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Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series.

ABSTRACT: BACKGROUND:Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited. METHODS:A multicenter, retrospective case series investigation of consecutive BRAF-mutant patients with melanoma brain metastases (MBMs) treated with a combination of BRAF inhibitor encorafenib and MEK inhibitor binimetinib was conducted to evaluate the antitumor response. Assessments included the intracranial, extracranial, and global objective response rates (according to the modified Response Evaluation Criteria in Solid Tumors, version 1.1); the clinical benefit rate; the time to response; the duration of response; and safety. RESULTS:A total of 24 patients with stage IV BRAF-mutant MBMs treated with encorafenib plus binimetinib in 3 centers in the United States were included. Patients had received a median of 2.5 prior lines of treatment, and 88% had prior treatment with BRAF/MEK inhibitors. The intracranial objective response rate was 33%, and the clinical benefit rate was 63%. The median time to a response was 6 weeks, and the median duration of response was 22 weeks. Among the 21 patients with MBMs and prior BRAF/MEK inhibitor treatment, the intracranial objective response rate was 24%, and the clinical benefit rate was 57%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in patients with melanoma without brain metastases. CONCLUSIONS:Combination therapy with encorafenib plus binimetinib elicited intracranial activity in patients with BRAF-mutant MBMs, including patients previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted and ongoing.

SUBMITTER: Holbrook K

PROVIDER: S-EPMC7004095 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series.

Holbrook Kourtney K Lutzky Jose J Davies Michael A MA Davis Jessica Michaud JM Glitza Isabella C IC Amaria Rodabe N RN Diab Adi A Patel Sapna P SP Amin Asim A Tawbi Hussein H

Cancer 20191028 3

<h4>Background</h4>Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited.<h4>Methods</h4>A multicenter, retrospective case series investigation of consecutive BRAF-mutant patients with melanoma brain metastases (MBMs) treated with ...[more]

PMID: 31658370

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Project description:Background:Brain metastases are common in advanced melanoma and often necessitate corticosteroids such as dexamethasone to control symptoms and reduce peritumoral edema. Immunotherapy improves survival in metastatic melanoma, but concomitant treatment with corticosteroids may reduce efficacy. Here, we report the use of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, as a steroid-sparing agent in melanoma patients with brain metastases treated with immunotherapy. Methods:Medical records and imaging were retrospectively analyzed for melanoma patients with brain metastases who received bevacizumab at our institution between 2012 and 2017. Results:12 melanoma patients with brain metastases received bevacizumab (5-7.5 mg/kg Q2-3 W; median 4 cycles, range 1-9). Patients were BRAF wild-type or resistant to BRAF/MEK inhibitor therapy. All had progressive intracranial disease after prior resection, stereotactic radiosurgery and/or whole brain radiotherapy, and up to four lines of previous systemic treatment. Prior to bevacizumab, all patients had radiologically defined peritumoral edema and nine required dexamethasone for symptom control. In 10 evaluable patients, six reduced their dexamethasone dose by more than 50%, and eight displayed reduced edema 4 weeks after bevacizumab. Seven patients experienced adverse events possibly related to bevacizumab, including intracranial hemorrhage, hypertension, and gastrointestinal bleeding. Ten patients received immunotherapy after bevacizumab. Five patients survived more than 6 months, including one who remained disease-free after 4 years and without neurological deficit despite being hemiplegic from edematous brain metastases prior to bevacizumab. Conclusion:In 12 very poor prognosis melanoma patients with brain metastases, bevacizumab was well-tolerated, associated with improved symptoms and reduced peritumoral edema despite weaning steroids, and facilitated treatment with immunotherapy that provided durable survival in a substantial proportion of cases.

Project description:BackgroundEncorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC). Although no formal comparison was planned, addition of binimetinib to encorafenib plus cetuximab did not provide significant efficacy advantage.Patients and methodsThis real-life study was aimed at evaluating safety, activity, and efficacy of encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mut mCRC treated at 21 Italian centers within a nominal use program launched in May 2019.ResultsOut of 133 patients included, 97 (73%) received encorafenib plus cetuximab (targeted doublet) and 36 (27%) the same therapy plus binimetinib (targeted triplet). Most patients had Eastern Cooperative Group Performance Status (ECOG-PS) of 0 or 1 (86%), right-sided primary tumor (69%), and synchronous disease (66%). Twenty (15%) tumors were DNA mismatch repair deficiency (dMMR)/microsatellite instability (MSI)-high. As many as 44 (34%) patients had received two or more prior lines of therapy, 122 (92%) were previously exposed to oxaliplatin, and 109 (82%) to anti-vascular endothelial growth factor (anti-VEGF). Most frequent adverse events were asthenia (62%) and anti-EGFR-related skin rash (52%). Any grade nausea (P = 0.03), vomiting (P = 0.04), and diarrhea (P = 0.07) were more frequent with the triplet therapy, while melanocytic nevi were less common (P = 0.06). Overall, ORR and disease control rate (DCR) were 23% and 69%, respectively, with numerically higher rates in the triplet group (ORR 31% versus 17%, P = 0.12; DCR 78% versus 65%, P = 0.23). Median PFS and OS were 4.5 and 7.2 months, respectively. Worse ECOG-PS, peritoneal metastases, and more than one prior treatment were independent poor prognostic factors for PFS and OS. Clonality of BRAF mutation measured as adjusted mutant allele fraction in tumor tissue was not associated with clinical outcome.ConclusionsOur real-life data are consistent with those from the BEACON trial in terms of safety, activity, and efficacy. Patients in good general condition and not heavily pretreated are those more likely to derive benefit from the targeted treatment.

Dataset Information

Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series.

Publications

Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series.

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