Samantha Dickson Brain Tumour Trust has welcomed the trial of a new drug, dabrafenib, for advanced melanoma, which offers a potential breakthrough in treatment of brain metastases. The drug works by blocking the activity of the cancer-causing mutated form of the BRAF gene, which occurs in about half of melanomas.
BRAF is a known oncogene, a gene that when mutated causes cancer. About 50% of patients with metastatic melanoma have a BRAF mutation in their tumour and it occurs in many other common cancer types including thyroid, colorectal, ovarian, and lung.
Importantly, BRAF mutations are also found in the majority of pilocytic astrocytoma brain tumours according to research conducted at Queen Mary, University of London and funded by Samantha Dickson Brain Tumour Trust. Pilocytic astrocytoma is the most common benign brain tumour in children. This means that drugs like dabrafenib may also have value in treating certain primary brain tumours such as pilocytic astrocytoma. Read more about this research here.
Chief Executive of Samantha Dickson Brain Tumour Trust, Sarah Lindsell, said: “We are pleased to see trials of new drugs and treatments taking place, especially for secondary brain tumours, about which so little is currently done. It is a real step forward for people with a secondary tumour from melanoma and we hope will lead to more positive outcomes for patients in the future. Brain metastases more generally are an increasing problem as improved treatments for cancers in other parts of the body mean more people are surviving these longer and, in some cases, going on to develop metastases in parts of the body such as the brain. SDBTT recently met with Cancer Research UK and Professor Mike Richards, the National Cancer Director at the Department of Health to discuss this issue.”
The following article was published in The Lancet today:
Trial of new drug, dabrafenib, for advanced melanoma offers potential breakthrough in treatment of brain metastases (The Lancet)
Results of a phase 1 trial published in this week’s Lancet show substantial shrinking of metastatic tumours in patients treated with a new drug, dabrafenib, that blocks the activity of the cancer-causing mutated form of the BRAF gene, which occurs in about half of melanomas. Dabrafenib also showed the most activity of any systemic treatment to date against secondary melanoma tumours in the brain.
BRAF is a known oncogene, a gene that when mutated causes cancer. About 50% of patients with metastatic melanoma have a BRAF mutation in their tumour and it occurs in many other common cancer types including thyroid, colorectal, ovarian, and lung. The most common BRAF mutations are Val600Glu and Val600Lys.
The initial stage of the study was designed to establish the safe dose. A total of 184 patients with incurable solid tumours were enrolled (156 with metastatic melanoma) and given escalating doses of dabrafenib. The investigators established a recommended phase 2 dose (RP2D) of 150 mg twice daily.
In the second stage, efficacy at the RP2D was studied in three groups of patients with BRAF-mutant tumours: those with advanced melanoma, with untreated melanoma brain metastases, and with other BRAF-mutant solid tumours.
“Brain metastases in most [nine of ten] patients given dabrafenib reduced in size, with four patients’ metastases completely resolving”, explains Dr Gerald Falchook from the University of Texas MD Anderson Cancer Center in the USA, who is lead co-author of the study with Dr Georgina Long from Melanoma Institute Australia and Westmead Hospital in Sydney, Australia. “Patients with melanoma and brain metastases typically survive for less than 5 months; yet in this study, all ten patients were alive at this stage and two patients had durable antitumour activity with survival beyond 12 months. One patient remains on treatment at 19 months”.
Melanoma is notoriously difficult to treat, and there is currently no systemic therapy that prolongs survival for advanced melanoma patients whose cancer has spread to the brain.
In the 36 patients with Val600 BRAF-mutant melanoma treated at the RP2D, half had confirmed responses (tumour shrinkage). In 27 patients with Val600Glu BRAF-mutant melanoma, the overall confirmed response rate of 56% was similar to that shown in a phase 3 trial of vemurafenib, the first approved treatment directed at Val600Glu BRAF-mutant melanoma.
Confirmed responses to treatment were also noted in 4 of 18 patients (22%) with Val600Lys mutant melanoma.
Dabrafenib also showed antitumour activity (partial responses and stable disease) in BRAF-mutant non-small-cell lung, colorectal, papillary thyroid, and ovarian cancers, and in gastrointestinal stromal tumour.
The most common grade 2 or higher side effects observed included cutaneous squamous-cell carcinoma (a less serious form of skin cancer; 11%), fatigue (8%), and pyrexia (6%).
The authors conclude: “The high response rate in melanoma brain metastases and the near-equivalent progression-free survival in patients with Val600Lys or Val600Glu BRAF-mutant melanoma justify the inclusion of such patients in further trials of potent BRAF inhibitors.”
In a linked Comment, Geoffrey Gibney and Vernon Sondak from H Lee Moffit Cancer Center and Research Institute, Florida, USA say: “[These findings] are impressive for two reasons: no previous systemic treatment has shown this degree of clinical activity against melanoma brain metastases, and dabrafenib was not predicted to cross the blood-brain barrier in substantial quantities…Overall, the prospects for use of BRAF-targeted treatment in new patient populations are encouraging.”
