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!
Obstructing the ‘inner eye’
07.07.2017 | Friedrich-Schiller-Universität Jena
Drone vs. truck deliveries: Which create less carbon pollution?
31.05.2017 | University of Washington
Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.
For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...
What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.
To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...
The research team of Prof. Dr. Oliver Einsle at the University of Freiburg's Institute of Biochemistry has long been exploring the functioning of nitrogenase....
A one trillion tonne iceberg - one of the biggest ever recorded -- has calved away from the Larsen C Ice Shelf in Antarctica, after a rift in the ice,...
Physics supports biology: Researchers from PTB have developed a model system to investigate friction phenomena with atomic precision
Friction: what you want from car brakes, otherwise rather a nuisance. In any case, it is useful to know as precisely as possible how friction phenomena arise –...
19.07.2017 | Event News
12.07.2017 | Event News
12.07.2017 | Event News
20.07.2017 | Information Technology
20.07.2017 | Materials Sciences
20.07.2017 | Physics and Astronomy