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What Is Braf Positive Melanoma

The Role Of Braf Inhibitors In Brain Metastases

BRAF-positive melanoma: what’s new?

Brain metastases are the most frequent intracranial tumors in adults and are up to ten fold more common than primary brain neoplasms. They are manifestations/complications of systemic tumors and in contrast to primary brain tumors do not constitute a separate disease entity . Melanoma is the third most frequent primary tumor type in terms of brain metastasis, after lung and renal cell cancers . BM are diagnosed in up to 10 % of melanoma patients during their disease course and BM are found at autopsy in up to 73 % of patients who died from disseminated cutaneous melanoma .

Patients with active BM have been excluded from prior and current vemurafenib trials. However, there are favorable preliminary efficacy data on other inhibitors of mutant BRAF, in patients with brain-metastatic melanoma and a single-arm, phase II, multicenter study, evaluating efficacy and safety of vemurafenib in patients with brain-metastatic melanoma has been initiated . Such systemic approaches are very promising, as expression of the therapeutic target has been shown to be homogenous throughout the tumor tissue and to be consistent between different tumor manifestations in individual patients .

Analogously, dabrafenib showed good efficacy on brain metastases .

Resistance Mechanisms To Combined Braf And Mek Inhibition And Icb Remain A Major Problem In Melanoma Therapy

Looking at the long-term data of each cTT study , most patients progress after approximately 12 months of therapy due to acquired resistance. Primary resistance to TT, i.e. direct lack of therapeutic response, occurs less frequently. There are many possible ways described in the literature regarding resistance mechanisms, one of which is alternative activation of the MAPK signaling pathway due to different receptor tyrosine kinases, e.g. EGFR, PDGFRB, and FGFR1 . Additionally, secondary mutations in the BRAF gene, as well as alternative splicing, have also been identified . Furthermore, patients harboring an activating NRAS mutation also showed higher rates of BRAFi/MEKi resistance, mostly due to activation of the PI3K/AKT signaling pathway . Other mutations of the PI3K/AKT signaling pathway have also been associated with a resistance to BRAFi/MEKi, e.g. PTEN loss-of-function mutations . Although of diverse nature, all mechanisms share one particular featurethey are unbreakable at this point in time. Unfortunately, cross-resistance to immune checkpoint inhibitions seems to exist on the molecular level .

Everyone Has The Braf Gene

BRAF is a gene that locks down a specific protein called B-Raf. This protein helps send signals inside your cells that are related to cell growth. Everyone has this gene, and when its working properly, its an important part of how cells operate. But when BRAF is faulty in some waysometimes known as changed or mutatedthen it might work against the body, by allowing some cancers to grow or even playing a role in that growth process.

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Genetic Testing Of Your Melanoma

If you are diagnosed with stage 3 or 4 melanoma, your doctor sends a sample of the melanoma for genetic testing. This is to look for changes in genes including the BRAF gene. This genetic change makes the melanoma cells produce too much BRAF protein, which can make melanoma cells grow.

About 40 to 50 out of every 100 people with skin melanoma have a change in the BRAF gene.

If you have changes in the BRAF gene, doctors describe your melanoma as BRAF positive. If you dont have changes, then your melanoma is BRAF negative. Knowing this can help your doctor make decisions about whether it would be helpful to give you targeted cancer drugs.

False Positives And Negatives

Immunohistochemistry against BRAF V600E. Positive case ...

Another potential risk is that test could either be a false positive or false negative. With a false negative test, a person who might otherwise respond to anti-BRAF therapies would not be offered these treatments.

With false positives there are risks as well. When tumors that are BRAF negative are treated with BRAF inhibitors it can actually stimulate the growth of the tumors , which could lead to worsening of a cancer. It may also result in a person not receiving therapy that might be effective.

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Braf Inhibition: Previous Experience

Sorafenib, a non-selective BRAF broad-spectrum kinase inhibitor with a bi-aryl urea structure, was originally developed in combination with carboplatin and taxol against lung cancer. Activity against melanoma was demonstrated in phase I studies, and so it was further developed for this indication in combination with the unusual combination of carboplatin and paclitaxel. Because of response rates over 30 % in phase II studies, its development was pursued into large phase III trials, but eventually it failed both in second- and first-line trials . In fact, the addition of sorafenib to carboplatin and paclitaxel did not improve any of the relevant end points over placebo plus CP in the second-line setting for patients with advanced melanoma .

Studies of sorafenib indicate that it lacks selectivity and potency for RAF, and that it is a highly potent inhibitor of VEGFR2, VEGFR3, and several other kinases . Sorafenib ultimately demonstrated clinical activity in renal cell carcinoma and hepatocellular cancer and is now approved for use in these indications. These findings suggest that the activity of sorafenib in RCC is likely attributable to its anti-angiogenic properties and that inhibition of RAF contributes little if at all to its clinical efficacy in this disease.

Braf Inhibitors For Metastatic Melanoma

Metastatic melanoma is cancer that has spread beyond its original location to other parts of the body. BRAF inhibitors are drugs that can shrink or slow the growth of metastatic melanoma in people whose tumors have a BRAF mutation. BRAF inhibitors include vemurafenib , dabrafenib ,and encorafenib .

MSK has taken a leadership role in the development of BRAF inhibitors for metastatic melanoma. In 2006, our doctors conducted the first clinical trial of vemurafenib, five years before the US Food and Drug Administration approved this treatment.

MSK experts are leading clinical trials to improve our ability to fight melanoma with BRAF inhibitors. Learn more about clinical trials for melanoma.

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Resistance To Braf And Mek Inhibitor Therapy

MAPK pathway inhibitors are an option for patients with BRAF V600-mutant advanced melanoma., , The introduction of BRAF inhibitor therapy was an important step forward in the treatment of BRAF-mutated melanoma. Yet up to one-half of patients with BRAF-mutated tumors did not respond to treatment in previous studies in those who did respond, acquired resistance generally developed at a median of 67 months with single-agent BRAF inhibitors., Combination treatment with BRAF and MEK inhibitors has been shown to significantly increase the proportion of patients with an objective response while also significantly delaying the development of acquired resistance., , , , Therefore, combination therapy is now considered a standard of care in patients with BRAF-mutated advanced melanoma.

Treatment May Be Different For Those With Braf Mutations

Advice for BRAF Patients: Debbie

If you have a mutation in your BRAF gene, melanoma cells will be making an altered form of protein that helps them grow. If thats the case, you’ll likely be treated with drugs that target this protein specifically. These meds are vemurafenib and dabrafenib . They’re designed to attack the BRAF protein directly, to reduce tumor size and slow its growth. Drugs that target the BRAF protein arent likely to work in patients whose melanomas have a normal BRAF gene.

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Patient And Clinical Characteristics

One hundred and five patients with Stage III melanoma and available BRAF mutational status met the inclusion criteria for our study. The demographic, clinical, pathological, and treatment characteristics are displayed in Table . In this cohort, 53 patients were found to be positive for a BRAF mutation and 52 were negative for a BRAF mutation . The BRAF+ patients were younger compared to BRAF– patients . There was no difference in the genders between the two groups . We found a statistically significant difference between the primary tumor sites between the two groups. BRAF+ patients were more likely to have tumors located in the trunk compared to the BRAF– patients while the BRAF– patients more commonly had primary tumors located in the head and neck regions .

Table 1 Demographic, clinical, pathological, and treatment characteristics of the BRAF+ and BRAF melanoma groups

Know About Braf Mutation Testing

Requesting a test for BRAF mutation is easyjust ask your health care provider.

Novartis offers the Know Now BRAF Testing Program at no cost to youwhether or not you are BRAF+. After taking a tissue sample, your health care provider will complete and send the BRAF Test Request Form to Quest Diagnostics. Ask your health care provider to request a testhe or she can download the BRAF Test Request Form or get answers to any questions by visiting KnowNowBRAF.com/hcp or calling 1-866-226-8046.

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Mutations Of The Braf Gene Are Related To Cancers

Although BRAF mutation and its connection to cancer was only identified in 2002, research done since then has pinpointed at least 30 different types of mutation that could be associated with cancers. The relationship between BRAF mutation and melanoma is particularly strong. The mutation doesnt play much of a role in other common cancers, such as lung cancer.

Targeting Braf Mutation Positive Cancers: Melanoma Lung And Colorectal

Targeting BRAF in Advanced Melanoma: A First Step toward ...

Mitogen-activated protein kinase is a key signaling pathway in a number of cancers. Mutations in various components of the MAPK pathway specifically BRAF have been described in melanoma , colorectal , thyroid , and Non-small cell lung cancer , as well as hairy cell leukemia . BRAF encodes a serine-threonine kinase causing downstream activation of MAPK signaling through phosphorylation of MEK 1 and 2 and subsequent phosphorylation of ERK 1 and 2.

Mutations in BRAF were initially described in 2002, with V600E being the most common mutation. Activating mutations in BRAF lead to constitutive activation of BRAF and hence RAF-MEK-ERK signaling cascade, promoting cell proliferation and survival while inhibiting apoptosis, and thus driving cancer growth.

Identification of BRAF mutations in various tumor types, as well as elucidation of their role as driver mutations, has led to development of various ATP-competitive RAF inhibitors. Vemurafenib and Dabrafenib are the two most extensively evaluated agents in this class.

In addition to BRAF, agents targeted to MEK have also been evaluated for inhibition of MAPK pathway and have shown activity, especially in melanoma. Based on scientific rationale and efficacy demonstrated in clinical studies, some of these agents are approved for melanoma. A number of studies are ongoing to also evaluate their role in other cancers especially lung, thyroid and colorectal cancer, each of which are discussed in more detail below.

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Vemurafenib: Phase I And Ii Results

In phase III studies, dacarbazine, the only chemotherapeutic agent approved by the U.S. Food and Drug Administration for the treatment of metastatic melanoma, was associated with a response rate of 7 to 12 % and a median overall survival of 5.6 to 7.8 months after the initiation of treatment.

Recently a selective and potent inhibitor of oncogenic mutant BRAF , vemurafenib , gave positive results in phase I and phase II trials 2) .

The structural formula of vemurafenib.

The phase I study was a multicenter, 55-solid cancer patients dose-escalation trial followed by a 32-melanoma patients extension phase involving the maximum dose that could be administered without adverse effects . Vemurafenib was administered at a starting dose of 160 mg daily and was generally well tolerated with no dose-limiting toxicity until the 720 mg twice-daily dose level was initiated. This trial demonstrated that vemurafenib has very impressive single-agent clinical activity, with unprecedented objective response rates in about 81 % and a confirmed response rate in about 56%of patients who had melanoma with the BRAFV600E mutation the study also showed a clear impact on PFS > 7 months and established the maximum tolerated dose to be 960 mg twice-daily. Responses were observed at all sites of disease, including the bone, liver and small bowel. During the dose escalation phase, responses were also observed in patients who were receiving doses below the recommended one .

Brafv600 Mutation Test: Who Should Do This

A BRAFV600 mutation test is necessary to determine if a patient might be a candidate for vemurafenib therapy. Together with the BRAF inhibitor, a mutation test has been approved by FDA, which is able to detect V600E, V600K and V600D substitutions more sensitively than Sanger sequencing . In many countries, strategies dedicated to tumor typing and based on different techniques have been settled. In any case quality control is warranted.

Taking into account the evidence from clinical trials, we strongly support the need to screen for the BRAF-V600 mutation all patients with advanced melanoma , who are most likely to derive benefit from vemurafenib treatment, especially when symptomatic with their disease. Patients with a high risk for recurrence are also reasonable to consider for mutation screening.

The adjuvant role of this agent is being studied in the BRIM-8 trial. This is a phase III, randomized, double-blind, placebo-controlled study of vemurafenib adjuvant therapy in patients with surgically-resected cutaneous BRAF mutant melanoma at high risk for recurrence.

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Cancers For Which Braf Testing May Be Done

BRAF mutations are found in a number of different cancer types, though the frequency of these mutations varies considerably. They are very common in metastatic melanoma and some other tumors. While less common in tumors such as non-small cell lung cancer, finding these mutations is important as treatment options are available that can extend life. Your doctor may recommend BRAF testing if you have:

  • Melanoma

Braf Inhibitors: Possible Role In The Braf

BRAF in Melanoma Explained

Even if vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form, it has also been demonstrated to be effective in inhibiting the V600K mutated form.

In fact, in vitro studies on melanoma cells isolated from primary or metastatic lesions showed that vemurafenib was also able to suppress the V600KBRAF activity . Beside preclinical data demonstrating similar kinase activity of the V600K and V600E mutations, clear evidences of clinical activity of vemurafenib in patients with documented V600K mutation suggest that these patients are eligible to vemurafenib treatment too .

On behalf of the latter evidences, it is noteworthy that EMAs CHMP positive opinion was not restricted to the V600E mutations like FDA approval, but included all kind of V600 mutations, comprising the less frequent ones.

In this sense, dabrafenib was also given for treatment of BRAF-V600K mutated patient in the phase II study , with an overall response rate of 13 % and a PFS of 19.7 weeks, which demonstrated an impact even in this population.

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Tumor Testing Vs Liquid Biopsy

Historically, testing done on a sample of tissue obtained via a biopsy has been the gold standard. Unfortunately, tissue biopsies are invasive and may not always be possible. In recent years, a simple blood test that looks for fragments of tumor DNA in the blood has offered an additional option for genomic testing. Liquid biopsies have been found to be comparable to tissue biopsies in some cases, though many oncologists believe that the ideal is to do genomic testing on both tissue and blood samples.

Institutional Review Board Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this review formal consent is not required.

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Braf Mutations Other Than Or In Addition To V600

Regarding BRAF mutational status, all four of the described cTT trials only included patients harboring a BRAF V600E/K mutation, yet less frequent BRAF mutations have been described. Recently, Menzer et al. analyzed the clinical outcomes of 103 patients harboring rare BRAF mutations or translocations . Of these patients, seven had been excluded from statistical analysis due to a co-existing BRAF V600E/K mutation. Of the remaining 96 patients, 58% received BRAFi/MEKi combination therapy 76% of the patients were treatment-naïve, whereas the remainder had prior treatment that mostly consisted of immunotherapy and chemotherapy. Elevated LDH levels at baseline were found in 42% of patients. The assessed 96 patients were split into two groups, depending on a BRAF V60 mutation and BRAF mutations affecting other codons or BRAF chromosome translocations resulting in a mutational activation of BRAF. OS for patients harboring a V600 mutation was 17.3 months , compared with 11.3 months for non-V600 mutations if treated with cTT. The median PFS was 8.0 months for V600 mutations and 3.3 months for non-V600 mutations. The ORR was 56% and 28%, respectively. Although only a small number of patients were included, activating mutations in BRAF outside of codon 600 seem to be associated with decreased efficacy of cTT.

Table 2 Baseline characteristics affecting the PFS of cTT or ICB in pivotal trials

Oncogenes And Tumor Suppressor Genes

BRAF

Most often, cancer develops after a series of mutations in both oncogenes and tumor suppressor genes occurs. Proto-oncogenes are normal genes that code for proteins that are important in stimulating cell growth and division. These genes are primarily active during fetal development in the uterus, and for short periods of time in adults to aid in tissue repair. When mutated, proto-oncogenes become oncogenes. These genes can be thought of as an accelerator on a car that is stuck in the on position. BRAF is a proto-oncogene that becomes an oncogene when mutated resulting in the continuous production of proteins that stimulate cell proliferation.

Tumor suppressor genes are genes that code for proteins that function to repair damaged DNA or eliminate cells that can’t be repaired. When these genes are damaged, they allow abnormal cells to continue to grow and reproduce. The BRCA genes are examples of tumor suppressor genes.

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