On April 8, 2020, encorafenib was approved for use in combination with cetuximab for the treatment of previously treated adult patients with metastatic colorectal cancer with a BRAF V600E mutation detected by a U.S. Food and Drug Administration (FDA)-approved test.^1,2

Encorafenib is not indicated for the treatment of patients with wild-type BRAF melanoma or wild-type BRAF colorectal cancer.

Supporting Efficacy Data

The current approval was based on findings in the encorafenib-plus-cetuximab group vs control group in the open-label, multicenter, phase III BEACON CRC trial (ClinicalTrials.gov identifier NCT02928224).³ Eligible patients had to have BRAF V600E mutation–positive metastatic colorectal cancer (detected by the Qiagen therascreen BRAF V600E RGQ PCR kit) with disease progression after one or two prior regimens. A total of 220 patients were randomly assigned to encorafenib at 300 mg once daily in combination with cetuximab, and 221 patients were assigned to a control group receiving either irinotecan or FOLFIRI (fluorouracil, leucovorin, irinotecan) plus cetuximab.

The study excluded patients with a history of Gilbert’s syndrome, abnormal left-ventricular ejection fraction, prolonged QTc (> 480 ms), uncontrolled hypertension, and a history or current evidence of retinal vein occlusion. Other eligibility criteria included the absence of prior treatment with a RAF, MEK, or EGFR inhibitor.

Patients had a median age of 61 years, 53% were female, 80% were white, and 15% were Asian. All had an Eastern Cooperative Oncology Group performance status of 0 (50%) or 1, 66% had received one prior therapy, 34% received two prior therapies, 93% had received oxaliplatin, and 52% had received irinotecan.

The major efficacy outcome measure was overall survival. The median overall survival was 8.4 months (95% confidence interval [CI] = 7.5–11.0 months) in the encorafenib-plus-cetuximab group vs 5.4 months (95% CI = 4.8–6.6 months) in the control group (hazard ration [HR] = 0.60, 95% CI = 0.45–0.79, P = .0003). The median progression-free survival on blinded independent central review was 4.2 months (95% CI = 3.7–5.4 months) vs 1.5 months (95% CI = 1.4–1.7 months; HR = 0.40, 95% CI = 0.31–0.52, P < .0001). Among the first 220 patients randomly assigned to the two groups (113 and 107), an objective response was observed in 20% vs 2% of patients (P < .0001), including a complete response in 5% vs 0%. The median duration of response was 6.1 months vs not reached.

How It Works

Encorafenib is a kinase inhibitor of BRAF V600E, as well as wild-type BRAF and CRAF in vitro cell-free assays. Mutations in the BRAF gene, such as those at BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth.

Encorafenib also binds to other kinases in vitro, including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36, and reduces ligand binding at clinically achievable concentrations. It inhibits the growth of tumor cell lines expressing BRAF V600E, D, and K mutations and produced tumor regression associated with RAF/MEK/ERK pathway suppression in mice with tumor cells expressing BRAF V600E.

In BRAF-mutant colorectal cancer, the induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. Coadministration of encorafenib and cetuximab had an antitumor effect greater than either drug alone in a mouse model of colorectal cancer with mutated BRAF V600E.

How It Is Used

The recommended dosage of encorafenib in the current indication is 300 mg orally once daily in combination with cetuximab until disease progression or unacceptable toxicity. The presence of a BRAF V600E mutation in tumor specimens must be confirmed using an FDA-approved test prior to initiating encorafenib treatment. Cetuximab prescribing information should be consulted for the recommended dosage when used in combination with encorafenib in this setting. Encorafenib must be discontinued if cetuximab is discontinued.

Recommended encorafenib dose reductions for adverse reactions are for 225 mg/d and then to 150 mg/d. Treatment should be discontinued if 150 mg/d is not tolerated.

Encorafenib product labeling provides detailed instructions on dose modifications for new primary malignancy; noncutaneous RAS mutation–positive malignancies, uveitis, QTc prolongation, hepatotoxicity, dermatologic toxicity, hemorrhage, recurrent grade 2 adverse reactions, and first occurrence of and recurrent grade 3 or 4 toxicity.

Coadministration of encorafenib with strong or moderate CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, indinavir) should be avoided. Prescribing information provides instructions on encorafenib dose reductions for strong or moderate inhibitors if coadministration cannot be avoided. Coadministration with strong or moderate CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin) should also be avoided. Coadministration of encorafenib with sensitive CYP3A4 substrates (eg, imatinib, anastrozole, paclitaxel) may increase toxicity or decrease the efficacy of these agents. Coadministration with hormonal contraceptives should be avoided.

Safety Profile

In BEACON CRC, the median duration of exposure to study therapy was 4.4 months in the encorafenib-plus-cetuximab group and 1.6 months in the control group (irinotecan or FOLFIRI plus cetuximab).

The most common adverse events of any grade (≥ 25%) in the encorafenib-plus-cetuximab group were fatigue (51% vs 50% in control group), nausea (34% vs 41%), diarrhea (33% vs 48%), dermatitis acneiform (32% vs 43%), abdominal pain (30% vs 32%), decreased appetite (27% vs 27%), arthralgia (27% vs 3%), and rash (26% vs 26%). The most common grade 3 or 4 adverse events included fatigue (7%), abdominal pain (4%), diarrhea (2%), and hemorrhage (2%). The most common grade 3 or 4 laboratory abnormalities in the encorafenib-plus-cetuximab group were lymphopenia (7%), increased alkaline phosphatase (4%), and anemia (4%).

Adverse events led to dose interruption of encorafenib in 33% of patients, with the most common causes being vomiting (4%), fatigue (4%), nausea (4%), pyrexia (3%), and diarrhea (3%), and to dose reduction in 9%, with the most common causes being fatigue (2%), arthralgia (2%), and peripheral neuropathy (2%). Adverse events led to permanent discontinuation of encorafenib in 10% of patients, with none of these adverse events occurring in more than one patient. One patient died of hemorrhage.

Encorafenib carries warnings/precautions for new primary malignancies (cutaneous and noncutaneous), tumor promotion in BRAF wild-type tumors, hemorrhage, uveitis, QT prolongation, and embryofetal toxicity. Patients should be monitored for malignancies and undergo dermatologic evaluations prior to, during, and following discontinuation of treatment. Ophthalmologic evaluation should be performed at regular intervals and for any visual disturbances. Electrolytes must be monitored before and during treatment. Patients should be advised not to breastfeed during encorafenib therapy. Fertility may be impaired in males. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves encorafenib in combination with cetuximab for metastatic colorectal cancer with a BRAF V600E mutation. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-combination-cetuximab-metastatic-colorectal-cancer-braf-v600e-mutation. Accessed April 17, 2020.

2. U.S. Food and Drug Administration: Highlights of Braftovi (encorafenib) capsules prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210496s006lbl.pdf. Accessed April 17, 2020.

3. Kopetz S, Grothey A, Yaeger R, et al: Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer. N Engl J Med 381:1632-1643, 2019.