On October 11, 2023, the BRAF inhibitor encorafenib (Braftovi) with the MEK inhibitor binimetinib (Mektovi) was approved for patients with metastatic non–small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by a U.S. Food and Drug Administration (FDA)-approved test.^1,2

The FDA also approved the FoundationOne CDx (tissue) and FoundationOne Liquid CDx (plasma) as companion diagnostics for encorafenib with binimetinib. If no mutation is detected in a plasma specimen, tumor tissue should be tested.

Supporting Efficacy Data

Approval was based on findings in 98 patients with no prior BRAF or MEK inhibitor treatment in the multicenter PHAROS trial (ClinicalTrials.gov identifier NCT03915951). Patients received encorafenib at 450 mg once daily and binimetinib at 45 mg twice daily until disease progression or unacceptable toxicity.

Among 59 treatment-naive patients, objective responses were observed in 44 patients (75%, 95% confidence interval [CI] = 62%–85%), including a complete response in 15%. The median duration of response was not estimable (95% CI = 23.1 months to not estimable). Among 39 previously treated patients, objective responses were observed in 18 patients (46%, 95% CI = 30%–63%), including a complete response in 10%. The median duration of response was 16.7 months (95% CI = 7.4 months to not estimable).

How It Is Used

The recommended doses are encorafenib at 450 mg once daily and binimetinib at 45 mg twice daily, given until disease progression or unacceptable toxicity. Concomitant use of encorafenib with strong or moderate CYP3A4 inhibitors (eg, clarithromycin, erythromycin, diltiazem), strong or moderate CYP3A4 inducers (eg, dexamethasone, carbamazepine, phenytoin), and hormonal contraceptives should be avoided.

Safety Profile

In the PHAROS study, the most common adverse events of any grade were fatigue (61%), nausea (58%), diarrhea (52%), musculoskeletal pain (48%), vomiting (37%), abdominal pain (32%), and visual impairment (29%). The most common grade 3 or 4 adverse events included fatigue (8%), dyspnea (8%), diarrhea (7%), and hypertension (5%). The most common grade 3 or 4 laboratory abnormalities were increased lipase (14%), hyponatremia (11%), anemia (11%), and increased aspartate transaminase (10%).

Serious adverse events occurred in 38% of patients, most commonly hemorrhage (6%); diarrhea (4%); and anemia, dyspnea, and pneumonia (3% each). Adverse events led to discontinuation of encorafenib in 16% of patients and binimetinib in 17%. Fatal adverse events occurred in 2% of patients.

Encorafenib has warnings or precautions for new primary malignancies, tumor promotion in BRAF wild-type tumors, cardiomyopathy, hepatotoxicity, hemorrhage, uveitis, QT prolongation, embryofetal toxicity, risks associated with encorafenib as a single agent when binimetinib is interrupted or discontinued, and risks associated with combination treatment with binimetinib or cetuximab.

Binimetinib has warnings or precautions for new primary malignancies, cardiomyopathy, venous thromboembolism, ocular toxicities, interstitial lung disease, hepatotoxicity, rhabdomyolysis, hemorrhage, and embryofetal toxicity. Patients should be advised not to breastfeed while taking either agent.

REFERENCES

1. Braftovi (encorafenib) capsules, for oral use, prescribing information, Array BioPharma Inc, October 2023. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/210496s014lbl.pdf. Accessed October 25, 2023.

2. Mektovi (binimetinib) tablets, for oral use, prescribing information, Array BioPharma Inc, October 2023. Available at https://www.pfizermedicalinformation.com/en-us/mektovi. Accessed October 25, 2023.