Canafenib/encofenib combination shows efficacy in BRAF V600E+ CRC subpopulation

Subgroup analysis data fromthe phase 3 BREAKWWATER trial (NCT04607421) showed that patients with BRAF Encorafenib plus cetuximab (EC) in patients with V600E-mutated metastatic colorectal cancer (mCRC) ) and modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improved outcomes such as objective response rate (ORR), duration of response (DOR), overall survival (OS), and progression-free survival (PFS).

Results presented during the 2025 ESMO Cancer Gastrointestinal Congress showed that by blinded independent central review (BICR), EC plus mFOLFOX6 (n=236) had an ORR of 65.7% (95% CI, 59.4%-71.4%) compared with FOLFO The ORR for XIRI (fluorouracil plus leuvovorin, oxaliplatin, and irinotecan) plus bevacizumab (n=59) was 55.9% (95% CI, 21.5%-78.5%) and 38 for FOLFOXIRI (n=8). 1% (95% CI, 29.1%-48.1%) with mFOLFOX6 plus bevacizumab (n=97), 22.2% (95% CI, 9.0%-45.2%) with mFOLFOX6 (n=18), 29.3% (95%CI: 17.6%-44.5%) with CAPOX (capecitabine plus oxaliplatin) plus bevacizumab (n=41), 16.7% (95%CI: 3.0%-56.4%) with CAPOX (n=6).

The median DOR for EC plus mFOLFOX6 was 13.9 months (95% CI, 10.9-18.5), FOLFOXIRI plus bevacizumab was 9.8 months, and mFOLFOX plus bevacizumab was 10.8 months. In the EC+mFOLFOX6 group, 71.0% of patients had a DOR of at least 6 months, and 34.8% of patients had a DOR of at least 12 months.

EC plus mFOLFOX6, FOLFOXIRI plus bevacizumab, mFOLFOX The median PFS for 6 plus bevacizumab, mFOLFOX6 and CAPOX plus bevacizumab were 12.8 months (95% CI, 11.2-15.9) and 10.1 months (95% CI, 8) respectively. .3-13.7), 6.8 months (95% CI, 5.7-8.5), 4.3 months (95% CI, 2.7-11.0), and 5.9 months (95% CI, 4.5-9.9). The median OS of each group were 30.3 months (95% CI, 2.17-NE), 17.4 months (95% CI, 14.3-23.4), 14.7 months, 11.6 months and 14.5 months respectively. These results are consistent with a previous analysis of chemotherapy with or without bevacizumab in the first-line treatment of BRAF V600E mCRC.

This open-label, multicenter, Phase 3 study enrolled patients with BRAF V600E mutant mCRC who were at least 16 years of age, or at least 18 years of age according to country, with measurable disease according to RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and acceptable bone marrow, liver, and renal function. The patient was unlikely to have received previous systemic therapy for metastatic disease. Patients with prior exposure to BRAF or EGFR inhibitors, symptomatic brain metastases, microsatellite instability-hyper/mismatch repair-deficient tumors, or RAS-mutant disease were excluded.

Patients (n=637) were randomly assigned in a 1:1:1 ratio to the EC group (n=158), EC plus mFOLFOX6 group (n=236), or mFOLFOX 6/FOLFOXIRI/CAPOX control group (n=243), with or without bevacizumab. Of note, the trial protocol was subsequently revised to limit randomization to the EC plus mFOLFOX6 and control groups. The primary endpoints are PFS in BICR and ORR in BICR, and a key secondary endpoint is OS.

Both primary endpoints were met. Based on the first 110 patients enrolled in both groups, the ORR was 61% (95% CI, 52%-70%) for patients who received EC plus mFOLFOX6, compared with 40% (95% CII, 31%-49%) for patients who received chemotherapy with or without bevacizumab (P=0.0008). These data support the FDA's decision in December 2024 to accelerate approval of EC plus mFOLFOX6 for patients with mCRC carrying the BRAF V600E mutation, which is detected by an FDA-approved test. Median PFS with EC plus mFOLFOX6 was 12.8 months compared with 7.1 months with standard care (HR, 0.53; 95% CI, 0.41-0.68; P < .001). 3 In an interim analysis, OS with EC and mFOLFOX 6 was significantly longer than standard care, with a median of 30.3 months versus 15.1 months (HR 0.49; 95% CI 0.38-0.63; P < 0.001).

Of all patients randomized to the control group (n=243), 24.3% received FOLFOXIRI plus bevacizumab3.3% received FOLFOSIR treatment, 39.9% received mFOLFOX6 combined with bevacizumab, 7.4% received mFOLFOX6, 16.9% received CAPOX combined with bevacizumab, 2.5% received CAPOX, and 5.8% did not receive treatment. Patients who received FOLFOXIRI plus bevacizumab were younger, more often were male, had an ECOG performance status of 0, had 3 or more organ involvement at baseline, and had left-sided tumors compared with EC+ patients.

Reference materials:https://www.braftovi.com/