Reference Detail

Ref Type Journal Article
PMID (29431699)
Authors Corcoran RB, André T, Atreya CE, Schellens JHM, Yoshino T, Bendell JC, Hollebecque A, McRee AJ, Siena S, Middleton G, Muro K, Gordon MS, Tabernero J, Yaeger R, O'Dwyer PJ, Humblet Y, De Vos F, Jung AS, Brase JC, Jaeger S, Bettinger S, Mookerjee B, Rangwala F, Van Cutsem E
Title Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer.
Journal Cancer discovery
Vol 8
Issue 4
Date 2018 Apr
URL
Abstract Text Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428-43. ©2018 AACR.See related commentary by Janku, p. 389See related article by Hazar-Rethinam et al., p. 417This article is highlighted in the In This Issue feature, p. 371.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E colorectal cancer sensitive Dabrafenib + Panitumumab Phase I Actionable In a Phase I trial, combination therapy consisting of Tafinlar (dabrafenib) and Vectibix (panitumumab) resulted in an overall response rate of 10% (2/20, 1 complete response, 1 partial response), stable disease in 80% (16/20), and a median progression-free survival of 3.5 months in patients with BRAF V600E colorectal cancer (PMID: 29431699; NCT01750918). 29431699
BRAF V600E colorectal cancer no benefit Panitumumab + Trametinib Phase I Actionable In a Phase I trial, combination therapy consisting of Vectibix (panitumumab) and Mekinist (trametinib) resulted in an overall response rate of 0% (0/31), stable disease in 55% (17/31), and a median progression-free survival of 2.6 months in patients with BRAF V600E colorectal cancer (PMID: 29431699; NCT01750918). 29431699
BRAF V600E colorectal cancer predicted - sensitive Dabrafenib + Panitumumab + Trametinib Phase I Actionable In a Phase I trial, combination therapy consisting of Tafinlar (dabrafenib), Vectibix (panitumumab), and Mekinist (trametinib) resulted in an overall response rate of 21% (19/91, 1 complete response, 18 partial response), stable disease in 65% (59/91), and a median progression-free survival of 4.2 months in patients with BRAF V600E colorectal cancer (PMID: 29431699; NCT01750918). 29431699