren, Tormod K

AU - Arkenau, Hendrik-Tobias

AU - Garcia-Alfonso, Pilar

AU - Pfeiffer, Per

AU - Orlov, Sergey

AU - Lonardi, Sara

AU - Elez, Elena

AU - Kim, Tae-Won

AU - Schellens, Jan H M

AU - Guo, Christina

AU - Krishnan, Asha

AU - Dekervel, Jeroen

AU - Morris, Van

AU - Calvo Ferrandiz, Aitana

AU - Tarpgaard, L S

AU - Braun, Michael

AU - Gollerkeri, Ashwin

AU - Keir, Christopher

AU - Maharry, Kati

AU - Pickard, Michael

AU - Christy-Bittel, Janna

AU - Anderson, Lisa

AU - Sandor, Victor

AU - Tabernero, Josep

PY - 2019/10/24

Y1 - 2019/10/24

N2 - BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).

AB - BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects

KW - Benzimidazoles/administration & dosage

KW - Carbamates/administration & dosage

KW - Cetuximab/administration & dosage

KW - Colorectal Neoplasms/drug therapy

KW - Disease Progression

KW - Electrocorticography

KW - Female

KW - Humans

KW - Intention to Treat Analysis

KW - Irinotecan/therapeutic use

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Mutation

KW - Proto-Oncogene Proteins B-raf/genetics

KW - Sulfonamides/administration & dosage

KW - Survival Analysis

U2 - 10.1056/NEJMoa1908075

DO - 10.1056/NEJMoa1908075

M3 - Article

C2 - 31566309

VL - 381

SP - 1632

EP - 1643

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 17

ER -