ArticlesDabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial
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.
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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
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These authors contributed equally