FDA Approves Liquid Biopsy CDx for Encorafenib Regimen in BRAF V600E+ CRC

The FDA has approved Guardant360® CDx for use as a companion diagnostic to identify patients with BRAF V600E-mutant metastatic colorectal cancer who could derive benefit from treatment with encorafenib (Braftovi) in combination with cetuximab (Erbitux) and chemotherapy, according to a press release from the developer, Guardant Health.¹

The companion diagnostic is the first FDA-approved liquid biopsy for comprehensive genomic profiling in colorectal cancer. It is also approved for non–small cell lung cancer and breast cancer.

Data from the phase 3 BREAKWATER trial (NCT04607421), which evaluated multiple encorafenib-based regimens in patients with previously untreated BRAF-mutant metastatic colorectal cancer, supported the FDA’s decisions. Notably, BREAKWATER highlighted that patients who received encorafenib with cetuximab and chemotherapy experienced improved efficacy, with Guardant360 CDx enabling ctDNA analysis for treatment selection and resistance monitoring.

“This latest approval highlights the growing impact of liquid biopsy across advanced cancer care and underscores the utility of Guardant360 CDx in enabling precision therapy selection for patients with diverse, hard-to-treat tumors including aggressive colorectal cancer,” Helmy Eltoukhy, chairman and co-chief executive officer of Guardant Health, stated in the press release.¹ “With multiple FDA-cleared companion diagnostic claims across lung and breast cancer, and now colorectal cancer, and the ability to comprehensively profile tumor genomics from a simple blood draw, Guardant360 CDx is helping clinicians match patients to the right targeted therapies faster and more effectively.”

The BREAKWATER Trial

Results from BREAKWATER were shared at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.² The median progression-free survival (PFS) was 12.8 months (95% CI, 11.2-15.9) with the encorafenib regimen compared with 7.1 months (95% CI, 6.8-8.5) with standard of care (HR, 0.53; 95% CI, 0.407-0.677; P <.0001). The median overall survival (OS) was 30.3 months (95% CI, 21.7-not evaluable) vs 15.1 months (95% CI, 13.7-17.7), respectively (HR, 0.49; 95% CI, 0.375-0.632; P <.0001).

The confirmed overall response rate (ORR) was 65.7% (95% CI, 59.4%-71.4%) with the encorafenib regimen vs 37.4% (95% CI, 31.6%-43.7%) with standard of care. Notably, 34.8% and 17.6% of responders, respectively, were patients with a duration of response of at least 12 months.

A total of 637 patients were randomly assigned in a 1:1:1 ratio to receive either encorafenib plus cetuximab (n = 158), encorafenib plus cetuximab and chemotherapy (n = 236), and standard of care (n = 243). Treatment consisted of encorafenib at 300 mg orally once daily and cetuximab at 500 mg/m² intravenously once every 2 weeks for both encorafenib and cetuximab groups, with the experimental regimen also receiving chemotherapy consisting of oxaliplatin, leucovorin, and 5-fluouracil (mFOLFOX6).³

Eligible patients in the trial were 16 years or older, although some countries required at least 18 years of age for enrollment; had BRAF V600E-mutant colorectal cancer; and had not received prior systemic treatment for metastatic disease. Additional enrollment criteria included measurable disease per RECIST v1.1 guidelines; an ECOG performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function.

The dual primary end points of the trial were PFS and ORR, both by blinded independent central review. OS was a key secondary end point.

Regarding safety, the median duration of treatment was 49.8 weeks (range, 1.3-161.9) with encorafenib plus cetuximab and chemotherapy and 25.9 weeks (range, 2.0-150.0) with standard of care. Any treatment-emergent adverse event (TEAE) was observed in 100% of patients who received the experimental regimen vs 99.1% of those who received standard of care. Grade 3 or 4 TEAEs occurred in 81.5% and 66.8%, respectively. Grade 5 TEAEs occurred in 4.3% and 4.4%, and serious TEAEs occurred in 46.1% and 38.9%.

TEAEs led to treatment discontinuation, dose reduction, and dose interruption in 26.7%, 65.5%, and 91.4% of the experimental group and 17.5%, 54.1%, and 73.4% of the standard of care group. Grade 3 or 4 treatment-related AEs occurred in 76.3% and 58.5%, respectively.

The most common TEAEs in the experimental group were nausea, anemia, diarrhea, decreased appetite, and vomiting compared with diarrhea, nausea, decreased neutrophil count, fatigue, and decreased appetite in the standard of care group.

References

1. Guardant Health receives FDA approval for Guardant360® CDx as companion diagnostic for BRAFTOVI® (encorafenib) combination in patients with BRAF V600E-mutant metastatic colorectal cancer. News release. Guardant Health. January 22, 2026. Accessed January 22, 2026. https://tinyurl.com/7xdhvacz
2. Elez E, Yoshino T, Shen L, et al. First-line encorafenib + cetuximab + mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): Progression-free survival and updated overall survival analyses. J Clin Oncol. 2025;43(suppl 17):LBA3500. doi:10.1200/JCO.2025.43.17_suppl.LBA3500
3. Kopetz S, Yoshino T, Van Cutsem E, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med. 2025;31(3):901-908. doi:10.1038/s41591-024-03443-3