Targeted Combo Boosts PFS in BRAF-Mutant Metastatic Colorectal Cancer

CHICAGO — Adding encorafenib (Braftovi) and cetuximab (Erbitux) to FOLFIRI chemotherapy significantly improved progression-free survival (PFS) as first-line treatment of BRAF V600E-mutated metastatic colorectal cancer, according to secondary analysis of a randomized trial.

Results from cohort 3 of the BREAKWATER trial showed that adding the two targeted therapies to FOLFIRI (leucovorin, fluorouracil, and irinotecan) chemotherapy nearly doubled median PFS to 15.2 months compared with 8.3 months in the control group of patients who received FOLFIRI with or without bevacizumab (Avastin).

That difference represented a clinically meaningful 56% reduction in risk of progression or death (HR 0.44, 95% CI 0.27-0.79, P=0.0002), reported Scott Kopetz, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, at the annual meeting of the American Society of Clinical Oncology (ASCO).

At a median follow-up of about 21 months in both arms, overall survival (OS) was longer in the encorafenib/cetuximab arm, with median OS not reached versus 20.3 months in the control arm (HR 0.56, 95% CI 0.34-0.94).

“The cohort 3 data support the use of FOLFIRI as an option with [encorafenib/cetuximab] as a new standard of care for this BRAF V600E-mutant metastatic colorectal cancer population, and highlight the importance of prompt biomarker testing to really understand which patients have BRAF V600E mutations prior to starting first-line treatment,” Kopetz said. “And this really allows improvement in personalized care.”

Results from the study were published concurrently in the Annals of Oncology.

The combination of encorafenib and cetuximab plus a different chemotherapy regimen — mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) — was granted accelerated approval by the FDA in December 2024 for patients with metastatic colorectal cancer with a BRAF V600E mutation, based on objective response rate results from the phase III portion of BREAKWATER that evaluated the triple therapy.

In February of this year, the combination of the two targeted agents plus fluorouracil-based chemotherapy gained traditional approval for that indication based on positive PFS and OS results from the phase III portion of BREAKWATER, as well as results from a study presented earlier this year at the ASCO Gastrointestinal Cancers Symposium showing cohort 3 met its primary endpoint of objective response rate with encorafenib/cetuximab and FOLFIRI.

The decision to evaluate the targeted therapy duo with FOLFIRI was taken recognizing that FOLFOX is not an optimal option for all patients, whether due to prior adjuvant therapy with FOLFOX, pre-existing neuropathy, or patient or provider preference for a regimen that does not induce neuropathy, Kopetz explained.

The flexibility of the chemotherapy backbone in combination with encorafenib and cetuximab is “clinically relevant,” said invited discussant Filippo Pietrantonio, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan. The choice between FOLFOX or FOLFIRI can be made according to safety profiles and patient preference along with residual neurotoxicity following oxaliplatin-based adjuvant chemotherapy, he added.

“Future academic clinical trials should focus on optimizing this strategy [of using encorafenib and cetuximab with a fluorouracil-based chemotherapy regimen] in the first-line setting, especially in frail and elderly patient populations, or in investigating maintenance approaches, or intermittent treatment strategies — all with the aim to reduce treatment burden and toxicity,” Pietrantonio suggested. “This is important for patients.”

Cohort 3 of BREAKWATER was conducted across 187 sites in 27 counties and included 147 patients randomly assigned to either the encorafenib/cetuximab or control arms.

Patients had a median age of 62 years, 46.3% were male, and about 60% had an ECOG performance status of 0. Most had right-sided tumors (53.7%), and almost all were microsatellite stable/proficient mismatch repair (93.9%).

PFS was 70.7% with the targeted-therapy combo and 30.5% in the control group at 12 months and 46.8% and 24.4%, respectively, at 18 months. Estimated OS was 72.0% and 54.5%, respectively, at 18 months.

Regarding safety, grade 3 or 4 treatment-emergent adverse events (TEAEs) were reported in 70.4% of patients in the encorafenib/cetuximab arm versus 80.9% in the control arm. Serious adverse event rates and treatment-related adverse events were similar in the two arms. Treatment discontinuation rates due to TEAEs were 14.1% in the encorafenib/cetuximab arm and 10.3% in the control arm.

Kopetz pointed out adverse event rates were comparable between groups despite the fact that patients in the encorafenib/cetuximab arm had longer exposure to treatment (a median duration of 67.9 weeks vs 32.1 weeks). He also noted there were higher rates of grade 3 or worse anemia in the encorafenib/cetuximab group, “consistent with what we know about the toxicities of encorafenib.”