Braftovi Regimen Is Promising in Metastatic Colorectal Cancer

A treatment combination of Braftovi (encorafenib), Erbitux (cetuximab) and chemotherapy showed promising anti-tumor activity in patients with BRAF V600E-mutant metastatic colorectal cancer who were previously treated with at least one line of systemic therapy, according to a presentation at the 2024 ESMO Congress.

A presentation at the conference highlighted updated safety results from the phase 3 BREAKWATER study, which included three components: a safety portion, a phase 3 randomization and a second randomization labeled as cohort 3.

The safety portion included two cohorts: Braftovi plus Erbitux and FOLFIRI chemotherapy (cohort 1); and Braftovi plus Erbitux and mFOLFOX6 chemotherapy (cohort 2). The phase 3 component randomized patients to three treatment groups: Erbitux alone; Erbitux plus mFOLFOX6 chemotherapy; or the control group of three chemotherapy regimens: FOLFIRI, mFOLFOX6, or capecitabine and oxaliplatin (CAPOX) with or without Avastin (bevacizumab). Cohort 3 randomly assigned patients to either Erbitux/FOLFIRI chemotherapy or FOLFIRI chemotherapy with or without Avastin.

Of note, the presentation of the BREAKWATER study at ESMO mainly focused on the safety portion, which included patients from cohort 1.

There were 30 patients enrolled in cohort 1. The median age was 56.5 years and 66.7% were men. The ECOG performance status was either 0 (ability to independently perform daily tasks; 73.3%) or 1 (ability to perform most daily tasks independently; 26.7%). Twelve patients had not received prior therapy, and 18 patients had one prior line of therapy.

In a presentation at the 2024 ESMO Congress, Dr. Josep Tabernero, head of the Department of Medical Oncology, Vall d’Hebron University Hospital and director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain, discussed findings from the trial. Tabernero reported that only one dose-limiting toxicity (DLT; side effects from drugs that prevent an increase in dose) occurred with the Erbitux/chemotherapy combination, which was grade 4 (life-threatening) neutropenia (lower levels of a white blood cell type) that lasted more than seven days.

Treatment-related side effects of any grade were experienced by 93.3% of patients, with 50% of patients experiencing grade 3 (severe)/4 treatment-related side effects, and 16.7% of patients experiencing a serious side effect related to study treatment. There were no deaths related to the study treatment.

Efficacy data showed an objective response rate (ORR; percentage of patients whose cancer shrunk or disappeared) of 83.3% in patients from cohort 1 receiving Braftovi, Erbitux plus chemotherapy in the first-line metastatic setting. There were two complete responses (CRs; disappearance of cancer), eight partial responses (PRs; cancer shrunk) and one patient with stable disease (SD; cancer did not improve or worsen). The median duration of response (DOR) was not estimable. The median progression-free survival (PFS; time patients are alive without their disease worsening) was not evaluable, meaning not enough patients had their disease worsened by the data collection date, and the median overall survival (OS; time patients live regardless of disease status) was not evaluable.

Among previously treated patients from cohort 1 receiving treatment as a second-line therapy, the ORR was 44.4%. There was one CR, seven PRs and seven patients with SD. The median DOR was 12.5 months. The median PFS was 12.6 months, and the median OS was 19.7 months.

“The combination of [Braftovi, Erbitux] plus chemotherapy was tolerable without new safety signals in patients with BRAF V600E-mutant metastatic colorectal cancer … [and] showed promising improvement in key efficacy measures,” said Tabernero.

The BREAKWATER trial assessed the combination of Braftovi and Erbitux with or without chemotherapy in patients with metastatic colorectal cancer. Patients must have confirmed stage 4 colorectal cancer harboring a BRAF V600E mutation. Patients were ineligible if they had tumors that are microsatellite instability-high or mismatch repair-deficient.

Safety Among Patients With Metastatic Colorectal Cancer

At the 2024 ESMO Congress, Tabernero shared data from cohort 1 of the safety portion, which evaluated the combination of Braftovi, Erbitux and chemotherapy. The primary goal of the safety portion of the trial was DLTs, with secondary goals including safety and antitumor activity. 

Additional safety data showed that all patients experienced treatment-emergent side effects, with 63.3% and 46.7% experiencing grade 3/4 treatment-emergent side effects and serious treatment-emergent side effects, respectively. Treatment-emergent side effects leading to dose reduction, dose interruption or permanent discontinuation of any drug occurred in 53.3%, 73.3% and 30% of patients, respectively. Treatment-emergent side effects were associated with two patient deaths.

Treatment-emergent side effects across all grades occurring in at least 30% of patients included nausea (50%), diarrhea (46.7%), constipation (43.3%), fatigue (43.3%), dermatitis acneiform (acne-like bumps; 40%), rash (33.3%) and skin hyperpigmentation (30%). Treatment-emergent side effects of grade 3 or worse included two cases of dermatitis acneiform and one case each of diarrhea, constipation and fatigue.

The Erbitux combination is currently approved by the FDA for use in patients previously treated for BRAF V600E-mutated metastatic colorectal cancer.

“Currently, there are no specifically targeted first-line treatments for BRAF V600E-mutant metastatic colorectal cancer, which highlights the unmet need for novel treatment options for this patient population,” said Tabernero.

In his concluding remarks, Tabernero said, “These results support the continued evaluation of Erbitux plus chemotherapy as a treatment option for patients with BRAF V600E-mutated metastatic colorectal cancer in cohort 3 of the BREAKWATER study.”

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