Encorafenib/Cetuximab Plus FOLFIRI Shows Promise in mCRC

Josep Tabernero, MD, PhD,

Combining encorafenib (Braftovi) and cetuximab (Erbitux; EC) with the chemotherapy regimen of fluorouracil, leucovorin, and irinotecan (FOLFIRI) was tolerable and showed promising antitumor activity in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC) treated with 1 or fewer prior lines of systemic therapy, according to updated results from the safety lead-in (SLI) portion of the phase 3 BREAKWATER study (NCT02928224).¹

In a presentation at the 2024 ESMO Congress, Josep Tabernero, MD, PhD, reported that only 1 dose-limiting toxicity (DLT) occurred with the EC/FOLFIRI combination, which was grade 4 neutropenia that lasted more than 7 days. Treatment-related adverse events (TRAEs) of any grade were experienced by 93.3% of patients, with 50% of patients experiencing a grade 3/4 TRAE, and 16.7% of patients experiencing a serious AE related to study treatment. There were no deaths related to study treatment.

Efficacy data showed an objective response rate (ORR) of 83.3% (95% CI, 55.2%-95.3%) per blinded independent central review (BICR) in patients receiving EC plus FOLFIRI in the first-line metastatic setting. There were 2 complete responses (CRs), 8 partial responses (PRs), and 1 patient with stable disease (SD). The median duration of response (DOR) was not estimable (NE; 95% CI, 12.4-NE). The median progression-free survival (PFS) per BICR was NE (95% CI, 13.8-NE), and the median overall survival (OS) was NE (95% CI, 23.7-NE).

Among previously treated patients receiving EC plus FOLFIRI as a second-line therapy, the ORR per BICR was 44.4% (95% CI, 24.6%-66.3%). There was 1 CR, 7 PRs, and 7 patients with SD. The median DOR was 12.5 months (95% CI, 5.5-NE). The median PFS per BICR was 12.6 months (95% CI, 6.9-18.0), and the median OS was 19.7 months (95% CI, 13.9-25.1).

“The combination of EC plus FOLFIRI was tolerable without new safety signals in patients with BRAF V600E-mutant mCRC…[and] showed promising improvement in key efficacy measures,” said Tabernero, who is 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.

About the BREAKWATER Study

The open-label, multicenter BREAKWATER study is assessing the combination of encorafenib and cetuximab with or without chemotherapy in patients with mCRC. Patients must have histologically or cytologically confirmed stage IV CRC harboring a BRAF V600E mutation. Patients are ineligible if they have tumors that are microsatellite instability-high or mismatch repair-deficient.

The study has 3 components: an SLI portion, a phase 3 randomization, and a second randomization labeled as cohort 3. The SLI includes 2 cohorts: EC plus FOLFIRI (cohort 1) and EC plus 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6; cohort 2). The phase 3 component is a 3-arm randomization to EC alone; EC plus mFOLFOX6; or the control arm of bevacizumab (Avastin) plus FOLFIRI, mFOLFOX6, or capecitabine and oxaliplatin (CAPOX). Cohort 3 is randomizing patients to either EC/FOLFIRI or FOLFIRI plus bevacizumab.

Microscopic, photorealistic image of colorectal cancer cells - Generated with Adobe Firefly

Although no prior systemic therapy will be allowed for the phase 3 or cohort 3 components, patients were eligible for the SLI phase if they had received 0 or 1 prior lines of systemic therapy. However, the prior treatment line could not include BRAF or EGFR inhibitors or both oxaliplatin and irinotecan.

At the ESMO Congress, Tabernero shared data from cohort 1 of the SLI, which evaluated EC plus FOLFIRI. These patients received encorafenib at 300 mg orally once daily plus 500 mg/m² of cetuximab intravenously every 2 weeks combined with FOLFIRI every 2 weeks in 28-day cycles. The primary end point of the SLI portion of the trial was DLTs, with secondary end points including safety, pharmacokinetics, and antitumor activity.

There were 30 patients enrolled in cohort 1. The median age was 56.5 years (range, 37-77), and 66.7% were male. Regarding race, 76.7% were White, 20% were Asian, and 3.3% were Black. ECOG performance status was either 0 (73.3%) or 1 (26.7%). Seventy percent of patients had right-side tumors, and 30% had left-side tumors. Sixty percent of patients had 2 or fewer organs involved, and 40% had at least 3 organs involved. Two-thirds (66.7%) of patients had liver metastases. Twelve patients had not received prior therapy, and 18 patients had 1 prior line of therapy.

Additional safety data showed that all patients experienced a treatment-emergent adverse event (TEAE), with 63.3% and 46.7% experiencing a grade 3/4 TEAE and serious TEAE, respectively. TEAEs leading to dose reduction, dose interruption, or permanent discontinuation of any drug occurred in 53.3%, 73.3%, and 30% of patients, respectively. TEAEs were associated with 2 patient deaths.

TEAEs across all grades occurring in at least 30% of patients included nausea (50%), diarrhea (46.7%), constipation (43.3%), fatigue (43.3%), dermatitis acneiform (40%), rash (33.3%), and skin hyperpigmentation (30%). TEAEs of grade 3 or higher included 2 cases of dermatitis acneiform and 1 case each of diarrhea, constipation, and fatigue.

The EC combination is currently approved by the FDA for use in patients previously treated for BRAF V600E-mutated mCRC.²

“Currently, there are no specifically targeted first-line treatments for BRAF V600E-mutant mCRC which highlights the unmet need for novel treatment options for this patient population,” said Tabernero.¹

In his concluding remarks, Tabernero said, “These results support the continued evaluation of EC plus FOLFIRI as a treatment option for patients with BRAF V600E–mutated mCRC in cohort 3 of the BREAKWATER study.”

REFERENCES:

1. Tabernero J, Yoshino T, Kim TW, et al. Encorafenib + cetuximab (EC) + FOLFIRI for BRAF V600E-mutant metastatic colorectal cancer (mCRC): Updated results from the BREAKWATER safety lead-in (SLI). Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 515MO.

2. FDA approves encorafenib in combination with cetuximab for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA. April 8, 2020. Accessed September 14, 2024. https://tinyurl.com/zurpab34