Triple Therapy in Metastatic CRC With BRAF Mutations: The New Standard of Care?

SAN FRANCISCO — First-line treatment with targeted therapies plus chemotherapy offered overall response benefits in BRAF V600E-mutant metastatic colorectal cancer (mCRC), according to the BREAKWATER trial.

The study looked at encorafenib (Braftovi) and cetuximab (Erbitux) plus mFOLFOX6 chemotherapy (EC-FOLFOX6) versus standard of care (SOC), and demonstrated a 60.9% overall response rate with EC-FOLFOX6 versus 40% with SOC chemotherapy with or without bevacizumab (Avastin), reported Scott Kopetz, MD, PhD, of the MD Anderson Cancer Center in Houston.

The median duration of response was 13.9 months in the EC-FOLFOX6 arm and 11.1 months in the SOC arm, with the percentage of patients with a response that lasted at least 6 months or 12 months in the EC-FOLFAX6 arm more than double that in the SOC arm — 68.7% versus 34.1%, and 22.4% versus 11.1%, respectively, he said in a presentation at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. Findings were published simultaneously in Nature Medicine.

While overall survival (OS) data were not mature at the time of this analysis, there was an OS trend that favored EC-FOLFOX6. At a median follow-up for OS of 10.3 months in the EC-FOLFOX6 arm, and 9.8 months in the SOC arm, median OS was not reached in the EC-FOLFOX6 arm and 14.6 months in the SOC arm (HR 0.47, 95% CI 0.318-0.691, P=0.0000454). OS rates were 92.3% versus 87.1% at 6 months and 79.5% versus 66.1% at 12 months.

“This study supports EC and FOLFOX as a new standard of care in the first line for patients with BRAF V600E-mutated metastatic colorectal cancer, ” Kopetz said.

He also reported that BREAKWATER results formed the basis for the FDA approval in 2024 of the regimen for the treatment of these patients, including in the first-line setting.

“There’s certainly an impressive improvement in response — basically 21 percentage points,” observed invited discussant Wells Messersmith, MD, of the University of Colorado Cancer Center in Aurora. “And all of us are used to BRAF being this really difficult to treat, really aggressive patient population, so these are, to me, practice-changing results.”

The OS results are also “impressive, at least initially,” Messersmith said.

Referring to a case of a patient, age 41, with BRAF V600E-mutated proficient mismatch repair, microsatellite stable (pMMR/MSS) CRC, Messersmith said that instead of waiting for second- or third-line BRAF-targeting therapy, “based on this abstract … if I see one of these patients next week I’m going to treat them with encorafenib, cetuximab, and FOLFOX as first-line therapy.”

BRAF V600E mutations occur in 8-12% of mCRCs, and it has emerged as a distinct subtype marked by a very poor prognosis compared with wild-type disease, as well as resistance to standard chemotherapy regimens.

Kopetz noted that preclinical data showed there was a benefit in combining encorafenib, cetuximab, and cytotoxic chemotherapy, and that encorafenib plus cetuximab is approved for BRAF V600E-mutant CRC in second- and later-line settings based on results from the BEACON study.

“Despite this promising option of targeted treatments in the second and later lines as demonstrated in the BEACON study, first-line chemotherapies with or without a biologic agent (eg, bevacizumab) have had limited efficacy for BRAF V600E-mutant mCRC,” wrote Kopetz and colleagues in Nature Medicine.

“There are currently no first-line activation pathway-targeted treatments indicated for patients with BRAF V600E-mutant mCRC,” they added, so “a treatment that can demonstrate improved efficacy in the first-line setting is needed given the poor prognosis compared with BRAF wild-type mCRC.

BREAKWATER is an open-label, multicenter, phase III study that enrolled patients with previously untreated BRAF V600E-mutant mCRC. Patients had to have measurable disease and an MSS tumor. They were randomized to one of three treatment arms:

• SOC: Investigator’s choice of chemotherapy with or without bevacizumab (n=243)
• Triple combination: EC-FOLFOX6 (n=236)
• Dual combination: Encorafenib plus cetuximab: (n=158). Results from this group will be reported at a later date.

The median age of patients was 61; 49.5% were female; about 60% were white; and around 37% were Asian. ECOG performance status 1 was seen in 42%; most had tumors that were on the right; and 95.2% were pMMR/MSS.

The authors reported that treatment-emergent adverse events (TEAEs) occurred in 99.6% in the EC-FOLFOX6 arm versus 97.8% in the SOC arm. The most frequent TEAEs were nausea (51.1% vs 48.2%, respectively), anemia (36.4% vs 22.8%), diarrhea (34.2% vs 46.9%), decreased appetite (33.3% vs 25.0%), vomiting (33.3% vs 21.1%) and neutrophil count decreased (32.0% vs 28.1%).

Grade 3/4 TEAEs occurred in 74.0% of patients in the EC-FOLFOX6 arm versus 61.0% in the SOC arm, while grade 3/4 treatment-related AEs (TRAEs) occurred in 69.7% versus 53.9% of patients, respectively. Kopetz noted that there were no grade 5 TRAEs in the experimental arm.

“These encouraging data support this regimen to potentially become the new SOC in BRAF V600E-mutant mCRC; prespecified analyses of mature progression-free survival and overall survival data are planned,” the authors wrote.