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!
The importance of biodiversity in forests could increase due to climate change
17.11.2017 | Deutsches Zentrum für integrative Biodiversitätsforschung (iDiv) Halle-Jena-Leipzig
Win-win strategies for climate and food security
02.10.2017 | International Institute for Applied Systems Analysis (IIASA)
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
17.11.2017 | Physics and Astronomy
17.11.2017 | Health and Medicine
17.11.2017 | Studies and Analyses