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."
Dr Gerald Falchook, The University of Texas MD Anderson Cancer Center, Texas, USA. T) +1 713 792-0661 E) gfalchoo@mdanderson.org
Dr Georgina Long, Melanoma Institute Australia and Westmead Hospital in Sydney, Australia. T) +61 2 9911 7200 E) georgina.long@sydney.edu.au
Dr Vernon Sondak, H Lee Moffit Cancer Center and Research Institute, Florida, USA. T) +1 813 745 8788 E) Vernon.sondak@moffitt.org
Journal
The Lancet