Elsevier

The Lancet

Volume 379, Issue 9829, 19–25 May 2012, Pages 1893-1901
The Lancet

Articles
Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial

https://doi.org/10.1016/S0140-6736(12)60398-5Get rights and content

Summary

Background

Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases.

Methods

We undertook a phase 1 trial between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function. BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose. Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours, including those with non-Val600Glu mutations, in three cohorts: metastatic melanoma, melanoma with untreated brain metastases, and non-melanoma solid tumours. This study is registered with ClinicalTrials.gov, number NCT00880321.

Findings

We enrolled 184 patients, of whom 156 had metastatic melanoma. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51·9–83·7) and confirmed responses in 18 (50%, 32·9–67·1). 21 (78%, 57·7–91·4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35·3–74·5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer.

Interpretation

Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours.

Funding

GlaxoSmithKline.

Introduction

Oncogenic mutations that cause activation of BRAF occur in many tumour types, such as cutaneous melanoma (50% of cases), papillary thyroid cancer (46%), borderline ovarian tumours (34%), biliary tract cancer (11%), colorectal cancer (10%), non-small-cell lung cancer (2%), and hairy cell leukaemia (100%).1, 2 The most common mutation—substitution of valine with glutamic acid at aminoacid position 600 (Val600Glu)—locks BRAF into its active conformation, which has at least ten times higher activity than does wild-type BRAF.1, 2 In 7–21% of patients with BRAF-mutant melanoma,3, 4 substitution with lysine (Val600Lys) also results in activation.2 Other activating mutations have been reported, but are less common than are Val600Glu and Val600Lys.3, 4 Mutant BRAF correlates with poor prognosis in colorectal cancer,5 papillary thyroid cancer,6 and metastatic melanoma.4

Patients with metastatic melanoma have a poor outlook, with median overall survival of 9–11 months.7 However, patients with melanoma brain metastases have a median survival of only 4–5 months.8 In patients with stage IV disease, brain metastases are present in 20% at diagnosis8 and in 40–45% of patients overall,8, 9 and contribute to death in 20–54%.10 Systemic treatments are not highly effective in melanoma metastatic to the brain, with a response noted in 10% of patients or fewer.11, 12, 13 Possible non-systemic treatments are surgery, and stereotactic or palliative whole-brain radiotherapy.11, 14

BRAF-mutant melanoma cells display features of oncogene addiction (ie, dependence on an activated oncogene or pathway for survival and growth) in vitro.15 The BRAF inhibitor vemurafenib has clinical activity in patients with metastatic melanoma and Val600Glu mutant BRAF, with confirmed responses noted in 48% of patients, and those given this drug have higher survival than do those given dacarbazine.16 Patients with active brain metastases have been excluded from reports of clinical trials of vemurafenib.16, 17, 18

Dabrafenib (GSK2118436) is a potent ATP-competitive inhibitor of BRAF kinase and is selective for mutant BRAF in kinase panel screening, cell lines, and xenografts.19 We aimed to investigate the safety and tolerability of dabrafenib, and establish the recommended phase 2 dose of dabrafenib in patients with incurable solid tumours, enriching for patients with BRAF-mutant cancers, including a cohort with melanoma and untreated, asymptomatic brain metastases.

Section snippets

Participants

In this phase 1 study, we enrolled patients at eight study centres in Australia and the USA (appendix) between May 27, 2009, and March 2, 2011. Eligible patients had a histologically confirmed solid tumour for which no curative treatment was available, were 18 years or older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less (patients with an ECOG status of 2 could be enrolled with the approval of the study's medical monitor), and had adequate organ function (

Results

We enrolled 184 patients, of whom 156 had melanoma (figure 1). Three of the patients with melanoma were BRAF wild-type, and 153 had mutations (130 Val600Glu; 18 Val600Lys; one Val600Gly [reported at time of data cutoff and preparation of this report, but subsequently shown to be a Val600Glu mutation]; two Lys601Glu; one Val600_Lys601delinsGlu; one unknown mutation type). Table 1 shows the baseline characteristics of the 36 patients with Val600 BRAF-mutant melanoma treated at the RP2D. Poor

Discussion

Dabrafenib's toxic effects were mild, and only three toxic effects of grade 2 or higher were recorded in more than 5% of patients. Furthermore, we have shown that targeted treatment has activity in melanoma and previously untreated brain metastases. Brain metastases in most patients given dabrafenib reduced in size, with four patients’ metastases completely resolving. Intracranial disease reduction was accompanied by extracranial reduction. Patients with melanoma and brain metastases typically

References (34)

  • CM Balch et al.

    Final version of 2009 AJCC melanoma staging and classification

    J Clin Oncol

    (2009)
  • MA Davies et al.

    Prognostic factors for survival in melanoma patients with brain metastases

    Cancer

    (2011)
  • MS Carlino et al.

    Differences between Australia (OZ) and the United States (US) in the patterns, prognosis, and treatment of melanoma CNS metastases: analysis from the PHAMOUS (prognostic heterogeneity in patients with advanced melanoma between OZ and the US) study

    Pigment Cell Melanoma Res

    (2010)
  • J Skibber et al.

    Cranial irradiation after surgical excision of brain metastases in melanoma patients

    Ann Surg Oncol

    (1996)
  • F Mornex et al.

    A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma

    Melanoma Res

    (2003)
  • SS Agarwala et al.

    Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase 2 study

    J Clin Oncol

    (2004)
  • H Aoyama et al.

    Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial

    JAMA

    (2006)
  • Cited by (0)

    These authors contributed equally

    View full text