Abstract PO-073: Mutational status and clinical outcomes following systemic therapy and focal radiation for melanoma brain metastases

Abstract BACKGROUND The BRAF V600E mutation is present in approximately 50% of patients with melanoma and is an important prerequisite for a response to targeted therapies such as BRAF inhibitors. In the majority of patients, the BRAF mutational status is based on the analysis of tissue samples from the extracranial primary tumor only. Since the extracranial and intracranial BRAF mutational status may be discrepant, the additional information on the BRAF mutational status of melanoma brain metastases would be of clinical value, e.g., for the prediction of response to targeted therapies. Here, we evaluated the potential of MRI radiomics for the determination of the intracranial BRAF mutational status in patients with melanoma brain metastases. PATIENTS AND METHODS Fifty-nine patients with melanoma brain metastases from two university hospitals (group 1, 45 patients; group 2, 14 patients) were operated with subsequent genetic analysis of the intracranial BRAF mutational status. All patients underwent structural MRI preoperatively. Areas of contrast enhancement were manually segmented and analyzed. Group 1 was used for model training and validation, group 2 for model testing. After image preprocessing and radiomics feature extraction, a test-retest analysis was performed to identify robust features prior to feature selection. Finally, the best performing radiomics model was applied to the test data. Diagnostic performances were evaluated using receiver operating characteristic (ROC) analyses. RESULTS Twenty-two patients (49%) in group 1, and 6 patients (43%) in group 2 had an intrametastatic BRAF V600E mutation. Using the best performing six parameter radiomics signature, a linear support vector machine classifier yielded an area under the ROC curve (AUC) of 0.92 (sensitivity, 83%; specificity, 88%) in the test data. CONCLUSION The developed radiomics classifier allows a non-invasive prediction of the intracranial BRAF V600E mutational status in patients with melanoma brain metastases and may be of value for treatment decisions.

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New Era in the Management of Melanoma Brain Metastases

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_200819 ◽

2018 ◽

pp. 741-750 ◽

Cited By ~ 18

Author(s):

Hussein A. Tawbi ◽

Celine Boutros ◽

David Kok ◽

Caroline Robert ◽

Grant McArthur

Keyword(s):

Brain Metastases ◽

Systemic Therapy ◽

Single Agent ◽

Local Treatment ◽

New Era ◽

Therapeutic Modalities ◽

Melanoma Brain Metastases ◽

Extracranial Disease ◽

Induce Response ◽

The Impact

The remarkable advances in the systemic therapy of metastatic melanoma have now extended the 1-year overall survival rate from 25% to nearing 85%. Systemic treatment in the form of BRAF-targeted therapy and immunotherapy is slowly but surely proving its efficacy in the treatment of metatstatic brain metastases (MBM). Single-agent BRAF inhibitors provide an intracranial response rate of 25% to 40%, whereas the combination of BRAFi/MEKi leads to responses in up to 58%. However, the durability of responses induced by BRAFi/MEKi seems to be even shorter than in extracranial disease. On the other hand, single-agent ipilimumab provides comparable clinical benefit in MBMs as it does in extracranial metastases. Single-agent PD-1 anitbodies induce response rates of approximately 20%, and those responses appear durable. Similarly the combination of CTLA-4+ PD-1 antibodies induces durable responses at an impressive rate of 55% and is safe to administer. Although the local treatment approaches with radiation and surgery remain important and are critically needed in the management of MBM, systemic therapy offers a new dimension that can augment the impact of those therapies and come at a potentially lower cost of neurocognitive impairment. Considerations for combining those modalities are direly needed, in addition to considering novel systemic combinations that target mechanisms specific to MBM. In this report, we will discuss the underlying biology of melanoma brain metastases, the clinical outcomes from recent clinical trials of targeted and immunotherapy, and their impact on clinical practice in the context of existing local therapeutic modalities.

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Outcome and Prognostic Factors of Stereotactic Radiosurgery (SRS) for Melanoma Brain Metastases (MBM) in Era of Effective Systemic Therapy

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2016.06.2408 ◽

2016 ◽

Vol 96 (2) ◽

pp. E710-E711

Author(s):

E.S. Choong ◽

S. Lo ◽

G.B. Fogarty ◽

G.V. Long ◽

A.M. Menzies ◽

...

Keyword(s):

Prognostic Factors ◽

Brain Metastases ◽

Stereotactic Radiosurgery ◽

Systemic Therapy ◽

Melanoma Brain Metastases

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1077P Treatment outcomes in patients (pts) with melanoma brain metastases (MBM) undergoing systemic therapy: A systematic literature review (SLR) and meta-analysis (MA) of real-world evidence (RWE)

Annals of Oncology ◽

10.1016/j.annonc.2021.08.1462 ◽

2021 ◽

Vol 32 ◽

pp. S892-S893

Author(s):

G.V. Long ◽

H.A. Tawbi ◽

N. Meyer ◽

B. Breznen ◽

C. Vyas ◽

...

Keyword(s):

Literature Review ◽

Brain Metastases ◽

Treatment Outcomes ◽

Systematic Literature Review ◽

Real World ◽

Systemic Therapy ◽

Meta Analysis ◽

Real World Evidence ◽

Melanoma Brain Metastases

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THER-10. IMPACT OF BRAF MUTATIONAL STATUS ON THE EFFICACY OF IMMUNOTHERAPY FOR MELANOMA BRAIN METASTASES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.053 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i12-i13

Author(s):

Adam Lauko ◽

Soumya Sagar ◽

Addison Barnett ◽

Wei Wei ◽

Samuel Chao ◽

...

Keyword(s):

Brain Metastases ◽

Tertiary Care ◽

Rank Test ◽

P Value ◽

Wild Type ◽

Braf Mutations ◽

Mutational Status ◽

Melanoma Brain Metastases ◽

Melanoma Patients ◽

Braf Mutant

Abstract BACKGROUND: BRAF mutations occur in 50% of melanoma patients. Targeted agents – BRAF and MEK inhibitors and immunotherapy improve survival of melanoma patients with BRAF mutations. These agents have intracranial efficacy as shown in clinical trials. However, the efficacy of immunotherapies (immune checkpoint blockade) in melanoma brain metastases and the correlation with BRAF status is not as well characterized. METHODS: We reviewed 351 patients with melanoma brain metastases treated at our tertiary care center between 2000 and 2018, 75 of which received immunotherapy with known BRAF mutational status. Two-year, 5-year, and median overall survival (OS) was calculated from the start of immunotherapy to compare the efficacy of immunotherapy in BRAF mutant and BRAF wild type patients using the log-rank test. RESULTS: At the time of diagnosis of brain metastasis, the median age was 61 (23–87) years, median KPS was 80 (50–100), number of intracranial lesions was 2 (1–15), and 79% had extra-cranial metastases. Sixty-three patients were treated with stereotactic radiosurgery (SRS), 27 underwent whole brain radiation (WBRT) and 21 underwent surgery. When treated with immunotherapy, BRAF mutant and BRAF wild type median survival was 15.7 months (95% CI=9.4 – 42.4) and 6.9 (95% CI=4.1– 26.7) months (p-value=0.205), respectively. Two-year BRAF mutant and BRAF wild type survival was 35% (95% CI=21 – 58) and 28% (95% CI=16 – 51), and 5-year survival was 22% (95% CI=10 – 46) and 23% (95% CI=11 – 47), respectively. CONCLUSIONS: Twenty percent of patients with BRAF mutant and BRAF wild-type patients treated with immunotherapy derive a long-term benefit from immunotherapy and multimodality treatment and are alive 5 years from diagnosis of brain metastases. This was rarely seen in the pre-immunotherapy era in melanoma brain metastases. There was no difference in outcome based on the BRAF mutational status with use of immunotherapy in melanoma brain metastases.

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