Triple BRAF/EGFR/MEK Inhibition Achieves 21% Response in BRAF V600E Colorectal Cancer with cfDNA Resistance Tracking
This phase 1 trial demonstrated that combined dabrafenib, trametinib and panitumumab overcame adaptive MAPK feedback reactivation in BRAF V600E colorectal cancer, achieving a 21% response rate versus 5% with BRAF inhibitor monotherapy. Pharmacodynamic analysis of paired biopsies confirmed that efficacy correlated with degree of MAPK suppression. Serial cell-free DNA analysis revealed emergent KRAS and NRAS mutations at progression, establishing cfDNA as a real-time window into resistance evolution.
The original study
Combined BRAF, EGFR, and MEK Inhibition in Patients with
- Authors
- Corcoran RB, André T, Atreya CE, Schellens JHM, Yoshino T, Bendell JC, et al.
- Journal
- Cancer discovery
- Type
- Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
- PMID
- 29431699
Original abstract
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.