In November 2009, the IMWG convened its 7th working meeting in Berlin. This was an important milestone meeting for IMWG, as AIM announced its funding to initiate the IMWG's first independent research program. This new international program will 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, along with colleagues from the Universities of Pittsburgh, Essen (Germany) and Siena (Italy). As we uncover early information from this project, we hope to identify genetic and protein targets in brain metastases. This information will aid the IMWG to focus its questions, in order to do a broader study of these "paired" melanoma tissues from many more patients located in IMWG centers across the world. Our ultimate goal is to determine if the IMWG can identify current 'novel' drugs used in other cancers, for improving the lives and survival of patients with melanoma brain metastases.
In another key discussion at the meeting, we debated the value of an early time point for evaluating the ongoing results from clinical studies in advanced melanoma, before the study allows an evaluation of overall survival. To date, no study of any available or investigational drug therapy has produced a positive impact on melanoma patients' overall survival. This earlier endpoint, "progression free survival" (PFS), means patients are alive without any indication of progression of their melanoma following the most recent therapy. The weakness of watching for PFS as a measure of a drug's effectiveness, is that the times for 'watching for progression' are not always a fixed 'appointment' across all of the many patients involved in a clinical trial. So, there can be variation in exactly when the finding of progression is observed in one patient as opposed to other patients.
The U.S. FDA has recently held a meeting about PFS, and they said that the improvement in length of time of PFS and lack of disease progression for PFS really has to be "clinically-meaningful." While PFS allows a quicker endpoint for looking at trial results, we all have to better understand the meaning of an increased number of months and quality of life (without side effects) behind these PFS findings. As well, the statistics behind PFS have to be supported by a large enough number of patients in a study, in order to avoid a 'chance' finding that PFS is not really worthwhile. The IMWG is continuing to evaluate many published trials in advanced melanoma, with the kind support of one of our outstanding biopharma company statisticians. We are entering an analysis which could reveal the level of PFS statistics, which may lead to a signal for the potential of an Overall Survival (OS) finding in the future. We hope to meet as a group with regulatory officials from the US and European Union, to further discuss the value of PFS for melanoma patients and for speeding the findings from new drug studies in advanced melanoma.
IMWG members also discussed the October 2009 meeting of the FDA Oncology Drugs Advisory Committee (external clinical advisors to the FDA). The drug Peg-IntronÒ was studied in a large European trial in the adjuvant (post-surgery) setting of early-stage melanoma (EORTC 18991). The key finding was an improvement in relapse-free survival, although there was much debate about the safety profile and potential impact on these patients when the ultimate benefit of increased overall survival may not be achieved. The FDA is now considering the ODAC recommendation for possible approval of this drug, as a new option for adjuvant therapy of melanoma.
The members of IMWG presented several studies in advanced melanoma which are expected to release results in the next 1-2 years. A shared study in Germany (DeCOG) and the EORTC group is evaluating Peg-Intron + Sorafanib. Early data in another study from the US and Europe for a new "B-RAF inhibitor" shows several patients with exciting remissions so far, but with return of the disease in a short time. This new drug therapy provides us with a "view through the keyhole" into the challenging biology of metastatic melanoma, but clearly this new class of drugs will have to be optimized to ensure the remissions are lasting. The IMWG will continue to discuss strategies for improving these drugs, and for combinations, with world-leading experts in the field of B-RAF.
In the USA, the SWOG cooperative group is evaluating two combinations of available novel cancer therapies: sorafanib + temsirolimus vs. sorafinib + tipifarnib. The ECOG study group is evaluating a drug used in leukemia (dasatinib) in a type of melanoma with a special genetic mutation (C-Kit). ECOG is also studying Peg-Intron in patients where the tumor has elevated bFGF levels.
These trials represent a new beginning, to explore the unique 'biologic signature' of melanoma while trying to rapidly apply some of the most recent and exciting drugs in oncology to improve the lives of people with melanoma.