TY - JOUR
T1 - Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-Mutant colorectal cancer
AU - Corcoran, Ryan B.
AU - Atreya, Chloe E.
AU - Falchook, Gerald S.
AU - Kwak, Eunice L.
AU - Ryan, David P.
AU - Bendell, Johanna C.
AU - Hamid, Omid
AU - Messersmith, Wells A.
AU - Daud, Adil
AU - Kurzrock, Razelle
AU - Pierobon, Mariaelena
AU - Sun, Peng
AU - Cunningham, Elizabeth
AU - Little, Shonda
AU - Orford, Keith
AU - Motwani, Monica
AU - Bai, Yuchen
AU - Patel, Kiran
AU - Venook, Alan P.
AU - Kopetz, Scott
N1 - Publisher Copyright:
© 2015 by American Society of Clinical Oncology.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - Purpose To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC). Patients and Methods A total of 43 patients with BRAF V600-mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples. Results Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft- bearing mice and the biopsied lesions from each corresponding patient. Conclusion The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.
AB - Purpose To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC). Patients and Methods A total of 43 patients with BRAF V600-mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples. Results Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft- bearing mice and the biopsied lesions from each corresponding patient. Conclusion The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.
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U2 - 10.1200/JCO.2015.63.2471
DO - 10.1200/JCO.2015.63.2471
M3 - Article
C2 - 26392102
AN - SCOPUS:84951745408
SN - 0732-183X
VL - 33
SP - 4023
EP - 4031
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 34
ER -