TY - JOUR
T1 - Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406)
AU - Kopetz, Scott
AU - Guthrie, Katherine A.
AU - Morris, Van K.
AU - Lenz, Heinz Josef
AU - Magliocco, Anthony M.
AU - Maru, Dipen
AU - Yan, Yibing
AU - Lanman, Richard
AU - Manyam, Ganiraju
AU - Hong, David S.
AU - Sorokin, Alexey
AU - Atreya, Chloe E.
AU - Diaz, Luis A.
AU - Allegra, Carmen
AU - Raghav, Kanwal P.
AU - Wang, Stephen E.
AU - Lieu, Christopher H.
AU - McDonough, Shannon L.
AU - Philip, Philip A.
AU - Hochster, Howard S.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - PURPOSE: BRAFV600E mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of BRAFV600E by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. METHODS: One hundred six patients with BRAFV600E-mutated metastatic CRC previously treated with one or two regimens were randomly assigned to irinotecan and cetuximab with or without vemurafenib (960 mg PO twice daily). RESULTS: Progression-free survival, the primary end point, was improved with the addition of vemurafenib (hazard ratio, 0.50, P = .001). The response rate was 17% versus 4% (P = .05), with a disease control rate of 65% versus 21% (P < .001). A decline in circulating tumor DNA BRAFV600E variant allele frequency was seen in 87% versus 0% of patients (P < .001), with a low incidence of acquired RAS alterations at the time of progression. RNA profiling suggested that treatment benefit did not depend on previously established BRAF subgroups or the consensus molecular subtype. CONCLUSION: Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in BRAFV600E-mutated CRC.
AB - PURPOSE: BRAFV600E mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of BRAFV600E by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. METHODS: One hundred six patients with BRAFV600E-mutated metastatic CRC previously treated with one or two regimens were randomly assigned to irinotecan and cetuximab with or without vemurafenib (960 mg PO twice daily). RESULTS: Progression-free survival, the primary end point, was improved with the addition of vemurafenib (hazard ratio, 0.50, P = .001). The response rate was 17% versus 4% (P = .05), with a disease control rate of 65% versus 21% (P < .001). A decline in circulating tumor DNA BRAFV600E variant allele frequency was seen in 87% versus 0% of patients (P < .001), with a low incidence of acquired RAS alterations at the time of progression. RNA profiling suggested that treatment benefit did not depend on previously established BRAF subgroups or the consensus molecular subtype. CONCLUSION: Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in BRAFV600E-mutated CRC.
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U2 - 10.1200/JCO.20.01994
DO - 10.1200/JCO.20.01994
M3 - Article
C2 - 33356422
AN - SCOPUS:85101090946
SN - 0732-183X
VL - 39
SP - 285
EP - 294
JO - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
IS - 4
ER -