Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial

被引:5
|
作者
Kopetz, Scott [1 ]
Murphy, Danielle A. [2 ]
Pu, Jie [3 ]
Ciardiello, Fortunato [4 ]
Desai, Jayesh [5 ]
Van Cutsem, Eric [6 ,7 ]
Wasan, Harpreet Singh [8 ]
Yoshino, Takayuki [9 ]
Saffari, Hedieh [10 ]
Zhang, Xiaosong [10 ]
Hamilton, Phineas [2 ]
Xie, Tao [2 ]
Yaeger, Rona [11 ]
Tabernero, Josep [12 ,13 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
[2] Pfizer, La Jolla, CA USA
[3] Pfizer, New York, NY USA
[4] Univ Campania Luigi Vanvitelli, Naples, Italy
[5] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia
[6] Univ Hosp Gasthuisberg, Leuven, Belgium
[7] Katholieke Univ Leuven, Leuven, Belgium
[8] Hammersmith Hosp, Imperial Coll London, Div Canc, London, England
[9] Natl Canc Ctr Hosp East, Kashiwa, Japan
[10] Pfizer, South San Francisco, CA USA
[11] Mem Sloan Kettering Canc Ctr, New York, NY USA
[12] Cent Univ Catalonia, Univ Vic, Vall dHebron Hosp Campus, Barcelona, Spain
[13] Cent Univ Catalonia, Univ Vic, Vall dHebron Inst Oncol VHIO, Barcelona, Spain
关键词
MUTATIONAL SIGNATURES; ACQUIRED-RESISTANCE; COMBINED BRAF; INHIBITION; SUBTYPES; COMBINATION; DABRAFENIB; MECHANISMS; TRAMETINIB; SUBSETS;
D O I
10.1038/s41591-024-03235-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)+/- binimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. A greater understanding of biomarkers predictive of response to Enco+Cetux +/- Bini treatment is of clinical relevance. In this prespecified, exploratory biomarker analysis of the BEACON CRC study, we characterize genomic and transcriptomic correlates of clinical outcomes and acquired resistance mechanisms through integrated clinical and molecular analysis, including whole-exome and -transcriptome tissue sequencing and circulating tumor DNA genomic profiling. Tumors with higher immune signatures showed a trend towards increased OS benefit with Enco+Bini+Cetux. RAS, MAP2K1 and MET alterations were most commonly acquired with Enco+Cetux +/- Bini, and more frequent in patients with a high baseline cell-cycle gene signature; baseline TP53 mutation was associated with acquired MET amplification. Acquired mutations were subclonal and polyclonal, with evidence of increased tumor mutation rate with Enco+Cetux +/- Bini and mutational signatures (SBS17a/b). These findings support treatment with Enco+Cetux +/- Bini for patients with BRAF-V600E-mutant mCRC and provide insights into the biology of response and resistance to MAPK-pathway-targeted therapy. ClinicalTrials.gov registration: NCT02928224 Prespecified exploratory genomic and transcriptomic profiling of tumor tissues and circulating tumor DNA from patients with BRAF-V600E-mutant metastatic colorectal cancer who participated in the phase 3 BEACON CRC trial identifies biomarkers of response and mechanisms of acquired resistance to treatment with the BRAF inhibitor encorafenib plus the anti-EGFR antibody cetuximab, with or without the MEK inhibitor binimetinib.
引用
收藏
页码:3261 / 3271
页数:11
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