Braftovi Combo Improves Response in BRAF V600E Metastatic Colorectal Cancer

Braftovi (encorafenib) plus Erbitux (cetuximab; EC) and FOLFIRI (folinic acid, fluorouracil and irinotecan) showed significant objective response rate (ORR) benefits versus the control regimen of FOLFIRI with or without Avastin (bevacizumab), in addition to a trend for improved overall survival (OS) and a tolerable safety profile in patients with BRAF V600E–mutant metastatic colorectal cancer (mCRC).

Data from the primary analysis of ORR by blinded independent central review (BICR) in cohort 3 of the phase 3 BREAKWATER study were presented during the 2026 Gastrointestinal Cancers Symposium (ASCO GI). The confirmed ORR with EC plus FOLFIRI in evaluable patients (73 patients) was 64.4% versus 39.2% with the control regimen (74 patients), meeting the primary end point of the study. Among those who responded to EC plus FOLFIRI, 4.1% achieved a complete response, 60.3% experienced a partial response, and 20.5% had stable disease; 1 patient each experienced non-CR/non–progressive disease (PD) and PD. Nine patients were not evaluable for response.

Moreover, the median time to response (TTR) with EC plus FOLFIRI was 6.9 months versus 7.1 months with the control regimen, and the estimated duration of response (DOR) in both arms was not estimable. In the EC/FOLFIRI arm, 57.4% of patients experienced a DOR of at least 6 months and 4.3% had a DOR of 12 months or longer. In the control arm, 34.5% of patients responded to treatment for at least 6 months, and no patients responded for at least one year.

Although the data are immature, a trend for an OS improvement was also observed with EC plus FOLFIRI vs the control regimen.

“BREAKWATER cohort 3 supports the option of FOLFIRI as a backbone in combination with EC as a potential new first-line standard of care for patients with BRAF V600E–mutant mCRC,” Dr. Scott Kopetz, said in a presentation of the data. Kopetz is the deputy chair for Translational Research and professor in the Department of Gastrointestinal (GI) Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. He is also a leader of the Department of Cancer Center Support Grant, GI Program; TRACTION medical director in the Division of Therapeutics Discovery; and associate vice president for Translational Integration.

What is the Design of the BREAKWATER Study in BRAF V600E–Mutant mCRC?

Study participants were randomly assigned 1:1 to receive EC plus FOLFIRI or the control regimen of FOLFIRI with or without Avastin. In addition to the primary end point of ORR by BICR, a key secondary end point was progression-free survival (PFS) by BICR. Other secondary end points comprised OS, DOR, TTR and safety.

Previous data from the study indicated that EC plus mFOLFOX6 led to significant improvements in ORR and PFS by BICR, as well as OS, compared with the control regimen in this population. In December 2024, the FDA granted accelerated approval to EC plus mFOLFOX6 for patients with mCRC harboring a BRAF V600E mutation based on earlier data from BREAKWATER.

Additional findings from the safety lead-in portion of the study revealed “encouraging response rates” with EC plus FOLFIRI, according to Kopetz, as well as PFS. He noted, “This promising activity was seen despite modestly lower exposure to irinotecan when combined with [Braftovi], in line with the predicted CYP3A-meditated interaction between [Braftovi] and irinotecan.”

What is the Safety Profile of EC Plus FOLFIRI in Patients With BRAF V600E–Mutated mCRC?

All patients who received EC plus FOLFIRI experienced treatment-emergent side effects compared with 98.5% of those who received the control treatment. Severe or life-threatening side effects, known as grade 3 or 4 events, occurred in 63.4% of patients in the EC plus FOLFIRI group and 70.6% of those in the control group. Treatment-related side effects led to death in 3 patients who received EC plus FOLFIRI and in 1 patient who received the control regimen.

Serious treatment-related side effects were reported in 39.4% of patients treated with EC plus FOLFIRI and in 36.8% of those treated with the control regimen.

Side effects also affected how treatment was given. Among patients who received EC plus FOLFIRI, 64.8% required a dose reduction and 74.6% had a temporary pause in treatment because of side effects. In this group, 11.3% permanently stopped at least one study treatment due to treatment-related side effects. In the control group, 41.2% of patients needed a dose reduction and 67.6% had treatment interrupted, while 8.8% permanently discontinued treatment due to side effects.

Overall, treatment-related side effects occurred in 97.2% of patients who received EC plus FOLFIRI and 95.6% of those who received the control regimen. Severe or life-threatening side effects occurred in 53.5% and 54.4% of patients, respectively. Fatal treatment-related side effects, known as grade 5 events, occurred in 1.4% of patients in the EC plus FOLFIRI group and 1.5% of those in the control group. Serious treatment-related side effects were reported in 23.9% of patients treated with EC plus FOLFIRI compared with 19.1% of those treated with the control regimen.

“No new safety signals were observed, and AEs were consistent with those that were expected for each of the study drugs,” Kopetz said.

The most common treatment-related side effects reported in at least 15% of patients who received EC plus FOLFIRI included nausea, which was mild or moderate in 56% of patients and severe in 3%; diarrhea, reported by 41% of patients with 10% experiencing severe symptoms; vomiting, reported by 38% with 3% severe; hair loss in 31% with 1% severe; anemia in 25% with 7% severe; and decreased neutrophil counts in 15%, all of which were severe.

Other common side effects included decreased appetite in 25% of patients with 4% severe; fatigue in 30%, all mild or moderate; neutropenia in 14% with 11% severe; skin darkening in 23%, all mild or moderate; dry skin in 21%; weakness in 15% with 3% severe; weight loss in 18%; joint pain in 17%; hand-foot syndrome in 17%; rash in 17%; decreased white blood cell counts in 10% with 7% severe; and constipation in 15%.

References

1. “BREAKWATER: Primary analysis of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC)” by Dr. Kopetz, et al., J Clin Oncol.
2. “Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial” by Dr. Kopetz, et al., Nat Med.
3. “Encorafenib, cetuximab and mFOLFOX6 in BRAF-mutant colorectal cancer” by Dr. Elez, et al., N Engl J Med.
4. “FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation” by Dr. FDA, et al., FDA.
5. “515MO Encorafenib + cetuximab (EC) + FOLFIRI for BRAF V600E-mutant metastatic colorectal cancer (mCRC): Updated results from the BREAKWATER safety lead-in (SLI)” by Dr. Tabernero, et al., Ann Oncol.

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