Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
ENCO+CETU
Small bowel and appendix
Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR). Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.
For patients with previously treated BRAF V600E-mutated metastatic colorectal cancer (mCRC)*, who have good performance status, adequate organ function, and have not received prior EGFR or BRAF inhibitors.
*Patients with small bowel adenocarcinoma or appendiceal carcinoma may be considered for cetuximab funding if funding criteria are met. Refer to NDFP form for details.
encorafenib
Exceptional Access Program
(encorafenib - In combination with cetuximab or panitumumab in previously treated BRAF V600E-mutated metastatic colorectal cancer, according to clinical criteria)
(EAP Website)
(Refer to EAP for full details.
)
cetuximab
New Drug Funding Program
(Cetuximab - In Combination with Encorafenib for Previously Treated Metastatic Colorectal Cancer)
(NDFP Website
)
Weekly Cetuximab Schedule:
| encorafenib | 300 mg | PO | Daily Continuous |
| cetuximab | 400 mg /m² | IV | Day 1, Week 1 (loading dose) |
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| cetuximab | 250 mg /m² | IV | Day 1, Week 2 onwards |
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OR
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| encorafenib | 300 mg | PO | Daily Continuous |
| cetuximab | 500 mg /m² | IV | Day 1 |
Encorafenib: CONTINUOUS TREATMENT
Cetuximab 250 mg/m2 : REPEAT WEEKLY or
Cetuximab 500 mg/m2 : REPEAT EVERY 2 WEEKS
Until disease progression or unacceptable toxicity
Minimal
- Also refer to CCO Antiemetic Recommendations.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Cetuximab Premedications (prophylaxis for infusion reaction):
- H1-receptor antagonist (e.g. diphenhydramine 50 mg IV) 30-60 minutes prior to the dose.
- Corticosteroid IV 30-60 minutes prior to the dose.
- Consider discontinuing pre-medications after the 2nd infusion based on clinical judgment and the presence/severity of IR.
Other Supportive Care:
- Patients should use sun protection while receiving cetuximab and for 2 months after treatment completion.
- Consider pre-emptive therapy for EGFR inhibitor-related skin toxicity; the following was shown to be of benefit with panitumumab treatment, starting the day before treatment and continued until week 6. (Lacouture et al, 2010):
- Skin moisturizer applied to the face, hands, feet, neck, back and chest in the morning
- Sunscreen to exposed areas (SPF > 15, UVA and UVB) before going outdoors
- Hydrocortisone 1% cream to the face, hands, feet, neck, back and chest at bedtime
- Doxycycline (or minocycline) PO
- Refer to the Canadian recommendations for the management of skin rash during EGFR-targeted monoclonal antibody treatment for GI malignancies. (Melosky et al, 2009)
Doses should be modified according to the protocol by which the patient is being treated.
BRAF V600E mutation should be confirmed by a validated test prior to starting treatment.
Correct electrolyte imbalances prior to and during treatment.
A dermatologic evaluation should be performed prior to initiating treatment.
Refer to Interactions Section for dosing recommendations when co-administered with CYP3A4 inhibitors.
Dosage with toxicity
| Dose Level | Encorafenib Dose (mg daily) |
Cetuximab Dose |
Cetuximab Dose (mg/m² weekly) |
| 0 | 300 | 500 | 250 |
| -1 | 225 | 400 | 200 |
| -2 | 150 | 300 | 150 |
| -3 | Discontinue | Discontinue | Discontinue |
Encorafenib Dosage Modification for Toxicity
| Toxicity / Severity | Action# | |
|
Non-cutaneous malignancy |
Discontinue if RAS mutation-positive. | |
| Any new or worsening visual disturbance | Refer to ophthalmologist. | |
| Uveitis | Grade 1 not responding to ocular therapy |
Hold encorafenib for up to 6 weeks. If improved to Grade < 1, resume at same dose. |
| Grade 2 not responding to ocular therapy |
Hold encorafenib for up to 6 weeks. If improved to Grade < 1, resume at 1 dose level ↓. |
|
| Grade 3 | ||
| Grade 4 | Discontinue. | |
| QT Prolongation |
QTcF > 500 ms |
Hold until QTcF < 500 ms, then resume at 1 dose level ↓. If > 1 recurrence, discontinue. |
| QTcF > 500 ms AND > 60 ms increase from baseline |
Discontinue. | |
| Increase in AST or ALT | Grade 2, without improvement for 2 weeks |
Hold until < Grade 1 or baseline. Resume at same dose. |
| Grade 3 or 4 | See Other Adverse Reactions below. | |
| Hand-foot Syndrome | Grade 2, without improvement for 2 weeks |
Hold until < Grade 1. Resume at same dose for first occurrence. Resume at same dose or with 1 dose level ↓ if recurrent. |
| Grade 3 |
Hold until < Grade 1. |
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|
Other Dermatologic Reactions* |
Grade 2, without improvement for 2 weeks |
Hold until < Grade 1. Resume at same dose. |
| Grade 3 |
Hold until < Grade 1. Resume at same dose for first occurrence. Resume at 1 dose level ↓ if recurrent. |
|
| Grade 4 | Discontinue. | |
| Other Adverse Reactions (including hemorrhage)* | Grade 2, recurrent |
Hold for up to 4 weeks. If improves to < Grade 1 or baseline, resume at 1 dose level ↓. Discontinue if no improvement. |
| Grade 3, 1st occurrence | ||
| Grade 3, recurrent | Consider discontinuing. | |
| Grade 4, 1st occurrence |
Discontinue If improves to < Grade 1 or baseline, resume at 1 dose level ↓. Discontinue if no improvement. |
|
| Grade 4, recurrent | Discontinue. | |
#In the event that either encorafenib or cetuximab is discontinued due to unacceptable toxicity, the other drug must also be discontinued.
*Excluding new primary cutaneous malignancies, other ocular events, ILD/pneumonitis, cardiac dysfunction, CPK elevation, rhabdomyolysis, and VTE
Cetuximab Dosage Modification for Non-skin Toxicity
| Toxicity | Action | Next cycle* |
| Pneumonitis | Hold and investigate | Discontinue if confirmed. |
| Keratitis | Hold and refer to ophthalmologist | Consider discontinuation |
*In the event that either encorafenib or cetuximab is discontinued due to unacceptable toxicity, the other drug must also be discontinued.
Cetuximab Dosage Modification for Toxicity
|
Grade 3 or 4 Rash |
Action |
Outcome |
Cetuximab Dose* |
|
1st occurrence |
Delay infusion |
Improvement |
Resume at same dose |
|
No improvement |
Discontinue |
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2nd occurrence |
Delay infusion |
Improvement |
Resume at 1 dose level ↓ |
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No improvement |
Discontinue |
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| 3rd occurrence | Delay infusion 1 to 2 weeks |
Improvement | Resume at 1 dose level ↓ |
| No improvement | Discontinue | ||
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4th occurrence |
Discontinue |
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*In the event that either encorafenib or cetuximab is discontinued due to unacceptable toxicity, the other drug must also be discontinued.
Cetuximab - Management of Infusion-related Reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
| Grade | Management | Re-challenge |
| 1 or 2 |
Restart: |
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| 3 or 4 |
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Hepatic Impairment
Population pharmacokinetic model suggests hepatic impairment has no significant impact on cetuximab pharmacokinetics.
For increased AST/ALT during encorafenib treatment, refer to dose modifications table above.
| Hepatic Impairment | Encorafenib Starting Dose |
| Mild (Child-Pugh Class A) | 300 mg Daily |
| Moderate (Child-Pugh Class B) | No data available. |
| Severe (Child-Pugh Class C) |
Renal Impairment
Population pharmacokinetic model suggests renal impairment has no significant impact on cetuximab pharmacokinetics.
Encorafenib:
| Creatinine Clearance (mL/min) | Encorafenib Starting Dose |
| > 30 | No dose adjustment recommended |
| < 30 | No data available. |
Dosage in the Elderly
No dose adjustment required for patients > 65 years. There are insufficient data around the use of encorafenib in combination with cetuximab for mCRC in patients > 65 years or older to assess differences in efficacy or safety compared to younger patients.
Refer to encorafenib, cetuximab drug monograph(s) for additional details of adverse effects.
|
Very common (≥ 50%) |
Common (25-49%) |
Less common (10-24%) |
Uncommon (< 10%), but may be severe or life-threatening |
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Refer to encorafenib, cetuximab drug monograph(s) for additional details.
- Avoid if possible concomitant use of strong or moderate CYP3A4 inhibitors with encorafenib. Reduce encorafenib dose if used in combination; see dosage table below.
- Avoid concomitant use of strong or moderate CYP3A4 inducers with encorafenib.
- Avoid concomitant use with sensitive CYP3A4 substrates (e.g., hormonal contraceptives) where a minimal decrease in concentration may lead to therapeutic failure. If coadministration of a sensitive substrate cannot be avoided, adjust substrate dose based on its product monograph recommendations.
- Avoid concomitant use of QT/QTc prolonging agent with encorafenib due to additive risk of toxicity.
- Additive mucocutaneous toxicity may occur when cetuximab is given in combination with radiation.
Encorafenib Dose with CYP3A4 Inhibitors
| Planned Dose (mg) | Encorafenib Dose* (mg daily) | |
| with Strong CYP3A4 inhibitor | with Moderate CYP3A4 inhibitor | |
| 300 | 75 | 150 |
| 225 | 75 | 75 |
| 150 | 75^ | 75 |
*Resume previous dose after the inhibitor has been discontinued for 3 to 5 elimination half-lives.
^Monitor patients for adverse reactions and use clinical judgment; encorafenib exposure at 75mg daily (with a strong CYP3A4 inhibitor) is expected to be similar to the exposure at the 225mg daily dose (in the absence of a CYP3A4 inhibitor).
Refer to encorafenib, cetuximab drug monograph(s) for additional details.
Administration: Encorafenib
- Administer encorafenib with or without food.
- Capsules should be swallowed whole with water. Do not crush, dissolve, or open capsules.
- Grapefruit, starfruit, Seville oranges, their juices or products should be avoided during encorafenib treatment.
- If a dose is missed, patient may take within 12 hours of the missed dose. If more than 12 hours has elapsed from the missed dose, the dose should be skipped and taken at the next scheduled time. Extra capsules should not be taken to make up for a missed dose.
- Do not take an additional dose if vomiting occurs after taking encorafenib.
- Store at 15 - 30°C in the original bottle. Protect from moisture and do not remove the desiccant.
Administration: Cetuximab
- Do not shake or further dilute the solution.
- DO NOT administer as an IV push or bolus.
- Transfer undiluted solution into a compatible empty infusion container.
- Cetuximab is compatible with:
- glass,
- polyolefin, polyethylene, ethylene vinyl acetate (EVA), DEHP plasticized PVC, or PVC bags,
- polyethylene, EVA, PVC, polybutadiene or polymethane infusion sets, and
- polyethersulfone, polyamide or polysulfone in-line filters.
- Administer the undiluted solution via a low protein binding 0.22-micrometer in-line filter, piggybacking to the patient’s infusion line.
- Infuse initial loading dose over 2 hours, and maintenance dose over 1 hour as tolerated. (May require infusion at slower rate in those who experienced infusion reactions).
- Prime administration line with drug solution before infusion and may use NS to flush line at the end of infusion.
- A 1-hour observation period is recommended following each cetuximab infusion. Longer observation periods may be required in those who experienced infusion reactions.
- Should not be mixed or diluted with other drugs.
- Store unopened vials at 2-8°C.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
Contraindications
- Patients who have a hypersensitivity to this drug or any of its components
Warnings/Precautions
- Patients must have a validated test to confirm BRAF V600/E mutation before treatment; paradoxical activation of MAP-kinase signaling may occur when BRAF wild-type cells are exposed to BRAF inhibitors, such as encorafenib.
- Cetuximab is not indicated for the treatment of colorectal cancer in patients with RAS mutations or unknown RAS status.
- Exercise caution with encorafenib in patients with diabetes or with risk factors for QT prolongation, including known long QT syndromes, bradyarrhythmias, heart failure, and taking other QT prolonging agents.
- Patients were excluded from clinical trials if they have a history of Gilbert’s syndrome, abnormal LVEF, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. Consider benefits vs risks of using encorafenib and cetuximab in these patients.
- Use caution when driving or operating a vehicle or potentially dangerous machinery as vision problems have been reported.
- Use caution in patients with a history of, or pre-existing keratitis, dry eyes or contact lens use.
- Patients with poor performance status, or cardiopulmonary disease are at increased risk of severe cetuximab hypersensitivity.
Pregnancy and Lactation
- This regimen is not recommended for use in pregnancy. Adequate non-hormonal contraception should be used by patients and their partners while on treatment and after the last treatment dose. Recommended methods and duration of contraception may differ depending on the treatment. Refer to the drug monograph(s) for more information.
- Breastfeeding is not recommended during treatment and after the last treatment dose. Refer to the drug monograph(s) for recommendations after the last treatment dose (if available).
- Fertility effects:
- Encorafenib: Probable
- Cetuximab: Unknown
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
Recommended Clinical Monitoring
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Electrolytes, including serum magnesium, potassium and calcium; Baseline, before each cetuximab dose, and monthly for 2 months following completion of therapy
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Renal function tests; Baseline, before each cetuximab dose, and as clinically indicated
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Liver function tests; Baseline, monthly, and as clinically indicated
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CBC; Baseline, and as clinically indicated
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Skin examination for any new cutaneous malignancies; Baseline, every 2 months during treatment, and continue for up to 6 months after the last dose
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ECG (especially in patients at risk for QT prolongation); Baseline and as clinically indicated
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Clinical toxicity assessment for infusion reactions, hypersensitivity, bleeding, thromboembolism, fatigue, hyperglycemia, new primary non-cutaneous malignancies, rash, nail, respiratory, ocular, and GI effects; At each visit
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Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
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Outpatient prescription for home administration (encorafenib)
Cetuximab:
CADTH Reimbursement Recommendation: Encorafenib (for the treatment of patients with metastatic colorectal cancer with a BRAF V600E mutation after prior therapy). Canadian Journal of Health Technologies. July 2021.
Cetuximab drug monograph, Ontario Health (Cancer Care Ontario).
Encorafenib drug monograph, Ontario Health (Cancer Care Ontario).
Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med 2019; 38:1632-43.
Lacouture, ME, Mitchell EP, Piperdi B et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 2010; 28: 1351-7.
Melosky B, Burkes R, Rayson D, et al. Management of skin rash during EGFR-targeted monoclonal antibody treatment for gastrointestinal malignancies: Canadian recommendations. Current Oncology 2009; 16(10): 14-24.
Somerset, Wiltshire, Avon and Gloucestershire Cancer Alliance. Cetuximab and Encorafenib. February 15, 2021.
Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study. J Clin Oncol 2021 Feb 1;39(4):273-84.
The Clatterbridge Cancer Centre NHS Foundation Trust. Encorafenib and Cetuximab Metastatic Colorectal Cancer. October 9, 2020.
April 2024 Modified interaction section
Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph. Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
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