Findings from the phase 3 BREAKWATER study indicate that encorafenib plus cetuximab and chemotherapy produces activity and is well-tolerated in metastatic colorectal cancer harboring BRAF V600E mutations.
Enocrafenib (Braftovi) with cetuximab (Erbitux) and chemotherapy was well-tolerated and resulted in anti-tumor responses in patients with BRAF V600E-mutant metastatic colorectal cancer (CRC), according to safety lead-in data from the phase 3 BREAKWATER study (NCT04607421) presented at the 2023 Gastrointestinal Cancers Symposium.1
“The work demonstrates encouraging safety and efficacy of the combinations of either FOLFOX or FOLFIRI and encorafenib/cetuximab, and strongly supports the currently enrolling phase 3 BREAKWATER study," Scott Kopetz, MD, told Targeted OncologyTM.
The combination of encorafenib plus cetuximab is FDA approved for the treatment of patients with previously treated BRAF V600E-mutated mCRC based on results from the phase 2 BEACON CRC trial (NCT02928224). In BEACON CRC, encorafenib/cetuximab, which was administered to 113 patients, achieved a median progression-free survival (PFS) of 4.3 months, and an objective response rate (ORR) of 19.5%.2 In a later study of first-line encorafenib in combination with binimetinib in patients with BRAF V600E-mutated mCRC (ANCHOR CRC; NCT03693170) a longer median PFS of 5.8 months was shown, as well as an ORR of 48%.3
The safety-lead in was designed to assess the toxicity of encorafenib/cetuximab plus chemotherapy before conducting the phase 3 study. Fifty-seven patients were included in the safety lead-in. All patients had BRAF V600E-mutant mCRC, received prior systemic therapy, and had evaluable disease, and ECOG performance status of 0 or 1, and adequate bone marrow, hepatic, and renal function. Patients could not have received prior treatment with BRAF or EGFR inhibitor, nor could they have been treated with oxaliplatin or irinotecan. Patients with symptomatic brain metastases or microsatellite instability-high, or mismatch repair deficient tumor were excluded from the study.
Patients in cohort 1 (n = 30) were given 300 mg encorafenib once daily (QD) plus 500 cetuximab mg/m2 every 2 weeks (Q2W) plus the combination of leucovorin, fluorouracil, and irinotecan (FOLFIR) Q2W in 29-day cycles. The 27 patients in cohort 2 received encorafenib/cetuximab and modified leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) Q2W in 28-day cycles.
The primary end point of the safety lead-in analysis was safety determined by the frequency of dose-limiting toxicities (DLTs). As a key secondary end point, safety was assessed by the percentage of patients with adverse events (AEs), dose interruptions, dose modifications, and treatment discontinuations. The study also assessed pharmacokinetics, and anti-tumor activity according to the ORR, duration of response (DOR), time to response (TTR), PFS, and overall survival (OS).
Efficacy results for patients being treated in the first and second line were evaluated separately.
Among those who received frontline encorafenib/cetuximab and mFOLFOX6 (n = 19), the ORR was 68.4% (95% CI, 46.0%-84.6%). Of the 68.4% of patients who achieved a response in this group, 5.3% had a complete response (CR), 63.2% had a partial response (PR), 21.1% had stable disease (SD), and 5.3% had progressive disease (PD).
The median PFS with frontline encorafenib/cetuximab and mFOLFOX6 was 11.1 months (95% CI, 8.5 to not evaluable [NE]).
Twelve patients received the frontline encorafenib/cetuximab and FOLFIRI, and among these patients, the ORR was 75.0% (95% CI, 46.8%-91.1%). CRs were observed in 16.7% of patients who responded to the combination, and there were PRs observed in 53.3%, and SD in 16.7. No patients in this group had PD. With frontline EC and FOLFIRI, the median PFS was NE (13.8-NE).
For second-line treatment, 8 patients were treated with encorafenib, cetuximab, and mFOLFOX6. The ORR in this group was 37.5% (95% CI, 13.7%-69.4%). No responses were CRs, but 37.5% of patients achieved a PR, 62.5% had SD, and no patients had PD.
The median PFS with second-line encorafenib/cetuximab and mFOLFOX6 was 10.8 months (95%CI, 4.3-NE).
The remaining 18 patients received the combination of encorafenib/cetuximab and FOLFIRI, in the second-line setting. The ORR observed in the group was 44.4% (95% CI, 24.6%-66.3%). Investigators observed CRs in 5.6% of patients, and PRs in 38.9%, SD in 38.9%, and no patients had PD.
Second-line treatment with encorafenib/cetuximab and FOLFIRI also achieved a median PFS of 12.6 months (95% CI, 6.9-NE).
“As an additional exploratory end point the BRAF V600E clearance was evaluated at week 6. This utilized Guardant Health 360 assay. And patients had paired samples at baseline and at week 6. Seventy-five percent of patients overall had a clearance of their BRAF V600E variant at that time point, reflecting activity of the regimen. And you can see that this was present both in first- and in second-line setting,” explained Kopetz, professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, during his poster presentation of BREAKWATER at the 2023 Gastrointestinal Cancers Symposium.
Circulating tumor DNA (ctDNA) profiling during treatment showed that the majority of patients had clearance of the BRAF V600E variant by week 6. Among those treated with encorafenib/cetuximab and FOLRIRI, the clearance was 57.1% for those treated in the first-line setting compared with 60.0% for those treated in the second-line. Patients who received encorafenib/cetuximab and mFOLFOX6 had 100.0% clearance when treated in the first-line setting vs 85.7%, when treated in the second-line.
Only 1 patient experienced a DLT during the safety lead-in, which was grade 4 neutropenia. The toxicity was resolved after day 7. Overall, treatment-emergent AEs (TEAEs) occurred in all patients in both cohorts. Serious AEs were observed in 48.1% of the mFOLFOX6 group vs 33.3% of those who were treated with FOLFIRI.
Grade ≥ 3 TEAEs occurred in 77.8% of patients in the encorafenib/cetuximab plus mFOLFOX6 cohort compared with 50.0% in the encorafenib/cetuximab plus FOLFIRI cohort, and TEAEs lead to dose reduction in 63.0% vs 40.0%, respectively. TEAEs leading to permanent discontinuation occurred in 18.5% vs 20%, respectively.
The majority of AEs in both cohorts were related to drugs used in the study. Serious AEs related to any drug occurred in 25.9% of patients treated with encorafenib/cetuximab plus mFOLFOX6 compared with 13.3% of the EC plus FOLFIRI cohort. There were no deaths resulting from TEAEs in either cohort.
The most common any-grade TEAEs observed in both cohorts were nausea (74.1%), pyrexia (48.1%), vomiting (40.7%), and diarrhea (33.3%).
“Early clearance of the ctDNA confirms this activity. And when we compare these results with historic results, both for first- or second-line chemotherapy, we're encouraged that this combination shows a high degree of activity,” said Kopetz. during his presentation.