This site is for New Zealand healthcare professionals. If you are a patient, please click here.

Please enter your email address to view the content of this website.

Not a member? Register
You are here: Home / Our Medicines / Zelboraf

Zelboraf

Zelboraf is a BRAF kinase inhibitor for metastatic melanoma.

zelboraf.jpg

Please review the Data Sheet before prescribing.

Zelboraf is a first-in-class potent inhibitor of oncogenic BRAF kinase.1

Zelboraf is a Prescription Medicine, available as 240 mg tablets for oral use.1

For information on dosage and administration of Zelboraf, please refer to the Data Sheet on the Medsafe website here.1

Medsafe registered indication1

Zelboraf is indicated for the treatment of unresectable stage IIIC or stage IV metastatic melanoma positive for the BRAF V600 mutation.

Zelboraf’s Mechanisms of Action

In cases of BRAF V600 mutation-positive metastatic melanoma, an overactive BRAF kinase protein leads to constitutive activation of the RAS-RAF pathway. 2

The constitutive activation of the RAS-RAF pathway can result in overactive cell proliferation, differentiation, and survival, contributing to the development and growth of metastatic melanoma.2,3

Zelboraf binds to the oncogenic mutant form of BRAF V600 kinase, preventing oncogenic BRAF from constitutively activating the RAS-RAF pathway.4

By inhibiting oncogenic BRAF V600, Zelboraf reduces oncogenic cell growth and proliferation.1,5,6

BRAF mutations in melanoma

Identification of BRAF V600 mutations is key to optimising treatment decisions and outcomes in metastatic melanoma, as only patients with the BRAF V600 mutations benefit from Zelboraf therapy. 7

Approximately 33% of metastatic melanoma patients in NZ are positive for BRAF V600 mutations.8

To be eligible for Zelboraf, patients must have their BRAF V600 mutation-positive tumor status confirmed by a clinically validated test.11

Detecting mutations

The advent of effective targeted therapy has highlighted the medical need for an accurate, rapid, and robust assay to detect mutations.9

The design of such an assay is complicated by a number of factors such as specimen age, tumour content, degree of necrosis, and presence of inhibitors; all of which confound assay results.9

In addition, the damaging effects of formalin fixation, or the melanin itself in melanoma, may interfere with the mutation detection.9

Lab-developed tests that detect BRAF mutations are not optimised to account for all these variables, potentially affecting validity and reproducibility of results, and have not been clinically validated with Zelboraf.9

The primary use of the cobas® 4800 BRAF V600 Mutation Test is for the detection of the BRAF V600 mutations in DNA extracted from formalin-fixed, paraffin-embedded human melanoma. It is intended to be used as an aid in selecting patients whose tumors carry BRAF V600 mutations for treatment with Zelboraf (vemurafenib).1,10,11

The cobas® 4800 BRAF V600 Mutation Test has a high sensitivity to the 91.9% of V600 mutations that are V600E, and cross-reactivity with V600K and V600D (6.1% and 1.3%, respectively).10,12

In the Phase 2 and 3 clinical trials, only patients that were positive for BRAF V600 mutations by the cobas® 4800 BRAF V600 Mutation Test were studied and shown to benefit from Zelboraf.9,13

Zelboraf’s Funding Status

Zelboraf is not funded by PHARMAC and patients will need to pay for treatment.

We provide a Patient Cost Share Programme to assist with the cost of Zelboraf for patients with BRAF V600 positive (BRAF V600+) metastatic melanoma. Please refer to the Patient Cost Share Programme section below for details.

References

  1. Zeboraf® (vemurafenib) Data Sheet. Available here.
  2. Lin K, Baritaki S, Militello L, et al. The Role of B-RAF Mutations in Melanoma and the Induction of EMT via Dysregulation of the NF-κB/Snail/RKIP/PTEN Circuit.Genes Cancer 2010;1(5):409–420.
  3. Wan PTC, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.Cell 2004;116(6):855–867.
  4. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.Nature 2010;467:596–599
  5. Yang H, Higgins, B, Kolinsky, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models.Cancer Res. 2010;70:5518–5527.
  6. Joseph EW, Pratilas CA, Poulikakos PI,et al.The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci. 2010;107:14903–14908.
  7. Chapman P, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation.N Engl J Med 2011;364:2507-2516.
  8. Jones AM, Ferguson P, Gardner J, et al. NRAS and EPHB6 mutation rates differ in metastatic melanomas of patients in the North Island versus South Island of New Zealand.Oncotarget. 2016 May 13. doi: 10.18632/oncotarget.9351. [Epub ahead of print].
  9. Halait H, Demartin K, Shah S, Soviero S, et al. Analytical performance of a real-time PCR-based assay for V600 mutations in the BRAF gene, used as the companion diagnostic test for the novel BRAF inhibitor vemurafenib in metastatic melanoma.Diagn Mol Pathol 2012;21:1-8.
  10. Anderson S, Bloom K J, Dino UV, et al. Multisite analytic performance studies of a real-time polymerase chain reaction assay for the detection of BRAF V600E mutations in formalin-fixed, paraffin-embedded tissue specimens of malignant melanoma. Arch Pathol Lab Med 2012;136:1-7.
  11. cobas® 4800 BRAF V600 Mutation Test FDA summary of safety and effectiveness data (SSED). http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110...
  12. Forbes S, Tang G, Bindal N, et al. COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer.Nucleic Acids Research 2010;38:D652–D657.
  13. Sosman JA, Kim KB,Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:704-14.

The Cotellic Zelboraf Cost Share Programme assists with the cost of Cotellic and Zelboraf for New Zealand patients with unresectable, stage IIIC or stage IV, BRAF V600 positive metastatic melanoma.

If your patient has private health insurance, it may be worthwhile they check their policy regarding cancer treatments like Cotellic and Zelboraf.

Health Insurance Quick Guide

All the details of the Cotellic Zelboraf Cost Share Programme are in the healthcare professional brochure. Click on the image below to download a copy.

Click on the images below to download copies of the Cotellic Zelboraf Cost Share Programme Enrolment Form and Easy Order Form.

BRAF mutation testing

We recommend clinicians use the cobas® 4800 BRAF V600 Mutation Test. The cobas® test is a polymerase chain reaction-based diagnostic test developed by Roche and clinically validated to identify tumours that carry the BRAF V600E mutation. The cobas® test is also the first FDA and CE-IVD approved test to help identify BRAF.1

Details of the cobas® test, and associated costs, can be obtained from the laboratories offering this test.


Reference

  1. The cobas® 4800 BRAF V600 Mutation Test and Package Insert. Available here

Zelboraf showed a survival benefit for patients with both pretreated and untreated BRAF V600 mutation-positive metastatic melanoma.1-3

Survival benefits were assessed in two studies, the BRIM3 (Phase 3) trial in previously untreated patients and the BRIM2 (Phase 2) trial in previously treated patients.1-2

BRIM31

BRIM 3 was a randomised, open-label, Phase 3 study that evaluated Zelboraf and dacarbazine in previous untreated BRAF V600E mutation-positive metastatic melanoma.Study participants (n=675) were randomised to receive either Zelboraf 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks.

The co-primary endpoints of overall survival (OS) and progression-free survival (PFS) were met:

  • Median OS of 13.6 months for Zelboraf compared to 9.6 months for dacarbazine (HR 0.62; p<0.001).
  • Median PFS of 5.32 months for Zelboraf compared to 1.61 months for dacarbazine (HR 0.26; p<0.001).

A total of 439 patients (65%) were evaluated for tumor response on the basis of having undergone randomisation at least 14 weeks before the clinical cut-off date.

In the Zelboraf group, most patients had a detectable decrease in tumor size, and 106 of 219 patients (48%; 95% CI, 42 to 55) had a confirmed objective response (including 2 patients with a complete response and 104 with a partial response), with a median time to response of 1.45 months.

In the dacarbazine group, a minority of patients had a detectable decrease in tumor size, and only 12 of 220 patients (5%; 95% CI, 3 to 9) met the criteria for a confirmed response (all partial responses), with a median time to response of 2.7 months.

In BRIM3, Zelboraf was associated with a highly significant improvement in Best Overall Response Rate (BORR = CR + PR) compared with dacarbazine (p<0.0001).1

BRIM22

BRIM2 was a randomised, open label, Phase 2 study that evaluated Zelboraf in previously treated patients with BRAF V600 mutation-positive melanoma.Study participants (n=132) received Zelboraf 960 mg orally twice daily.

The median duration of response was 6.7 months (95% CI, 5.6 to 8.1) and the median progression-free survival was 6.8 months.

The overall survival (OS) in BRIM2 was 15.9 months (95% CI, 11.6 to 18.3).

Key Safety Information

Zelboraf is generally well tolerated, with a manageable safety profile.3 For full safety information, please refer to the Zelboraf Data Sheet available here.3

Precautions3

Testing

  • Confirm BRAF V600 mutation-positive tumour status before treatment.

Cutaneous squamous cell carcinoma (cuSCC)

  • Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with Zelboraf
  • Dermatologic evaluation required prior to treatment; routine monitoring during and up to 6 months post-treatment.
  • Risk factors include age ≥ 65 years, prior skin cancer, chronic sun exposure.
  • Manage with excision and evaluation as per local standard of care.

Non-cutaneous SCC (non-cuSCC)

  • Reports of non-cuSCC have been received involving patients receiving Zelboraf
  • Head and neck examination prior to treatment, every 3 months during treatment.
  • Review routine chest CT scans prior to initiation, every 6 months during treatment and continue monitoring up to 6 months post-treatment.
  • Pelvic (for women) and anal examinations before and at end of treatment or when clinically indicated.

New primary melanoma

  • New primary melanomas have been reported in clinical trials
  • Monitor as per cutaneous SCC. Manage with resection.

Other malignancies

  • Use caution in patients with prior or concurrent cancer associated with RAS mutation.

Severe hypersensitivity/dermatological reactions

  • Severe dermatologic reactions have been reported in patients receiving Zelboraf
  • Serious hypersensitivity reactions, including anaphylaxis. Characterised by rash, erythema and hypotension.
  • Severe dermatological reactions including rare reports of SJS, TEN and DRESS.
  • Permanently discontinue treatment.

Potentiation of radiation toxicity

  • Cases of radiation recall and radiation sensitisation have been reported in patients treated with radiation either prior, during, or subsequent to Zelboraf treatment
  • Use with caution when given concomitantly or sequentially with radiation treatment.

Photosensitivity

  • Mild to severe photosensitivity was reported in patients who were treated with Zelboraf
  • Advise patients to avoid sun exposure and protect against sunburn; see Data Sheet for recommended dose modifications.

QT prolongation

  • Not recommended if QTc > 500 ms and in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or taking medicines known to prolong the QT interval.
  • Monitor ECG and electrolytes before treatment, monthly for the first 3 months and 3 monthly during treatment or after dose modification or clinically indicated.
  • If QTc prolonged (> 500 ms), temporarily interrupt treatment, correct electrolyte abnormalities and control cardiac risk factors.
  • If applicable, re-initiate at lower dose when QTc < 500 ms. If correction not achievable, treatment discontinuation may be required. See Data Sheet for further information.

Serious ophthalmologic reactions

  • Monitor routinely.

Creatinine

  • Mild to moderate abnormalities have been reported.
  • Measure serum creatinine before treatment and periodically during treatment as clinically indicated.
  • Dose reductions may be required. See Data Sheet for further information.

Liver injury

  • Liver injury, including cases of severe liver injury, has been reported.
  • Monitor liver enzymes and bilirubin before treatment and monthly during treatment.
  • Management may include dose reduction, treatment interruption or discontinuation.

Hepatic impairment

  • Use with caution.

Severe renal impairment

  • Use with caution.

Pregnancy: Category D

  • Contraception during treatment and 6 months post-treatment; avoid in lactation.

Interactions: Vemurafenib is a moderate inhibitor of CYP1A2 and an inducer of CYP3A4; consider dose reduction of P-gp substrates; caution in co-administration with warfarin. Concurrent administration with ipilimumab is not recommended.

Adverse effects3

Only very common side effects listed. See Data Sheet for full list.

  • Skin and subcutaneous tissue: rash; photosensitivity reaction; alopecia, pruritus, hyperkeratosis, maculo-papular and papular rash, actinic keratosis, dry skin, erythema, palmar-plantar erythrodysaesthesia syndrome.
  • Musculoskeletal and connective tissue: arthralgia, myalgia, pain (extremities, musculoskeletal and back), arthritis.
  • General: fatigue, peripheral oedema, pyrexia, asthenia.
  • Gastrointestinal: nausea, diarrhoea, vomiting, constipation.
  • Nervous system: headache, dysgeusia
  • Neoplasms: skin papilloma, cutaneous SCC, seborrheic keratosis.
  • Investigations: increased GGT, weight decreased.
  • Metabolism: decreased appetite
  • Respiratory, thoracic and mediastinal disorders: cough.
  • Injury, poisoning and procedural complications: sunburn.

Dose Modifications

Adverse drug reactions can generally be managed through dose modification, as shown in the tables below.3

Recommended Zelboraf Dose Modification

Toxicity Grade (CTC-AE)*

Zelboraf dose changes during
current treatment period

Dose modification at
resumption of treatment

Grade 1 or tolerable Grade 2

No change

N/A

Intolerable Grade 2 or Grade 3



1st Appearance^

Interrupt until resolved: grade 0 – 1

Reduce dose by 240 mg twice daily

2nd Appearance^

Interrupt until resolved: grade 0 – 1

Reduce dose by 240 mg twice daily

3rd Appearance^

Discontinue permanently

N/A

Grade 4



1st Appearance^

Discontinue permanently or interrupt
until resolved: grade 0 – 1

Reduce dose to 480 mg twice daily

2nd Appearance^

Discontinue permanently

N/A

*The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE)

^ Any AE where treatment interruption and dose reduction are clinically indicated and undertaken


Dose Modification Schedule Based On Prolongation of the QT Interval

Dose modification schedule based on
prolongation of the QT interval - QTc value

Recommended dose modification

QTc > 500 ms at baseline

Treatment not recommended.

QTc increase meets values of both > 500 ms and
> 60 ms change from pre-treatment values

Discontinue permanently.

1st occurrence of QTc > 500 ms during treatment
and change from pre-treatment value remains ≤ 60 ms

Temporarily interrupt treatment until QTc decreases below 500 ms.

See monitoring measures in section PRECAUTIONS, QT Prolongation.

Reduce dose by 240 mg twice daily.

2nd occurrence of QTc > 500 ms during treatment
and change from pre-treatment value remains ≤ 60ms

Temporarily interrupt treatment until QTc decreases below 500 ms.

See monitoring measures in section PRECAUTIONS, QT Prolongation.

Reduce dose by 240 mg twice daily.

3rd occurrence of QTc > 500 ms during treatment
and change from pre-treatment value remains ≤ 60ms

Discontinue permanently.


Please contact the Roche team for further information on the efficacy and/or safety of our products

References

  1. Chapman P, Hauschild A, Robert C, et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation.N Engl J Med 2011;364:2507-2516.
  2. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAFV600 Mutant Advanced Melanoma Treated with Vemurafenib.N Engl J Med. 2012;366:704-14.
  3. Zelboraf® (vemurafenib) Data Sheet. Available here.