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BRAF V600 Mutation and BRAF Kinase Inhibitors in Conjunction With Stereotactic Radiosurgery for Intracranial Melanoma Metastases: A Multicenter Retrospective Study.

ABSTRACT: BACKGROUND:The BRAF mutation has been identified as a potent target for the treatment of metastatic melanoma and BRAF inhibitors (BRAFi) have demonstrated promising results against melanoma brain metastases (BM). OBJECTIVE:To further investigate the effectiveness of this combined treatment regimen. METHODS:In this multicenter retrospective cohort study, 198 patients with known BRAF mutation status and treated with stereotactic radiosurgery (SRS) between 2011 and 2015 were identified. Kaplan-Meier methodology and multivariate regression analysis was then used to compare survival based on each parameter. RESULTS:The median survival after the diagnosis of BM in patients with BRAF mutation who received BRAFi was increased compared to survival in patients with wild-type BRAF (BRAF wt). In multivariate analysis, the BRAF mutation was an independent, positive prognostic factor with a hazard ratio of 0.59. BRAF mutated Patients who received BRAFi following SRS had improved survival compared to patients who received it before (P < .001) or concurrently (P = .007). PD-1 inhibitors improved survival, with more pronounced effect in patients not carrying the BRAF mutation. Among the patients who were treated with BRAFi, 10.4% developed intracerebral hematoma (ICH), in comparison to 3% of patients who were not treated with BRAFi (P = .03). CONCLUSION:In the setting of widespread use of BRAFi, the presence of a BRAF mutation is an independent predictor of better prognosis in patients with melanoma BM that underwent SRS. The effect of BRAFi is optimal when treatment is initiated at least 1 wk following SRS. BRAFi may increase the frequency of asymptomatic ICH.

SUBMITTER: Mastorakos P

PROVIDER: S-EPMC6505443 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose:Stereotactic radiosurgery (SRS) in combination with immunotherapy (IMT) or targeted therapy is increasingly being used in the setting of melanoma brain metastases (MBMs). The synergistic properties of combination therapy are not well understood. We compared the distant intracranial failure rates of intact MBMs treated with SRS, SRS?+?IMT, and SRS?+?targeted therapy. Methods and materials:Combination therapy was defined as delivery of SRS within 3 months of IMT (anti-CTLA-4 /anti-PD-1 therapy) or targeted therapy (BRAF/MEK inhibitors). The primary endpoint was distant intracranial failure after SRS, which was defined as any new MBM identified on brain magnetic resonance imaging. Outcomes were evaluated using the Kaplan Meier method and Cox proportional hazards. Results:A total of 72 patients with melanoma with 233 MBMs were treated between April 2006 and April 2016. The number of MBMs within each treatment group was as follows: SRS: 121; SRS?+?IMT: 48; and SRS?+?targeted therapy: 64. The median follow-up was 8.9 months. One-year distant intracranial control rates for SRS, SRS?+?IMT, and SRS?+?targeted therapy were 11.5%, 60%, and 10%, respectively (P?<?.001). On multivariate analysis, after adjusting for steroid use and number of MBMs, SRS?+?IMT remained associated with a significant reduction in distant intracranial failure compared with SRS (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29-0.80; P?=?.003) and compared with SRS?+?targeted therapy (HR, 0.41; 95% CI, 0.25-0.68; P?=?.001).One-year local control for SRS, SRS?+?IMT, and SRS?+?targeted therapy was 66%, 85%, and 72%, respectively (P?=?.044). On multivariate analysis, after adjusting for dose, SRS?+?IMT remained associated with a significant reduction in local failure compared with SRS alone (HR, 0.37; 95% CI, 0.14-0.95; P?=?.04). Conclusions:SRS with immunotherapy is associated with decreased distant and local intracranial failure compared with SRS alone. Prospective studies are warranted to validate this result.

Project description:BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.

Project description:BackgroundUntil 50% of patients with renal cancer or melanoma, develop brain metastases during the course of their disease. Stereotactic radiotherapy has become a standard of care for patients with a limited number of brain metastases. Given the radioresistant nature of melanoma and renal cancer, optimization of the fractionation of stereotactic radiotherapy is needed. The purpose of this retrospective study was to elucidate if hypofractionated stereotactic radiotherapy (HFSRT) impacts local control of brain metastases from radioresistant tumors such as melanoma and renal cancer, in comparison with radiosurgery (SRS).MethodsBetween 2012 and 2016, 193 metastases, smaller than 3 cm, from patients suffering from radioresistant primaries (melanoma and renal cancer) were treated with HFSRT or SRS. The primary outcome was local progression free survival (LPFS) at 6, 12 and 18 months. Overall survival (OS) and cerebral progression free survival (CPFS) were secondary outcomes, and were evaluated per patient. Objective response rate and radionecrosis incidence were also reported. The statistical analysis included a supplementary propensity score analysis to deal with bias induced by non-randomized data.ResultsAfter a median follow-up of 7.4 months, LPFS rates at 6, 12 and 18 months for the whole population were 83, 74 and 70%, respectively. With respect to fractionation, LPFS rates at 6, 12 and 18 months were 89, 79 and 73% for the SRS group and 80, 72 and 68% for the HFSRT group. The fractionation schedule was not statistically associated with LPFS (HR = 1.39, CI95% [0.65-2.96], p = 0.38). Time from planning MRI to first irradiation session longer than 14 days was associated with a poorer local control rate. Over this time, LPFS at 12 months was reduced from 86 to 70% (p = 0.009). Radionecrosis occurred in 7.1% for HFSRT treated metastases to 9.6% to SRS treated metastases, without any difference according to fractionation (p = 0.55). The median OS was 9.6 months. Six, 12 and 18 months CPFS rates were 54, 24 and 17%, respectively.ConclusionFractionation does not decrease LPFS. Even for small radioresistant brain metastases (< 3 cm), HFSRT, with 3 or 6 fractions, leads to an excellent local control rate of 72% at 1 year with a rate of 7.1% of radionecrosis. HFSRT is a safe and efficient alternative treatment to SRS.

Project description:BackgroundResistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.MethodsIn this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.ResultsDose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03).ConclusionsDabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

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BRAF V600 Mutation and BRAF Kinase Inhibitors in Conjunction With Stereotactic Radiosurgery for Intracranial Melanoma Metastases: A Multicenter Retrospective Study.

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