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ASCO: Targeted Tx Stalls Melanoma Progress
  By Crystal Phend, Senior Staff Writer, MedPage Today

Published: June 04, 2012

Action Points

· Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

· A novel drug (dabrafenib) targeted at the BRAF mutations common in metastatic melanoma was associated with an improvement in progression-free survival by 70% in patients with BRAF-mutated tumors compared with standard chemotherapy.

· The most common adverse events seen with dabrafenib were hyperkeratosis in 51%, palmar-plantar hyperkeratosis in 21%, arthralgia (16%), and fatigue and headache (both 17%), with treatment discontinuation due to adverse events uncommon at 3%.

CHICAGO -- A novel drug targeted at the BRAF mutations common in metastatic melanoma appears to substantially slow progression, a clinical trial showed.

Dabrafenib boosted progression-free survival (PFS) by 70% in patients with BRAF-mutated tumors compared with standard chemotherapy alone (P<0.0001), Axel Hauschild, MD, of Universitaetsklinikum Schleswig-Holstein in Kiel, Germany, and colleagues found.

The median time to progression or death reached 5.1 months compared with 2.7 on dacarbazine (DTIC-Dome) chemotherapy, the group reported here at the American Society of Clinical Oncology (ASCO) meeting.

"For BRAF-mutated patients, standard of care is no longer DTIC. Each and every patient needs to be offered a BRAF inhibitor," Hauschild said at an ASCO. "It's the beginning of a completely new era in treatment of metastatic melanoma."

Dabrafenib selectively blocks BRAF similar to vemurafenib (Zelboraf), which was approved for metastatic and unresectable melanoma last fall.

Both oral agents target the V600E mutation that accounts for most of the roughly half of advanced melanomas with a BRAF mutation.

The BREAK-3 trial included 250 patients with stage III, V600E-mutated metastatic melanoma randomized to 150 mg of dabrafenib twice daily or 1,000 mg of IV dacarbazine chemotherapy every 3 weeks, with the option to cross over at signs of disease progression.

Most patients had disease control on dabrafenib. Best confirmed response rates with the drug and with chemotherapy, respectively were:

· Complete response in 3% versus 0%

· Partial response in 50% versus 19%

· Stable disease in 40% versus 30%

With just 12% of patients having died, the overall survival results were too immature to present, according to Hauschild.

Treatment-related adverse events were nearly all grade 3 or less. The most common adverse events were hyperkeratosis in 51%, palmar-plantar hyperkeratosis in 21%, arthralgia (16%), and fatigue and headache (both 17%).

Treatment discontinuation due to adverse events was uncommon at 3% in both groups.

Drugmaker GlaxoSmithKline announced plans to apply for FDA approval of both dabrafenib and trametinib as single agents for treatment of metastatic melanoma.

"The next step is the combination of BRAF and MEK inhibition with dabrafenib and trametinib, not only for stage IV but also in the adjuvant setting," Hauschild said.

Another trial reported at the meeting showed high disease response rates with that combination. Others are ongoing.

The results from the BREAK-3 trial confirms that BRAF targeting is effective, but may give dabrafenib the edge with regard to safety, noted ASCO press conference moderator Sylvia Adams, MD, of New York University Langone Medical Center in New York City.

The novel drug showed a lower risk of the serious skin events seen with vemurafenib. Dabrafenib was associated with a 7% risk of squamous cell carcinoma or keratoacanthoma and a 3% rate of photosensitivity in the trial.

After 50 years without any good treatments, the recent blossoming in metastatic melanoma options in the clinic, and on the horizon, may mean some work in sorting out treatment algorithms, acknowledged Caroline Robert, MD, PhD, of Institut Gustave Roussy in Villejuif, France.

"It's not a problem, it's good news," Roberts told reporters at the press conference, where she presented similarly good results with another novel drug in the related MEK pathway, trametinib.

What it also means is that mutation testing is becoming increasingly important in melanoma, Hauschild noted.

An upcoming update of German guidelines makes BRAF testing mandatory, he told MedPage Today.

The study was sponsored by GlaxoSmithKline (GSK).

Hauschild reported consulting or advising for and receiving honoraria and research funding from GSK.

A number of co-authors reported employment and stock ownership with GSK.

Robert reported consulting for or receiving honoraria from BMS, Roche, GSK, Bayer, and Novartis; receiving fees for participation in review activities from Roche and GSK; and payment for development of education presentations from BMS and Roche.

Primary source: American Society of Clinical Oncology Source reference: Hauschild A, et al. "Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma" ASCO 2012; Abstract LBA8500.


GSK presents positive results for investigational BRAF and MEK inhibitors dabrafenib and trametinib at ASCO

Issued: Monday 04 June 2012, London UK

Phase III studies of single agent therapy in metastatic melanoma with BRAF V600 mutations meet primary endpoints

Findings from GlaxoSmithKline (GSK) plc's Phase III clinical study programme evaluating single agent therapy with the targeted anti cancer agents, dabrafenib and trametinib, in patients with BRAF V600 mutation positive metastatic melanoma were presented today at the Annual Meeting of the American Society of Clinical Oncology in Chicago. The Phase III data for trametinib were also published online today in the New England Journal of Medicine.

Both the BREAK3 study of dabrafenib (BRAF inhibitor) and the METRIC study of trametinib (MEK 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. Additionally, patients in the METRIC study who received trametinib lived significantly longer (Overall Survival or OS) than those who received chemotherapy with dacarbazine. OS data are not yet mature in the BREAK3 trial.

"The results from the clinical studies of dabrafenib and trametinib presented at this meeting represent important progress towards understanding how these investigational agents could benefit patients with advanced and metastatic melanoma. Importantly, trametinib is the first MEK inhibitor to demonstrate clinical benefit in a late phase melanoma trial." said Dr. Rafael Amado, Head of Oncology R&D for GlaxoSmithKline. "We are planning regulatory submissions for dabrafenib and trametinib as single agent therapies and have recently started a Phase III programme to further investigate the effect of the combination in this disease."

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 ((third power) 20%) 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%).

The METRIC study enrolled patients with BRAF V600E or K mutation positive metastatic melanoma, and included patients who had one prior regimen of chemotherapy. The median PFS of 4.8 months in the trametinib arm was significantly greater than the 1.5 month median PFS in the chemotherapy arm with a 55% reduction in risk of disease progression or death (HR 0.45; p<0.0001) in the trametinib arm. Additionally, a significant Overall Survival benefit was gained by the trametinib arm at the interim analysis (HR 0.54;p=0.0136). The most commonly reported ((third power) 20%) AEs in the trametinib arm were rash (57%), diarrhoea (43%), fatigue (26%), and peripheral oedema (26%). Other adverse events associated with trametinib in this study include hypertension (15%), chorioretinopathy (< 1%) and decrease in ejection fraction/ventricular dysfunction (7%).

Additional results from early phase studies of both investigational medicines were presented at this meeting including a Phase II study of dabrafenib in patients with BRAF V600 mutation positive metastatic melanoma with concurrent metastases to the brain and a Phase I/II study of the combination of dabrafenib and trametinib in patients with BRAF V600 mutation positive metastatic melanoma.

In all of these studies, 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.

What is BREAK3?

BREAK3 is a Phase III, randomised, open-label study comparing the efficacy, safety, and tolerability of dabrafenib to dacarbazine in patients with advanced (Stage III) or metastatic (Stage IV) melanoma who harbour a BRAF V600E mutation. The primary endpoint of the study was progression free survival. Patients randomised to dacarbazine and whose disease progressed were allowed to crossover and receive dabrafenib. The study enrolled 250 patients from around the world, including the United States, Australia, Canada, and Europe.

What is METRIC?

The METRIC Phase III study of trametinib, a MEK inhibitor, in patients with advanced/metastatic melanoma enrolled 322 patients with BRAF V600E or K mutation who had no more than one prior regimen of chemotherapy and no prior BRAF inhibitor treatment. The primary endpoint of the study was progression free survival. Patients randomised to the chemotherapy cohort were allowed to crossover to receive trametinib therapy upon independent confirmation of documented disease progressed. The study was conducted in Europe (Austria, Belgium,Czech Republic, France, Germany, Greece, Italy, Norway, Poland, Russia, Sweden, Switzerland, Ukraine, United Kingdom), North America (US, Canada), Argentina, Australia, and New Zealand

About dabrafenib

Dabrafenib is an investigational, orally bioavailable inhibitor of the BRAF protein. Dabrafenib was discovered and developed at GSK.

About trametinib

Trametinib is an investigational, orally bioavailable inhibitor of the MEK protein. Trametinib was discovered by Japan Tobacco and in-licensed by GSK in 2006.

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