"Metastatic melanoma has a devastating prognosis and is one of the top causes of cancer death in young patients," says Keith Flaherty, MD, director of Developmental Therapeutics at the Massachusetts General Hospital (MGH) Cancer Center, lead and corresponding author of the NEJM article. "Until now, available therapies were few and unreliable, so these findings can really change the outlook for patients whose tumors are fueled by this mutation."
Although surgical removal is usually successful in treating early-stage melanoma, once the skin tumor has spread to other sites in the body, the outlook has been grim. The two FDA-approved drugs – interleukin-2 and dacarbazine – produce a response in only 10 to 20 percent of patients. The current prognosis for survival in metastatic melanoma is 9 months or less, with 9,000 people dying in the U.S. each year.
The role in melanoma of the BRAF mutation – which keeps the protein constantly activated and driving cell growth – was discovered in 2002 by researchers at the Sanger Institute in Britain. Flaherty – who was then at the University of Pennsylvania Abramson Cancer Center – began to explore whether drugs targeting the mutation might interfere with tumor growth. After one potential drug was not effective, he began working in collaboration with Paul Chapman, MD, of Memorial Sloan-Kettering Cancer Center in New York to study PLX4032, an agent developed by Plexxikon and licensed to Roche Pharmaceuticals. Initial trial results were disappointing, but a new formulation that increased the bioavailability of PLX4032 proved to have rapid results that are being reported in the NEJM paper.
The initial stage of the study – led by Flaherty, Chapman and colleagues at six sites in the U.S. and Australia – was designed to establish the effective dose. It enrolled 55 cancer patients, most with metastatic melanoma, who received escalating doses of PLX4032 until unacceptable side effects occurred. BRAF mutations were present in the melanomas of 16 participants in the latter part of this stage, and in 11 of those patients, tumors quickly shrank or, in one instance, disappeared. Three participants with BRAF-mutated thyroid cancers also had their tumors shrink or stabilize in response to PLX4032 treatment.
The second stage enrolled 32 patients with BRAF-mutated melanoma who received the PLX4032 dosage established in the first phase: 960 mg twice a day. In 26 of those participants, tumors shrank more than 30 percent, meeting the criteria for clinical response, and completely disappeared in two. Since another two participants had some reduction in the size of their tumors, Flaherty projects that PLX4032 appears to shrink tumors in approximately 90 percent of patients with BRAF-mutated melanomas.
"One of the things that make these results truly remarkable is that this drug works so reliably," he explains. "And patients who have been experiencing symptoms like pain and fatigue begin to feel better within a week of starting treatment, giving them a much better quality of life.
As seen in trials of other targeted cancer treatments, resistance to PLX4032 developed in the tumors of many participants, leading to resumed tumor growth. Currently tumor suppression has been maintained from about three months to longer than two years, with an average progression-free survival of eight months, and follow-up studies are exploring how resistance occurs and potential strategies to get around it. Two additional MGH-based clinical trials are now underway – a phase 2 study in patients unsuccessfully treated with the FDA-approved drugs, enrollment for which is complete, and a larger phase 3 study that compares PLX4032 with dacarbazine in newly diagnosed patients.
"Until now, we've never had a credible first treatment option for metastatic melanoma, so this has completely transformed how we approach treatment for patients with the BRAF mutation," says Flaherty, who is a member of the Harvard Medical School faculty. "Although we don't know how long response may last, the ability to beat this disease down in the short term will buy us time to strategize second-line therapies and design the next generation of trials."
Along with senior author Paul Chapman, MD, Memorial Sloan-Kettering Cancer Center, co-authors of the NEJM article are Igor Puzanov, MD, and Jeffrey Sosman, PhD, Vanderbilt University; Kevin Kim, MD, M.D. Anderson Cancer Center; Antoni Ribas, MD, University of California at Los Angeles; Grant McArthur, MB, BS, PhD, Peter MacCallum Cancer Centre, East Melbourne, Australia; Peter O'Dwyer, MD, University of Pennsylvania Abramson Cancer Center; Richard Lee, MD, PhD, and Joseph Grippo, Roche Pharmaceuticals, and Keith Nolop, MD, Plexxikon. The study was funded by Plexxikon and Roche.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.
Katie Marquedant | EurekAlert!
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.
Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
16.01.2017 | Power and Electrical Engineering
16.01.2017 | Information Technology
16.01.2017 | Power and Electrical Engineering