encorafenib
Regulatory sources consulted
Approved indications
- Never as monotherapy. With binimetinib: unresectable/metastatic BRAF V600E/K melanoma or metastatic BRAF V600E NSCLC. In BRAF V600E metastatic colorectal cancer: with biweekly cetuximab and mFOLFOX6 or FOLFIRI, or with weekly cetuximab after prior therapy.
Contraindications
Absolute
- CIMA: hypersensitivity to the active substance or excipients; the FDA label establishes no formal contraindications.
Clinical warnings
- Do not use monotherapy because of paradoxical progression risk. Monitor new malignancies/RAS, liver function, hemorrhage, uveitis, and QT. Withhold if QTc >500 ms; discontinue if it also increases >60 ms. — OpenFDA, set_id 235dfc38-0f0b-4037-b501-7a9f4294740c
- With binimetinib, monitor LVEF at baseline, at 1 month, and every 2–3 months, and apply its ocular, pulmonary, thrombotic, and muscular warnings. — OpenFDA, set_id 235dfc38-0f0b-4037-b501-7a9f4294740c
- Perform dermatologic examination before starting, every 2 months during treatment, and for up to 6 months afterward; excise and evaluate suspicious lesions. — OpenFDA, set_id 235dfc38-0f0b-4037-b501-7a9f4294740c
Drug interactions
- HighCYP3A4 inhibitors or inducers
Mechanism: They substantially alter encorafenib exposure.
Recommendation: Avoid strong/moderate inhibitors. If unavoidable: current dose 450 mg→225 mg with a moderate or 150 mg with a strong inhibitor; 300 mg→150/75 mg; 225 mg→75/75 mg; 150 mg→75/75 mg. Return to the prior dose 3–5 half-lives after stopping the inhibitor. Avoid inducers.
OpenFDA, set_id 235dfc38-0f0b-4037-b501-7a9f4294740c
- HighOATP1B1/1B3 or BCRP substrates and QT drugs
Mechanism: Encorafenib may increase substrate exposure and add QT risk.
Recommendation: Monitor toxicity and avoid QT drugs when possible.
OpenFDA, set_id 235dfc38-0f0b-4037-b501-7a9f4294740c
Adverse events
Common (≥1%)
fatigue · nausea · vomiting · abdominal pain · arthralgia · diarrhea
Pregnancy and lactation
Verify pregnancy. Women must use non-hormonal contraception during treatment and for 2 weeks afterward. Do not breastfeed during treatment or for 2 weeks afterward. It may impair male fertility.
Recent literature (PubMed)
First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for BRAF V600E-mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P<0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for BRAF V600E-mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall survival are now available. We randomly assigned patients with untreated BRAF V600E-mutated metastatic colorectal cancer to receive EC, EC+mFOLFOX6, or standard care. The two primary end points were objective response (reported previously) and progression-free survival according to blinded independent central review in the EC+mFOLFOX6 group and the standard-care group. The key secondary end point was overall survival. Significantly longer progression-free survival was seen with EC+mFOLFOX6 than with standard care (median, 12.8 vs. 7.1 months; hazard ratio for progression or death, 0.53; 95% confidence interval [CI], 0.41 to 0.68; P<0.001). In an interim analysis, overall survival was significantly longer with EC+mFOLFOX6 than with standard care (median, 30.3 vs. 15.1 months; hazard ratio for death, 0.49; 95% CI, 0.38 to 0.63; P<0.001). The incidence of serious adverse events during treatment was 46.1% with EC+mFOLFOX6 and 38.9% with standard care. Safety profiles were consistent with those known for each agent. This trial showed significantly longer progression-free survival and overall survival with first-line treat
To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC). ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. Five systematic reviews and 10 randomized controlled trials met the systematic review inclusion criteria. Doublet chemotherapy should be offered, or triplet therapy may be offered to patients with previously untreated, initially unresectable mCRC, on the basis of included studies of chemotherapy in combination with anti-vascular endothelial growth factor antibodies. In the first-line setting, pembrolizumab is recommended for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumors; chemotherapy and anti-epidermal growth factor receptor therapy is recommended for microsatellite stable or proficient mismatch repair left-sided treatment-naive RAS wild-type mCRC; chemotherapy and anti-vascular endothelial growth factor therapy is recommended for microsatellite stable or proficient mismatch repair RAS wild-type right-sided mCRC. Encorafenib plus cetuximab is recommended for patients with previously treated BRAF V600E-mutant mCRC that has progressed after at least one previous line of therapy. Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients with colorectal peritoneal metastases; however, the addition of hyperthermic intraperitoneal chemotherapy is not recommended. Stereotactic body radiation therapy may be recommended following systemic therapy for patients with oligometastases of the liver who are not considered candidates for resection. Selective internal radiation therapy is not routinely recommended for patients with unilobar or bilobar metastases of the liver. Perioperative chemotherapy or surgery alone should be offered to patients with mCRC who are candidates for potentially curative resection of liver metastases. Multidisciplinary team management and shared decision
Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, 2.443; 95% confidence interval (CI): 1.403-4.253; 99.8% CI: 1.019-5.855; one-sided P = 0.0008). Median duration of response was 13.9 versus 11.1 months. At this first interim analysis of overall survival, the hazard ratio was 0.47 (95% CI: 0.318-0.691; repeated CI: 0.166-1.322). Serious adverse event rates were 37.7% versus 34.6%. The safety profiles were consistent with those known for each agent. BREAKWATER demonstrated a significantly improved response rate that was durable for first-line EC+mFOLFOX6 versus SOC in patients with BRAF V600E mCRC. ClinicalTrials.gov identifier: NCT04607421 .
Treatment with encorafenib plus binimetinib and encorafenib monotherapy is associated with improved progression-free survival (PFS) and overall survival (OS) compared with vemurafenib in patients with BRAF V600E/K-mutant metastatic melanoma. We report results from the 7-year analysis of COLUMBUS part 1 (NCT01909453) at 99.7 months (median duration between randomization and data cutoff). 577 patients with locally advanced unresectable or metastatic BRAF V600E/K-mutant melanoma who were treatment-naive or progressed after first-line immunotherapy were randomized 1:1:1 to encorafenib 450 mg once daily (QD) plus binimetinib 45 mg twice daily (BID) (n = 192), vemurafenib 960 mg BID (n = 191), or encorafenib monotherapy 300 mg QD (n = 194). No prior BRAF/MEK inhibitor was allowed. Seven-year PFS and OS rates (95 % CI) were 21.2 % (14.7-28.4 %) and 27.4 % (21.2-33.9%) in the encorafenib plus binimetinib arm and 6.4 % (2.1-14.0 %) and 18.2 % (12.8-24.3 %) in the vemurafenib arm, respectively. Median melanoma-specific survival (95 % CI) was 36.8 months (27.7-51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8-25.9 months) in the vemurafenib arm. Thirty-four long-term responders (complete/partial response ongoing at 7 years) were identified across arms. This is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/). No information is available on the clinical use of binimetinib during breastfeeding. Because binimetinib is 97% bound to plasma proteins, and the half-life of the drug is 3.5 hours, the amount in milk is