The International Melanoma Working Group (IMWG) convened its 9th working meeting on December 4-5, 2010, in Naples, Italy. Melanoma experts from across the globe attended the meeting. The theme was Strategies to Optimize Clinical Trial Outcomes: Understanding and Overcoming Resistance.
Drawing on its international network of top-tier researchers, the IMWG is embarking on its first clinical trial.
This trial will use GSK2118346 in patients with operable brain metastases and a proven V600E mutation. Brain metastases are a huge challenge in melanoma. They are both common and lethal. Up to 80% of patients with melanoma have brain metastases at autopsy, and these "secondary tumors" are the direct cause of death in nearly 50% of patients.
Historically, these metastases have been extremely resistant to treatment by surgical, radiologic, or chemotherapeutic approaches, and patients often die within a few months of a brain metastases diagnosis. However, a recent report from an ongoing, Phase 1,2 study raised new hope with an emerging therapeutic, GSK2118436, which is a selective inhibitor of mutant forms of BRAF. As reported at the 35th European Society for Medical Oncology (ESMO) meeting, GSK2118436 effectively controlled the growth of brain metastases in a subgroup of 10 patients with advanced melanoma and untreated brain metastases, causing tumor shrinkage in 9 out of 10 patients.
Investigators then moved on to a discussion of another newly initiated IMWG protocol, which just received industry funding commitment. This protocol will collect presurgical brain metastases samples from patients with operable brain metastases in order to create a melanoma brain metastases bank. The investigators discussed the trial design, criteria for participation, and refined their research agenda for this exciting and timely research.
Both of these endeavors, focusing melanoma brain metastases, are meant to address this large unmet clinical and research need. Collectively, these protocols should help characterize behavior of melanoma brain metastases compared with metastases in other body regions, serve as a model system in which to test emerging agents, and provide molecular correlates of clinical activity.
In their discussion, IMWG investigators discussed preliminary data on the impact of different inhibitors on melanoma cell lines with varied mutations, sharing some intriguing predictors of response and nonresponse. The panelist then discussed the research agenda for these samples, reviewed some of the nuts-and-bolts of conducting this research, and invited additional participation in the protocol.
Moving beyond a strict focus on brain metastases, the IMWG investigators also discussed other important melanoma research topics.
In addressing resistance mechanisms, the investigators reviewed pathways of resistance as well as the rationale for combination approaches to thwart resistance.
BioPharma provided updates on various investigational agents. They weighed in on melanoma clinical trial design challenges--including end points, duration of treatment, adjuvant trials, and the problem of crossover. Finally, recognizing that this shifting focus to a more tailored approach to melanoma therapeutics raises the bar for pathologic analyses.
The investigators stressed the evolving role for routine pathology, immunopathology, and molecular pathology in both clinical trials and in support of clinical decision-making for melanoma therapy selection.
Our December International Melanoma Working Group (IMWG) meeting will be the largest IMWG meeting held in 4 years - encompassing 21 IMWG melanoma expert members, 3 invited guest investigators, and 15 industry research and marketing representatives. These melanoma experts will travel from around the world - Australia, Europe, and the United States - to attend the meeting.
A small, preliminary biologic investigation of melanoma brain metastases cell lines will be presented. This probe study is looking at one of the most active pathways in melanoma involving cell reproduction and growth of tumors: activation of RAS-MEK in melanoma. We know that certain new drugs (not yet approved for human use) can block this pathway, but apparently not sufficiently in these brain metastases cell lines to cause a significant stoppage of tumor growth.
At the meeting, clinical investigators from the University of Pittsburgh will further discuss a recently approved protocol for possible use by other IMWG members. The protocol outlines a study that will actually begin to systematically collect brain metastases samples and paired melanoma samples, along with cerebral spinal fluid.
Once collected, these paired tissues will be examined for any unique signature of proteins involved in cell division and multiplication to see if the brain met cell lines are different, and if the brain metastases can be specially treated with existing or emerging novel cancer drugs. As an offshoot of that study, the IMWG members will tackle the issue of brain immunology.
Since Fall 2009, there has been excitement generated by reports from Australian and American researchers involving the inhibition of a genetic target called BRAF, present in the cell proliferation pathway of melanoma.
A new drug by Plexxicon/Roche has shown a few surprising, but short-lived partial remissions of some patients' metastatic melanoma.
Experts are now carefully looking at patients' melanomas which express a genetic mutation called BRAF-V600E against other patients' samples that express a wild-type B-RAF, to see if the new drug works better for one or another type of melanoma.
Other experts are looking at important cell-growth pathways and other genes which are interrupted or energized, when BRAF is blocked by the new drugs, to better understand the type of short-remission and 'escape' of the melanoma from this promising therapeutic approach. Other clinical experts are now focusing on a second BRAF inhibitor from GlaxoSmithKline. The IMWG will be looking at possible BRAF combinations with other agents.
The IMWG convened its 8th working meeting in Lansdowne, Virginia.
The meeting began with continuing discussion on the IMWG's first independent research program -- an attempt to uncover the biological characteristics of melanoma brain metastases, which may be different from the primary melanoma.
Dr. Christine Falk, from the University of Heidelberg, is leading this research endeavor. Dr. Falk has received melanoma cell lines and these cell lines will be reviewed to see if we can identify differences in cell line by site and whether we can identify potential targets for drug combinations. It was discussed, that moving forward, viable frozen brain tissue needed to be banked in order to be able to study drug sensitivity in fibroblasts and tumor cells.
Another key discussion was the continuation of an ongoing study being conducted by the IMWG with the help of one of our biopharma statisticians. This study will try to determine whether there is merit in evaluating ongoing results of clinical trials in advanced melanoma patients at an earlier time point, before the study allows for an evaluation of overall survival. This could potentially help speed clinical trial results.
After looking at several large studies there is some evidence of a relationship between PFS (progression free survival) and OS (overall survival), but it is very weak given the size of effect seen so far. It was decided to await the results of several upcoming Phase III trials and to consider LDH subsets.
Dr. Richard Marais, one of the world's experts on BRAF, was a guest speaker. Dr. Marais -- Professor of Molecular Oncology at The Institute of Cancer Research in London, England -- is leading the search to understand the underlying causes of melanoma and to develop new treatments for this disease.
Professor Marais was instrumental in explaining how a genetic mutation that occurs in about half of melanomas triggers the disease. Ultraviolet radiation from excessive sun exposure is known to cause skin cancer and Professor Marais has revealed the role that a gene called BRAF plays in this process. He is now helping lead the search for new drugs that will block this mutated gene, which could potentially be used to treat a large number of these cancers.
IMWG members also engaged in several discussions about primary and secondary resistance and the need to identify the major resistance mechanisms before embarking on combination drug trials. To accomplish this goal, the importance of obtaining post-therapy biopsies and then additional biopsies at the time of the relapse/progression was stressed, as well as saving viable frozen tumor, sorting melanoma from normal from stroma, and then examining signaling biochemistry and gene expression profiling.
At the next meeting, the IMWG will further expand on the brain metastases trial, examine BRAF inhibitor resistance, and look at the emerging data on CTLA4 Antibodies and Parp Inhibitors. Hopefully, by the time of that meeting, the landscape for melanoma patients will be much more hopeful with new agents in the offering.