Generic Name and Formulations:
Vemurafenib 240mg; tabs.
Company:
Genentech, Inc.
Indications for ZELBORAF:
Treatment of unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.
Adult Dose for ZELBORAF:
Swallow whole with water. Take in the AM and PM (approx. 12 hours apart). ≥18yrs: 960mg twice daily; until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions or QTc prolongation: see literature. Dose reductions <480mg twice daily: not recommended.
Children's Dose for ZELBORAF:
<18yrs: not recommended.
Pharmacological Class:
Kinase inhibitor.
Warnings/Precautions:
Not for use in wild-type BRAF melanoma. Confirm BRAFV600E mutation-positive melanoma with FDA-approved test before treating. Risk of cutaneous squamous cell carcinoma (cuSCC): ≥65 years, prior skin cancer, chronic sun exposure; if occurs, do excision and continue without dose adjustment. Do dermatologic eva luation before therapy, every 2 months during, and consider monitoring 6 months after. Long QT syndrome or QTc >500ms, uncorrectable electrolyte abnormalities, or concomitant drugs that prolong the QT interval: not recommended. Monitor electrolytes before therapy and after dose adjustments. Monitor ECG at Day 15 of treatment, monthly during the 1st 3 months, then every 3 months thereafter, or more as needed. If QTc >500ms, interrupt therapy, correct electrolytes, and control cardiac risk factors. Severe hepatic or renal impairment. Monitor liver enzymes, bilirubin before therapy and monthly, or as needed. Monitor for ophthalmologic reactions routinely. Avoid sun exposure. Pregnancy (Cat. D); avoid. Use adequate contraception during therapy and for at least 2 months after. Nursing mothers: not recommended.
Interactions:
Concomitant CYP3A4, CYP1A2 or CYP2D6 substrates with narrow therapeutic indices: not recommended; if CYP1A2 or CYP2D6 substrates unavoidable, consider dose reduction of substrates. Caution with concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin) or inducers (eg, phenytoin, rifampin). May potentiate warfarin; monitor INR.
Adverse Reactions:
Arthralgia, rash, alopecia, fatigue, photosensitivity, nausea, pruritus, skin papilloma; cuSCC, severe hypersensitivity or dermatologic reactions (discontinue if occurs), prolonged QTc, uveitis.
How Supplied:
Tabs—120
Zelboraf and Companion Diagnostic Test Approved for Metastatic Skin Cancer
Zelboraf (vemurafenib) 240mg tablets by Genentech The FDA has approved Zelboraf (vemurafenib tablets; Genentech and Plexxikon) for the treatment of metastatic or unresectable melanoma in patients whose tumors express the BRAF V600E gene mutation. A companion diagnostic test, the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems) has been approved to help determine if a patient's melanoma cells have the BRAF V600E mutation. Zelboraf was reviewed under the FDA's expedited six-month priority review program.
The approvals of Zelboraf and the cobas 4800 BRAF V600 Mutation Test were based on data from BRIM3, a Phase 3, international, randomized, open-label, controlled, multicenter trial of 675 patients with late-stage melanoma with the BRAF V600E mutation who had not received prior therapy. Patients were assigned to receive either Zelboraf or dacarbazine. The trial was designed to measure overall survival. The median survival of patients receiving Zelboraf has not been reached (77% still living) while the median survival for those who received dacarbazine was 8 months (64% still living).
Zelboraf, an oral, small molecule, kinase inhibitor, will be available in a 240mg dosage strength tablet.
Molecular Analysis of Melanomas
There is considerable potential in diagnosing and treating melanoma in the future using molecular analysis, which may allow for its genetic decoding and personalization of treatment.
During Friday's plenary session, at the 2012 American Academy of Dermatology Summer Meeting, Hensin Tsao, MD, PhD, presented the “Role of Molecular Analysis in Melanoma.”
In addition to traditional methods of monitoring high-risk patients, “molecular analysis of blood or tissue can identify each patient's individual risk for melanoma,” stated Dr. Tsao. Mutations present in the P16 protein, BRCA1-associated protein-1 (BAP1 gene mutation), red-hair gene melanocortin 1 receptor (MC1R), micropthalmia-associated transcription factor (MITF) gene, and changes in tyrosinase can all be detected– any of which can signal an increased risk for melanoma.
Molecular analysis has also uncovered molecular grades in melanoma from high to low, indicating actual changes in the tumor itself. This will take diagnoses of melanomas to the next level, beyond the Breslow scale on melanoma thickness. It will improve the understanding of the complexities that define an aggressive tumor vs. a non-aggressive tumor and how the host interacts with that tumor.
Furthermore, molecular analysis could also reveal the organ from which the cancer originated, how the host factor is playing out, and whether the melanoma contains an immune signature inviting a welcomed immune response.
The genetic decoding of melanoma has led to the discovery of the v-raf murine sarcoma viral oncogene homolog B1 (the BRAF gene) which has led to targeted treatments. Zelboraf (vemurafenib tablets; Genentech) is the first anti-BRAF treatment that has been successful in treating metastatic melanoma.
Dr. Tsao shared what he felt was the biggest challenge, “Because the cancer genome is so mutable, often cancer cells will escape treatment strategies through a series of novel resistance mechanisms that have come to light in melanoma.”
Vemurafenib, Dabrafenib Linked to Cutaneous Side Effects
Vemurafenib, Dabrafenib Linked to Cutaneous Side Effects (HealthDay News) – The selective small molecule inhibitors of BRAF, vemurafenib and dabrafenib, are associated with diverse cutaneous side effects, including both malignant and benign growths, when used to treat patients with melanoma with the BRAF V600E mutation, according to research published online May 21 in the Journal of the American Academy of Dermatology.
Emily Y Chu, MD, PhD, of the Hospital of the University of Pennsylvania in Philadelphia, and colleagues eva luated the cutaneous adverse effects of vemurafenib and dabrafenib in 13 patients being treated for metastatic melanoma and one patient being treated for metastatic thyroid cancer.
The researchers found that, at an average of 12.6 weeks following initiation of treatment, but as early as one week, patients began displaying skin side effects. All 14 patients displayed at least one skin side effect, and 13 of the 14 patients displayed at least two different types of skin reactions. Eight patients developed one or more keratoacanthoma-like squamous cell carcinomas; 11 developed benign verrucous keratosis; eight developed single or multiple acantholytic dyskeratosis lesions consistent with warty dyskeratomas and Darier- or Grover-like rashes, respectively; and one patient developed palmoplantar hyperkeratosis.
"In summary, we have described several cutaneous side effects associated with selective BRAF inhibitor therapy for metastatic melanoma and thyroid cancer, many of which may be attributed to paradoxical activation the MAPK signaling pathway in nontumor cells," the authors write. "Awareness on the part of dermatologists and oncologists of the potential side effects of selective BRAF inhibitors will become increasingly important as these agents are used more widely."
Several authors disclosed financial ties to Roche, Genentech, and GlaxoSmithKline.
New Treatments for Advanced Melanoma
New Treatments for Advanced Melanoma In 2012, it is estimated that over 76,000 men and women in the United States will be diagnosed with melanoma, and close to 9,200 will die of the disease.1 Over 800,000 men and women have a history of melanoma, with a lifetime risk of 1 in 51 for both sexes.2 Melanoma, a major form of morbidity and mortality in the U.S., accounts for approximately 5% of skin cancers, but is the cause of the vast majority of skin cancer deaths.1 It is the fifth most common type of cancer among men and seventh among women.3 Melanoma is the second most common type of invasive cancer in young adults, second only to breast cancer.4 This trend is of particular concern, since the incidence of cutaneous melanoma is rapidly rising among young adults, especially women.5 With melanoma cases on the rise, there is a definite need for new treatment options.
Current research is focusing on regulatory pathways that stimulate the immune response against cancer cells. This can be done by blocking inhibitory immune checkpoint receptors such as cytotoxic T-lymphocyte-associated-protein 4 (CTLA-4) that down-regulates T-cell activation pathways. Anti-CTLA-4 is one of the first immunostimulatory monoclonal antibodies that has been used in malignant melanoma.6 Ipilimumab (Yervoy, Bristol-Myers Squibb), a fully human monoclonal antibody (IgG1) indicated for the treatment of unresectable or metastatic melanoma, blocks CTLA-4 and promotes antitumor immunity.7,8,9 Ipilimumab monotherapy in Phase 2 clinical trials has demonstrated antitumor activity in patients with metastatic melanoma.10,11,12 It has also demonstrated antitumor activity when combined with other anticancer agents, including vaccines such as the anticancer vaccine HLA-A*0201-restricted peptides derived from the melanosomal protein, glycoprotein 100 (gp100).13,14
Hodi and colleagues eva luated the efficacy of ipilimumab with or without gp100 compared to gp100 alone in 676 HLA-A*0201-positive patients with unresectable stage 3 or 4 melanoma whose cancer had progressed while receiving therapy for metastatic disease.15 Patients were randomized in a 3:1:1 ratio to receive either ipilimumab 3mg/kg gp100 (N=403), ipilimumab 3mg/kg alone (N=137), or gp100 alone (N=136). Each regimen was administered every 3 weeks. The primary endpoint was overall survival. The median overall survival time was 10.0 months in patients receiving ipilimumab plus gp100 compared to 6.4 months in those receiving gp100 alone (P<0.001; HR 0.68). Median survival time was 10.5 months for patients receiving ipilimumab alone compared with 6.4 months for gp100 alone (P=0.003: HR 0.66). No differences in overall survival were observed between the 2 ipilimumab groups. Grade 3 or 4 immune-related adverse events occurred in 10% to 15% of patients receiving ipilimumab, and in 3% of those receiving gp100 alone. Even though adverse events were severe, long-lasting, or both, they were reversible with appropriate therapy. Hodi and colleagues concluded that ipilimumab with or without gp100 improved overall survival in patients with metastatic melanoma.
Despite ipilimumab's therapeutic success, its overall response rate is 10% to 15% in patients with advanced melanoma.15,16 When disease progression occurs, localized radiotherapy is administered to relieve tumor pressure. In some instances, the addition of radiotherapy results in an abscopal effect. The abscopal effect refers to a rare phenomenon of tumor regression at a sight distant from the primary site of radiotherapy. Localized radiotherapy has been shown to induce the abscopal effect in some types of cancer, including melanoma.17 The biologic characteristics underlying this effect are not clearly understood but may be mediated by immunologic mechanisms.18 Ipilimumab has also been shown to enhance immunity to NY-ES-01 and patients with pre-existing NY-ESO-1 antibodies seem to benefit even more. NY-ESO-1 is an antigen expressed in 30% to 40% of patients with advanced melanoma. It is not present in normal adult tissue except in testicular germ cells and the placenta.19
Postow and colleagues reported on the success of the addition of radiotherapy to a woman undergoing treatment for metastatic melanoma with ipilimumab and its effect on NY-ES-01.17 Radiotherapy was administered in order to reduce tumor pressure on her spine. Four months later, her spinal tumor, as well as tumors distant to the primary site of radiotherapy, began to shrink as is seen with the abscopal phenomenon. One metastatic lesion was removed prior to ipilimumab treatment and the NY-ESO-1 expression was confirmed. Temporal associations were also noted and included tumor shrinkage with antibody responses to NY-ESO-1, changes in peripheral-blood immune cells, and increases in antibody responses to other antigens after radiotherapy. This patient's unexpected systematic response to radiotherapy in combination with ipilimumab provides new insights and may open the door for new therapeutic options for treating advanced melanoma.
Though these results appear promising, the vast majority of patients with metastatic melanoma do not respond to the anti-CTLA-4 antibody and still need effective treatment options. In 2002, researchers at the Sanger Institute discovered that mutations in the gene encoding the serine/threonine protein kinase B-RAF (BRAF) occurred in more than 60% of melanomas initially tested.20 Melanomas that carry the BRAF V600E mutation activate the mitogen-activated protein kinase (MAPK) pathway at a continuous rate, thereby promoting cell proliferation and preventing apoptosis.21 Vemurafenib (Zelboraf, Genentech, Inc.), a new agent approved in 2011 in the battle against melanoma, was developed as a potent kinase inhibitor with specificity for the BRAF V600E mutation within cancer cells.
Sosman and colleagues eva luated the overall response rate, duration of response, and overall survival of vemurafenib in previously treated patients with BRAF V600 mutant-metastatic melanoma.22 In this multicenter, Phase 2 trial, 132 patients received vemurafenib 960mg orally twice daily until the development of unacceptable adverse effects or disease progression. Patients with disease progression could continue with vemurafenib if it was thought that the patient would benefit clinically. Median follow-up was 12.9 months with a range of 0.6 to 20.1 months. The confirmed overall response rate was 53%, with 6% experiencing a complete response, and 47% experiencing a partial response. The median duration of response was 6.7 months and median progression-free survival was 6.8 months. Primary disease progression was only observed in 14% of treated patients. Response was not necessarily observed right away. Some patients did not start to experience a response until 6 months after treatment started. The median overall survival was 15.9 months. Vemurafenib appeared to be well tolerated. The more commonly reported adverse effects included grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. This clinical trial was able to demonstrate that vemurafenib can induce clinical responses in previously treated patients with BRAF V600 mutant-metastatic melanoma over an extended period of time (16 months).
The search for safe and effective advanced melanoma cancer treatment therapies has been a long and difficult struggle. The introduction of ipilimumab and vemurafenib may be the beginning of the identification of melanoma treatment options that improve survival outcomes based upon patient immune response.
