FDA Approves Guardant360 as Encorafenib Companion Diagnostic in BRAF V600E-Mutant mCRC

The FDA has granted accelerated approval to the Guardant360 CDx as a companion diagnostic to identify patients with BRAF V600E–mutant metastatic colorectal cancer (mCRC) who may benefit from treatment with encorafenib (Braftovi) in combination with cetuximab (Erbitux) and chemotherapy.¹

The approval was supported by findings from the phase 3 BREAKWATER trial (NCT04607421), in which encorafenib plus cetuximab and mFOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil [5-FU]) significantly improved overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) vs standard-of-care (SOC) therapy.^1,2

Of note, data from BREAKWATER also supported the FDA’s decision to grant accelerated approval to encorafenib plus cetuximab and mFOLFOX6 for patients with mCRC harboring a BRAF V600E mutation, as detected by an FDA-approved test, in December 2024.³

“This latest approval highlights the growing [effect] 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 CRC,” Helmy Eltoukhy, chairman and co–chief executive officer of Guardant Health, stated in a news release.¹ “With multiple FDA-cleared companion diagnostic claims across lung and breast cancer, and now CRC, 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.”

Guardant360 CDx is the first liquid biopsy to be FDA approved for comprehensive genomic profiling. Using a simple blood draw to detect BRAF V600E mutations and other clinically relevant genetic alterations, the test improves the rapid identification of patients who may be eligible for FDA-approved regimens. Guardant360 CDx is also approved as a companion diagnostic for therapies in non–small cell lung cancer and breast cancer.

What was the design of the BREAKWATER trial?

The open-label, global, multicenter study enrolled patients at least 16 years of age, with mCRC who had measurable disease per RECIST 1.1 criteria and had not received prior systemic therapy in the metastatic setting.¹ The presence of a BRAF V600E mutation per local or central testing was required. Patients also needed to have an ECOG performance status of 0 or 1, along with adequate bone marrow, hepatic, and renal function. Prior exposure to BRAF or EGFR inhibitors; symptomatic brain metastases; RAS-mutated disease, and microsatellite instability–high/mismatch repair–deficient tumors—provided that patients were not ineligible for immune checkpoint inhibitors, were not permitted.

The study enrolled patients across 28 countries. Patients were randomly assigned in a 1:1:1 fashion to receive:

• Oral encorafenib at 300 mg once daily plus 500 mg/m² of intravenous (IV) cetuximab once every 2 weeks (n = 158)
• Encorafenib, cetuximab, and IV mFOLFOX6 (oxaliplatin at 85 mg/m², leucovorin at 400 mg/m², and 5-FU at 400 mg/m² as an IV bolus, followed by 5-FU at 2400 mg/m² as a continuous infusion over 46 to 48 hours) once every 2 weeks (n = 236)
• Investigator’s choice of SOC therapies, including: FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan), or CAPOX (capecitabine and oxaliplatin) with or without bevacizumab (Avastin) or mFOLFOX6 (n = 243)

Notably, enrollment onto the encorafenib/cetuximab-alone cohort was stopped following a protocol amendment; subsequently, patients were randomly assigned 1:1 to the other 2 arms. Key stratification factors included region (United States/Canada vs Europe vs rest of world) and ECOG performance status (0 vs 1).

The study’s dual primary end points were ORR and PFS per blinded independent central review. OS was a key secondary end point. Other secondary end points included time to response, duration of response, progression after next line of therapy, patient-reported outcomes, pharmacokinetics, safety, and biomarker end points.

What efficacy and safety data were reported with encorafenib/cetuximab/mFOLFOX6 Ffom BREAKWATER?

Findings published in The New England Journal of Medicine demonstrated that, at a median follow-up of 16.8 months (95% CI, 15.1-18.4) in the experimental arm and 9.8 months (95% CI, 8.5-13.0) in the SOC arm, encorafenib plus cetuximab and mFOLFOX6 produced a median PFS of 12.8 months (95% CI, 11.2-15.9) vs 7.1 months (95% CI, 6.8-8.5) with SOC (HR, 0.53; 95% CI, 0.407-0.677; P < .0001).²Moreover, patients in the encorafenib arm achieved a median overall survival (OS) of 30.3 months (95% CI, 21.7-not estimable) vs 15.1 months (95% CI, 13.7-17.7) for those in the SOC arm (HR, 0.49; 95% CI, 0.375-0.632; P < .0001).

Regarding safety, the incidence of serious treatment-emergent adverse effects in these respective arms was 46.1% vs. 38.9%. The safety profile of the encorafenib combination was consistent with those known for each individual agent.

In the study, Guardant360 CDx enabled rapid circulating tumor DNA analysis for treatment selection and resistance monitoring, according to Guardant Health.¹

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. Guardent Health. January 22, 2026. Accessed January 22, 2026. https://investors.guardanthealth.com/press-releases/press-releases/2026/Guardant-Health-Receives-FDA-Approval-for-Guardant360-CDx-as-Companion-Diagnostic-for-BRAFTOVI-encorafenib-Combination-in-Patients-with-BRAF-V600E-Mutant-Metastatic-Colorectal-Cancer/default.aspx
2. Elez E, Yoshino T, Shen L, et al. Encorafenib, cetuximab, and mFOLFOX6 in BRAF-mutated colorectal cancer. N Engl J Med. Published online May 30, 2025. doi:10.1056/NEJMoa2501912
3. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed January 22, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf