GSK announces overall survival results from phase III BREAK-3 study of Tafinlar® (dabrafenib) in patients with BRAF V600E-mutant metastatic melanoma

GSK announces overall survival results from phase III BREAK-3 study of Tafinlar® (dabrafenib) in patients with BRAF V600E-mutant metastatic melanoma

29 September 2014
Issued: London, UK

GSK today 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.[i] 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.[ii] Today's results 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.]1

"We are encouraged by the 45 per cent survival rate with dabrafenib at two years" said Dr. Paolo Paoletti, President of Oncology, GSK. "Treatments for melanoma have come a long way in recent years and we're now seeing the benefits precision medicines can bring to the right patients."

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.1

About BREAK-33
BREAK-3 (BRF113683) is a phase III, randomised, open-label study comparing the efficacy, safety, and tolerability of dabrafenib to 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.

About Tafinlar® (dabrafenib)
Dabrafenib targets BRAF, a key component of the MAPK (mitogen-activated protein kinase) pathway. In many types of melanoma, a mutated BRAF protein on the MAPK pathway disrupts normal cellular regulation and promotes increased cell production. Dabrafenib binds to the mutated BRAF protein, which may lead to an inhibition of oncogenic signalling, thus inhibiting the proliferation of tumour cells.3

In the European Union (EU), dabrafenib is a licensed monotherapy for the treatment of adult patients with unresectable (melanoma that cannot be removed by surgery) or metastatic melanoma (melanoma which has spread to other parts of the body) with a BRAF V600 mutation as detected by a validated test. Dabrafenib is also licensed in the U.S., Canada, and Australia. Full prescribing information can be accessed here: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002604/WC500149671.pdf

Safety Information[iii]
Toxicities with precautions for use include pyrexia (fever, including severe fever), cutaneous squamous cell carcinoma, new primary melanoma, non-cutaneous malignancy, renal failure, pancreatitis, uveitis (an inflammation of the middle, pigmented, vascular structure of the eye), and QT prolongation (a disorder of the heart's electrical system).

The safety profile of dabrafenib is based on integrated data from five clinical monotherapy studies and included approximately 580 patients with melanoma. The most frequently occurring adverse events (≥ 25 per cent) reported with dabrafenib were hyperkeratosis (a condition causing benign skin thickening or lesions), headache, pyrexia (fever), arthralgia (joint pain), fatigue and nausea.

Pyrexia: Fever has been reported in clinical trials. In 1 per cent of patients in clinical trials, serious febrile events and fever of any severity complicated by severe rigors or chills, dehydration, hypotension and/or renal insufficiency have been reported in patients in clinical trials.
Cutaneous Squamous Cell Carcinoma (cuSCC): Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with dabrafenib.
New primary melanoma: New primary melanomas have been reported in clinical trials.
Non-cutaneous malignancies: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signalling in BRAF wild-type cells with RAS mutations when exposed to BRAF inhibitors. This may lead to increased risk of non-cutaneous malignancies with dabrafenib exposure when RAS mutations are present. Cases of RAS-associated malignancies have been reported.
Renal failure: Renal failure has been identified in approximately 1 per cent of patients treated with dabrafenib. Observed cases were generally associated with pyrexia and dehydration. Granulomatous nephritis has been reported. Dabrafenib has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting.
Uveitis: Ophthalmologic reactions including uveitis and iritis have been reported.
Pancreatitis: Pancreatitis has been reported in approximately 1 per cent of dabrafenib-treated subjects.
Hyperglycemia: Hyperglycaemia has been reported in patients receiving dabrafenib.
QT prolongation: Worst-case QTc prolongation of > 60 millisecond (msec) was observed in 3 per cent of dabrafenib-treated subjects (one > 500 msec in the integrated safety population). Treatment with dabrafenib is not recommended in patients with uncorrectable electrolyte abnormalities (including magnesium), long QT syndrome or who are taking medicinal products known to prolong the QT interval. Initiation of treatment with dabrafenib is not recommended in patients with QTc > 500 msec.
Drug Interactions: Dabrafenib is a substrate of CYP2C8 and CYP3A4. Potent inducers and inhibitors of these enzymes should be avoided when possible as they may respectively decrease and increase, concentrations of dabrafenib. Dabrafenib is an inducer of CYP3A4 and CYP2C9 and may induce other CYP enzymes (e.g., CYP2C8, CYP2C19, CYP2B6) and transporters. Dabrafenib decreased the systemic exposure of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Concomitant use of dabrafenib with medicinal products that are sensitive substrates of these enzymes may result in loss of efficacy and should generally be avoided if monitoring for efficacy and dose adjustment is not possible. Agents that increase gastric pH might decrease the bioavailability of dabrafenib and should also be avoided when possible.

GSK – one of the world's leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information please visit www.gsk.com.

Cautionary statement regarding forward-looking statements
GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D 'Risk factors' in the company's Annual Report on Form 20-F for 2013.

References
[i] Hauschild A, Grob JJ, Demidov LV, et al. ABSTRACT 1092: "An Update on Overall Survival (OS) and Follow-On Therapies in BREAK-3, a Phase III, Randomized Trial: Dabrafenib (D) vs. Dacarbazine (DTIC) in Patient (pts) with BRAF V600E Mutation-Positive Metastatic Melanoma (MM)." European Society for Medical Oncology (ESMO) Congress 2014.

[ii] Hauschild A, Grob JJ, Demidov LV, et al. "Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial." Lancet 2012; 380: 358–65.

[iii] Tafinlar EU Summary of Product Characteristics, 30 August 2013. Accessed here: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002604/WC500149674.pdf

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