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Clinical Trials

Date: 2014-09-29

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 2014 Congress of the European Society for Medical Oncology (ESMO)

Company: GSK (UK)

Product: Tafinlar® (dabrafenib)

Action mechanism:

Dabrafenib is a selective inhibitor of B-RAF protein kinase carrying V600E mutation. It is currently being developed for the treatment of BRAF mutation-positive tumors.

Disease:

metastatic melanoma with BRAF V600 mutations

Therapeutic area: Cancer - Oncology

Country: Australia, Canada, Europe, USA

Trial details:

BREAK-3 (BRF113683) is a phase III, randomised, open-label study comparing the efficacy, safety, and tolerability of dabrafenib to dacarbazine (DTIC) in patients with advanced (Stage III) or metastatic (Stage IV) melanoma who harbour a BRAF V600E mutation. Patients with previously untreated BRAF V600E mutation-positive metastatic melanoma were randomly assigned to receive dabrafenib (150 mg twice daily, orally) or DTIC (1000 mg/m2 intravenously every three weeks). The primary endpoint of the study was PFS, and secondary prespecified endpoints included OS. No formal statistical testing was planned for the pre-defined secondary endpoint in this study, due to several study design related factors including the known confounding effect of the patient cross over. The primary analysis of the study was previously reported (Hauschild a, et al Lancet 2012; 380; 358-65). The study enrolled 250 patients from around the world, including the U.S., Australia, Canada, and Europe. 

Latest news:

* On September 29, 2014, GSK announced updated results for Tafinlar® (dabrafenib) from a planned analysis of the phase III BREAK-3 study in 250 patients with BRAF V600E mutant metastatic melanoma. These results, which include new survival data, showed 45 per cent of patients treated with dabrafenib were still alive at two years. The data were presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid. Analysis of the study’s primary endpoint, progression free survival (PFS), was reported in 2012. The results presented at ESMO relate to a secondary endpoint from this study, with a final analysis of the overall survival (OS) endpoint expected in 2016.

45 per cent of patients treated with dabrafenib only, were alive at two years compared to 32 per cent of patients who began treatment with dacarbazine (DTIC). 59 per cent of patients on DTIC treatment whose disease progressed subsequently received dabrafenib treatment and are included in the DTIC control arm results. While allowing this treatment cross over means patients in the control arm get the potential benefit of an active experimental drug, this can impact the comparative study findings as patients who received both medicines are included in the DTIC arm results. At the planned two year follow up, the study showed a median OS of 20.0 months for the dabrafenib arm (95% CI 16.8-24.4) compared to 15.6 months for the DTIC arm (95% CI 12.7-21.2) [Hazard Ratio (HR) 0.77 (95% CI 0.52-1.13) – not statistically significant.

The safety profile of dabrafenib observed in this analysis was consistent with that observed at the primary analysis of BREAK-3. The five most common adverse events (AEs) in patients treated with dabrafenib were hyperkeratosis (a condition causing benign skin thickening or lesions) (41%), arthralgia (joint pain) (37%), headache (36%), pyrexia (fever) (33%) and alopecia (hair loss) (29%). Serious adverse events (SAEs) in ≥5 per cent of patients treated with dabrafenib included cutaneous squamous-cell carcinoma/keratoacanthoma (10%) and pyrexia (5%). Noncutaneous malignancies occurred in four patients (2%) on dabrafenib, two patients (5%) who crossed over and in no patients treated with DTIC.

* On June 4, 2012, GSK has presented  positive results for investigational BRAF inhibitor dabrafenib at ASCO. The BREAK3 study of dabrafenib (BRAF inhibitor) demonstrated a statistically significant benefit in the length of time patients with BRAF V600 mutation positive advanced or metastatic melanoma lived without progression of their disease or death (Progression Free Survival or PFS) compared to those receiving chemotherapy.
The BREAK3 study enrolled patients with previously untreated BRAF V600E mutation positive metastatic melanoma and compared dabrafenib to dacarbazine.
In this study, dabrafenib treatment reduced the risk of disease progression or death by 70% (Hazard Ratio (HR) 0.30; p<0.0001) compared to chemotherapy. The median PFS was 5.1 months in the dabrafenib arm compared with 2.7 months in the dacarbazine arm.
The most commonly reported (³20%) adverse events (AEs) in the dabrafenib arm were hyperkeratosis (37%), headache (32%), pyrexia (25% Grade 1/2; 3% Grade 3), arthralgia (27%), skin papilloma (24%), alopecia (22%) and palmar-plantar erythrodysaesthesia syndrome (20%). Other skin-related toxicities of interest included photosensitivity (3%) and Grade 3 squamous cell carcinoma/keratoacanthoma (5%).

In this stud, patients were selected for eligibility based on the BRAF mutation status of their cancer. Testing was performed centrally by Response Genetics Inc (RGI). The important role of companion diagnostics to precisely identify patients who may derive benefit from these drugs is highlighted by the results of these studies. GSK and bioMerieux have collaborated to develop a companion diagnostic assay that specifically identifies BRAF V600 (V600E and V600K) mutations in tumour samples and aim to submit for US FDA Pre-Market Approval of the test in the near future.
GSK is also  planning regulatory submission for dabrafenib as single agent therapy.

Is general: Yes