An experimental drug targeting a common mutation in melanoma successfully shrank tumors that spread to the brain in nine out of 10 patients in part of an international phase I clinical trial report in the May 18 issue of The Lancet.
The drug dabrafenib, which targets the Val600 BRAF mutation that is active in half of melanoma cases, also cut the size of tumors in 25 of 36 patients with late-stage melanoma that had not spread to the brain. The drug also showed activity in other cancer types with the BRAF mutation.
"Nine out of 10 responses among patients with brain metastases is really exciting. No other systemic therapy has ever demonstrated this much activity against melanoma brain metastases," said study co-lead author Gerald Falchook, M.D., assistant professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.
Melanoma patients whose disease has spread to their brains have a median overall survival of four or five months, the researchers noted. Drugs used to treat brain metastases have response rates of 10 percent or lower. Surgery and stereotactic or whole-brain radiation also are used.
Tumor shrinkage in the nine responders ranged from 20 percent to 100 percent. In four cases, the brain metastases disappeared.
Drug's reach into brain a surprise
These results will need to be validated in additional clinical trials with larger groups of patients, Falchook said. "This changes how we think of this drug and exclusion criteria for future trials."
"Most clinical trials exclude patients with brain metastases because the drugs are assumed not to cross the blood-brain barrier," Falchook said. "These are the patients most in need of a clinical trial because their treatment options are so limited."
Dabrafenib, made by GlaxoSmithKline, was not designed to cross the blood-brain barrier, which protects the brain from toxic substances in the blood.
The drug's activity against brain metastases was initially a serendipitous finding at one study site. In one patient, a research PET scan performed just before starting dabrafenib revealed a brain metastasis, but this result was not available until after treatment began. The institution's ethics board approved the patient to continue treatment because a follow-up PET scan two weeks later showed decreased metabolic activity in the brain metastasis and subsequent MRIs showed a reduction in its size.
The team then designed a sub-study for 10 patients with untreated brain metastases, Falchook said. The mechanism by which dabrafenib reaches tumors in the brain is under investigation.
"In all of these patients with melanoma brain metastases, the tumors eventually progressed," Falchook said. Prevention of drug resistance remains a challenge in advanced cancers.
High response rate for those without brain metastases
184 patients enrolled at eight sites in the United States and Australia. Of these, 156 patients had melanoma that had spread to other organs. MD Anderson enrolled 64 patients.
The main purpose of a phase I clinical trial is to gradually escalate an experimental drug's dosage to evaluate side effects and establish the highest possible dose that can be safely given.
The researchers never reached a maximum-tolerated dose limit. No patients had to discontinue the drug due to side effects, and few patients experienced severe toxicity. "This is a very non-toxic drug, which is common with these newer, targeted therapies," Falchook said.
Based on response rates and the drug's pharmacokinetics – how the body metabolizes it – the team recommended an oral dose of 150 mg twice daily for future phase II and phase III trials. In the second stage of the phase I trial, they tested that dose in:
36 patients with melanoma with the Val600 BRAF mutation without brain metastases,10 patients with untreated melanoma brain metastases, and
18 (50 percent) had a confirmed response, meaning the reduction in size was observed in a second imaging scan at least one month later,17 (47 percent) stayed on the trial for more than six months, and
Among those with other types of cancers, patients with papillary thyroid, non-small cell lung and colorectal cancers had partial responses.
"This is further evidence that a tumor's molecular profile is as important, and possibly more important, than the organ where the cancer begins," Falchook said.
"We need to screen for BRAF and other molecular abnormalities in our patients' tumors," he said. "In many other tumor types BRAF mutations occur in small percentages of patients. If we're not testing for it routinely, these patients might never be treated with a promising targeted agent for their cancer."
Falchook has six melanoma patients still receiving dabrafenib, including five who are in complete remission. In addition, Falchook is still treating six papillary thyroid patients and one colorectal cancer patient whose tumors have not progressed on the treatment.
GlaxoSmithKline sponsored and funded the clinical trial. Phase II and phase III trials of dabrafenib for melanoma are under way.
Co-authors with Falchook are Razelle Kurzrock, M.D., of MD Anderson's Department of Investigational Cancer Therapeutics, and Kevin Kim, M.D. of MD Anderson's Department of Melanoma Medical Oncology; co-lead author Georgina Long, M.D., Ph.D., and senior author Richard Kefford, M.D., Ph.D., of Melanoma Institute Australia, Westmead Institute for Cancer Research and Westmead Hospital, University of Sydney, in Sydney, Australia; Tobias Arkenau, M.D., Ph.D., Prince of Wales Hospital, Randwick, Australia; Michael Brown, M.D., Ph.D., Royal Adelaide Hospital and University of Adelaide, Adelaide, Australia; Omid Hamid, M.D., and Steven O'Day, M.D., of The Angeles Clinic and Research Institute. Los Angeles, Calif.; Jeffrey Infante, M.D., Sarah Cannon Research Institute, Nashville, Tenn.; Michael Millward, M.D., Cancer Council of Western Australia, Sir Charles Gairdner Hospital and University of Western Australia, Perth, Australia; Anna Pavlick, M.D., New York University School of Medicine; and Samuel Blackman, M.D., Ph.D., C. Martin Curtis, Peter Lebowitz, M.D., Ph.D., Bo Ma, Ph.D., and Daniele Ouellet, Ph.D., of GlaxoSmithKline Research and Development, Philadelphia.
Scott Merville | EurekAlert!
New study shows nanoscale pendulum coupling
05.07.2019 | University of Barcelona
New unprinting method can help recycle paper and curb environmental costs
26.06.2019 | Rutgers University
Adjusting the thermal conductivity of materials is one of the challenges nanoscience is currently facing. Together with colleagues from the Netherlands and Spain, researchers from the University of Basel have shown that the atomic vibrations that determine heat generation in nanowires can be controlled through the arrangement of atoms alone. The scientists will publish the results shortly in the journal Nano Letters.
In the electronics and computer industry, components are becoming ever smaller and more powerful. However, there are problems with the heat generation. It is...
Scientists have visualised the electronic structure in a microelectronic device for the first time, opening up opportunities for finely-tuned high performance electronic devices.
Physicists from the University of Warwick and the University of Washington have developed a technique to measure the energy and momentum of electrons in...
Scientists at the University Würzburg and University Hospital of Würzburg found that megakaryocytes act as “bouncers” and thus modulate bone marrow niche properties and cell migration dynamics. The study was published in July in the Journal “Haematologica”.
Hematopoiesis is the process of forming blood cells, which occurs predominantly in the bone marrow. The bone marrow produces all types of blood cells: red...
For some phenomena in quantum many-body physics several competing theories exist. But which of them describes a quantum phenomenon best? A team of researchers from the Technical University of Munich (TUM) and Harvard University in the United States has now successfully deployed artificial neural networks for image analysis of quantum systems.
Is that a dog or a cat? Such a classification is a prime example of machine learning: artificial neural networks can be trained to analyze images by looking...
An international research group led by scientists from the University of Bayreuth has produced a previously unknown material: Rhenium nitride pernitride. Thanks to combining properties that were previously considered incompatible, it looks set to become highly attractive for technological applications. Indeed, it is a super-hard metallic conductor that can withstand extremely high pressures like a diamond. A process now developed in Bayreuth opens up the possibility of producing rhenium nitride pernitride and other technologically interesting materials in sufficiently large quantity for their properties characterisation. The new findings are presented in "Nature Communications".
The possibility of finding a compound that was metallically conductive, super-hard, and ultra-incompressible was long considered unlikely in science. It was...
24.06.2019 | Event News
29.04.2019 | Event News
17.04.2019 | Event News
19.07.2019 | Physics and Astronomy
19.07.2019 | Physics and Astronomy
19.07.2019 | Earth Sciences