Vemurafenib in patients with BRAFV600 mutation-positive melanoma with symptomatic brain metastases: Final results of an open-label pilot study

doi:10.1016/j.ejca.2013.11.002

European Journal of Cancer

Volume 50, Issue 3, February 2014, Pages 611-621

https://doi.org/10.1016/j.ejca.2013.11.002 Get rights and content

Abstract

Background & Aim

Brain metastases are frequent in patients with metastatic melanoma, indicating poor prognosis. We investigated the BRAF kinase inhibitor vemurafenib in patients with advanced melanoma with symptomatic brain metastases.

Methods

This open-label trial assessed vemurafenib (960 mg twice a day) in patients with BRAF^V600 mutation-positive metastatic melanoma with non-resectable, previously treated brain metastases. The primary end-point was safety. Secondary end-points included best overall response rate, and progression-free and overall survival.

Results

Twenty-four patients received vemurafenib for a median treatment duration of 3.8 (0.1–11.3) months. The majority of discontinuations were due to disease progression (n = 22). Twenty-three of 24 patients reported at least one adverse event (AE). Grade 3 AEs were reported in four (17%; 95% confidence interval [CI], 4.7–37.4%) patients and included cutaneous squamous cell carcinoma in four patients. Median progression-free survival was 3.9 (95% CI, 3.0–5.5) months, and median survival was 5.3 (95% CI, 3.9–6.6) months. An overall partial response (PR) at both intracranial and extracranial sites was achieved in 10 of 24 (42%; 95% CI, 22.1–63.4) evaluable patients, with stable disease in nine (38%; 95% CI, 18.8–59.4) patients. Of 19 patients with measurable intracranial disease, seven (37%) achieved >30% intracranial tumour regression, and three (16%; 95% CI, 3.4–39.6%) achieved a confirmed PR. Other signs of improvement included reduced need for corticosteroids and enhanced performance status.

Conclusions

Vemurafenib can be safely used in patients with advanced symptomatic melanoma that has metastasised to the brain and can result in meaningful tumour regression.

Introduction

Brain metastases are diagnosed in up to 50% of melanoma patients with metastatic disease and are found in most of those who die [1], [2], [3], [4], [5], [6], [7]. Cerebral metastases indicate poor prognosis (median survival is less than 6 months [3], [4], [8], [9]) and are associated with a wide spectrum of neurological symptoms that impact patient quality of life. Brain metastases frequently contribute to death in most patients [3], [4], [8], [9], [10].

Vemurafenib and dabrafenib have demonstrated efficacy in metastatic melanoma [11], [12], [13], [14], [15], [16], [17], [18], [19]. Efficacy data including progression-free survival (PFS) and overall survival (OS) led to the approval of both compounds in the United States and in Europe. While patients with active brain metastases were excluded from these trials, dabrafenib has demonstrated activity in patients with asymptomatic BRAF^V600E mutation-positive melanoma brain metastases [14].

Driven by the need for a therapy for patients with advanced melanoma and symptomatic brain metastases, a study was initiated in Switzerland to study the safety, tolerability and efficacy of vemurafenib in this population [20]

Section snippets

Study design

This was an open-label, single-arm, two-centre, study designed to evaluate the safety and efficacy of vemurafenib in patients with BRAF^V600 mutation-positive metastatic melanoma and unresectable brain metastases for whom at least one treatment for brain metastases had failed and who required corticosteroids for symptom control. Tumours were evaluated for the BRAF^V600 mutation using a polymerase chain reaction-based test (cobas® 4800 BRAF^V600 Mutation Test; Roche Molecular Systems, Branchburg,

Patient disposition

In total, 35 patients with metastatic melanoma were screened for the trial at two study centres in Switzerland. Main reasons for screening failure included negative BRAF^V600 mutation test result and death because of disease progression. Twenty-four patients were enrolled between November 2010 and November 2011 (Fig. 1).

Baseline characteristics

Baseline patient demographics and disease characteristics are summarised in Table 1. All patients were white, and the median age was 47 (range, 24–70) years. Fifteen (63%)

Discussion

This clinical trial evaluated vemurafenib in melanoma patients with previously treated symptomatic brain metastases who would not have previously been eligible for a clinical trial [21]. The most frequent AEs included arthralgia, seizures, alopecia, diarrhoea, dizziness, muscular weakness, maculopapular rash, paraesthesia, solar dermatitis and vomiting. This safety profile was similar to that reported in earlier studies and supports the feasibility of vemurafenib therapy in patients with

Contributors

Reinhard Dummer conducted the literature search, designed the study, collected data, analysed and interpreted the data, drafted and revised the manuscript and figures and approved the final version of the manuscript.

Simone M. Goldinger conducted the literature search, designed the study, collected data, analysed and interpreted the data, drafted and revised the manuscript and figures and approved the final version of the manuscript.

Christian P. Turtschi was responsible for informing potential

Role of the funding source

This study was sponsored by F. Hoffmann-La Roche Ltd and was designed by the academic investigators and representatives of the sponsor. Data were collected with the use of the Chiltern data management systems and were analysed by the Chiltern and sponsor’s statistical and programming teams. All authors contributed to the interpretation of data and the subsequent writing, reviewing and finalisation of the manuscript. Medical writing support for the methods and results sections was provided by

Conflict of interest statement

Reinhard Dummer receives research funding from Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche and has a consultant or an advisory board relationship with Novartis, Cephalon, Merck Sharp & Dohme, Roche, Bristol-Myers Squibb, GlaxoSmithKline and Spirig.

Simone M. Goldinger has no conflicts of interest.

Christian P. Turtschi has no conflicts of interest.

Nina B. Eggmann has no conflicts of interest.

Olivier Michielin has no conflicts of interest.

Lada Mitchell is an employee of F.

Acknowledgements

The authors thank all the patients who participated in this study. They also thank the clinical trial team for supporting the execution of the trial and F. Hoffmann-La Roche for funding the trial. In addition, they thank Florin Sirzen (Roche) and Christine Wilkinson Blanc (Phi-Medics Ltd) for their contributions to the overall interpretation of the data and Philipp Schlatter (Roche) and Gill Low (Chiltern) for the overall conduct of the study.

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Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases.
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Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAF^V600 mutation-positive cohort; the BRAF^V600 wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3–15·0) for the BRAF^V600 mutation-positive cohort and 6·2 months (3·5–23·0) for the BRAF^V600 wild-type cohort. Intracranial objective response rate was 42% (95% CI 29–54) by IRC assessment in the BRAF^V600 mutation-positive cohort and 27% (95% CI 8–55) by investigator assessment in the BRAF^V600 wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAF^V600 mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (11 [18%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAF^V600 wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients who received triplet therapy in the BRAF^V600 mutation-positive cohort and two (13%) of 15 in the BRAF^V600 wild-type cohort. No treatment-related deaths occurred.
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Citation Excerpt :
Targeted therapy has shown intracranial activity in patients with BRAFV600 mutation-positive melanoma, with intracranial response rates of 25–40% with BRAF inhibitor monotherapy and up to 58% with combined BRAF and MEK inhibition.1–7
Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases.
TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAF^V600 wild-type cohort and a BRAF^V600 mutation-positive cohort, recruited at 21 hospitals and oncology centres in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18 years or older with previously untreated metastatic melanoma, CNS metastases of 5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients in the BRAF^V600 wild-type cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral cobimetinib (60 mg once daily, days 1–21). Patients in the BRAF^V600 mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral cobimetinib (60 mg once daily, days 1–21); atezolizumab was withheld in cycle 1. Treatment was continued until progression, toxicity, or death. The primary outcome was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by independent review committee (IRC) using modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of early closure of the BRAF^V600 wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not done in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analysed in all patients who received at least one dose of study medication. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT03625141.
Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAF^V600 mutation-positive cohort; the BRAF^V600 wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3–15·0) for the BRAF^V600 mutation-positive cohort and 6·2 months (3·5–23·0) for the BRAF^V600 wild-type cohort. Intracranial objective response rate was 42% (95% CI 29–54) by IRC assessment in the BRAF^V600 mutation-positive cohort and 27% (95% CI 8–55) by investigator assessment in the BRAF^V600 wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAF^V600 mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (ten [17%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAF^V600 wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients in the BRAF^V600 mutation-positive cohort and two (13%) of 15 in the BRAF^V600 wild-type cohort. One death in the BRAF^V600 mutation-positive cohort (limbic encephalitis) was considered to be related to atezolizumab treatment.
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Citation Excerpt :
Systemic chemotherapy using classical agents such as temozolomide, dacarbazine or fotemustine has only limited efficacy in melanoma patients with BM.68 Monotherapy using the BRAF inhibitors vemurafenib or dabrafenib in BRAF-mutated patients with melanoma BM achieved intracranial response rates between 15% and 40%;69-71 and improved intracranial response rates up to 60% were observed with the combination of vemurafenib and dabrafenib in asymptomatic untreated BM, similar to the response rate in other organ sites with, however, overall short duration of response.72 Anti-PD-1 monotherapy or ipilimumab plus nivolumab has been investigated in patients with BM: in patients with asymptomatic BM, current data favour the combination with an overall response rate of ∼50%,73,74 reasonable response duration and PFS of >50% at 18 months.

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¹: Joint first authors.

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Vemurafenib in patients with BRAFV600 mutation-positive melanoma with symptomatic brain metastases: Final results of an open-label pilot study

Abstract

Background & Aim

Methods

Results

Conclusions

Introduction

Section snippets

Study design

Patient disposition

Baseline characteristics

Discussion

Contributors

Role of the funding source

Conflict of interest statement

Acknowledgements

Radiother Oncol

Lancet

Lancet Oncol

Lancet

Lancet Oncol

Lancet Oncol

Lancet Oncol

Lancet Oncol

Ann Oncol

Melanoma in the brain: biology and therapeutic options

Melanoma Res

Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma

J Neurosurg

Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post-brain metastases survival

Cancer

Determinants of outcome in melanoma patients with cerebral metastases

J Clin Oncol

Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma

Cancer

Vemurafenib in patients with BRAF^V600 mutation-positive melanoma with symptomatic brain metastases: Final results of an open-label pilot study