What is encorafenib?
Encorafenib is an oral kinase inhibitor of serine/threonine-protein kinase B-Raf otherwise known as BRAF.
How does encorafenib work?
BRAF is a proto-oncogene that perpetuates tumor cell growth as part of the mitogen-activated protein kinase (MAPK) pathway. BRAF mutations (V600E, D, and K) are found in the cancer cells of nearly 50 percent of patients with metastatic malignant melanoma. Through inhibition of BRAF cell lines, encorafenib induces MAPK pathway suppression and tumor regression.
What is this approved for?
Encorafenib is approved in combination with binimetinib, a MEK inhibitor, for the treatment of unresectable or metastatic melanoma with a BRAFV600E or K mutation. A companion diagnostic test, THxID BRAF Kit, was approved with encorafenib to detect the BRAF mutation.
Encorafenib was approved based on the COLUMBUS trial which was a randomized, controlled, open-label, multicenter, phase III trial. Patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma were randomized 1:1:1 to receive encorafenib 450 mg once daily with binimetinib 45 mg twice daily, encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. The primary endpoint was progression-free survival (PFS) (encorafenib + binimetinib vs. vemurafenib). Median follow-up was 16.6 months. Median PFS was 14.9, 9.6, and 7.3 months in the encorafenib + binimetinib, encorafenib and vemurafenib groups. A 25 percent and 32 percent decline in the risk of progression/death occurred in encorafenib + binimetinib versus encorafenib (HR=0.75, p=0.051) and encorafenib versus vemurafenib (HR=0.68, p=0.007), respectively (Lancet Oncol 2018:19:603-615).
In an updated publication, the median overall survival for encorafenib + binimetinib was 33.6 months versus 16.9 months for vemurafenib (HR=0.61, p<0.0001) (Lancet Oncol 2018;19:1315-1327).
How do you administer this drug?
Encorafenib is given as 450 mg orally once daily with or without food in combination with binimetinib 45 mg orally twice daily. Swallow capsules whole with water. Encorafenib may be dose modified to 300 mg daily or 200 mg daily. Dosage forms include 50 and 75 mg capsules.
Are there any pre-medications needed?
None required.
What are the common side effects associated with encorafenib (> or =10%)?
The addition of binimetinib to encorafenib reduces skin toxicity (i.e., dry skin, rash, palmar-plantar erythrodysesthesia, skin papillomas), headache, alopecia, and arthralgias/myalgias. Gastrointestinal toxicities (diarrhea, nausea, vomiting, abdominal pain), increases in creatine phosphokinase, and blurred vision were more common in the combination. Fatigue occurs in ~25 percent. Toxicities in all groups were primarily grade 1/2.
What are the uncommon side effects associated with encorafenib (less than 10%)?
New primary malignancies (all grade 19%, grade 3/4 3.2%) and hemorrhages of the rectum, hematochezia, fatal intracranial bleeding, uveitis, and QTc prolongation have occurred.
Are there any important drug interactions?
Encorafenib is metabolized by, inducer, and inhibitor of CYP3A4. Concurrent use with strong or moderate CYP3A4 inhibitors (e.g., verapamil, erythromycin, grapefruit juice) should be avoided. If alternative medications are not available, an encorafenib dose reduction must occur. Avoid simultaneous administration of strong and moderate CYP3A4 inducers (e.g., phenytoin, St. John's Wort). Concomitant use of sensitive CYP3A4 substrates (e.g., alprazolam) may result in altered exposure of these medications.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
Approximately 47 percent of encorafenib is excreted in the urine. Metabolism is hepatic via CYP3A4. There are no known renal or hepatic dose adjustments; however, dosing has not been studied in severe renal or moderate/severe hepatic dysfunction.
Practical tips
New primary cutaneous and non-cutaneous squamous cell malignancies have been observed. It is recommended that dermatologic evaluations should occur at baseline, every 2 months during treatment, and for up to 6 months following treatment discontinuation. Patients should also be monitored routinely for non-cutaneous malignancies. Avoid concurrent administration of medications known to prolong the QTc interval.
What should my patients know about encorafenib?
Patients should contact their health care provider if they experience:
* Bleeding (blood in the stool, pink or brown urine, coughing up blood, or coffee ground emesis)
* Change in or development of new skin lesions
* Changes in vision
* Rapid heartbeat, rhythm abnormalities, or syncope
Females should be advised of reproductive risk and avoid breastfeeding until 2 weeks after encorafenib discontinuation. Male infertility may also occur.
What else should I know about encorafenib?
If encorafenib is given as a single agent (or if binimetinib is held), encorafenib must be given as 300 mg once daily.
What useful links are available?
* https://www.braftovimektovi.com/
* https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm611981.htm
Any ongoing clinical trials for encorafenib?
Encorafenib is being studied in combination with binimetinib and PD-1 monoclonal antibodies, as well as cetuximab in select solid tumors. More information is available about these clinical trials at https://clinicaltrials.gov.
HEIDI D. FINNES, PHARMD, BCOP, is Senior Manager of Pharmacy Cancer Research and Assistant Professor of Pharmacy in the College of Medicine at Mayo Clinic, Rochester, Minn. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and serves as a Pharmacy Forum column co-editor. JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as a Pharmacy Forum column co-editor.