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Part II: Discussion on targeted therapy and genetics

Round table discussion between the editors of the Melanoma Resource Centre: Prof Reinhard Dummer, Dr James Larkin and Prof Dirk Schadendorf

Round Table Discussion - Paris, 3 July 2014

Round table discussion on targeted therapy and genetics, between the editors of the Melanoma Resource Centre: Prof Reinhard Dummer (Professor of the University of Zurich and Vice-Chairman of the Department of Dermatology in the University Hospital of Zürich, Switserland), Dr James Larkin (Consultant Medical Oncologist at The Royal Marsden, London, UK) and Prof Dirk Schadendorf (Director and Chair of the University Hospital Essen, Clinic for Dermatology, Germany).

Prof Reinhard Dummer, chairing this session, introduces the topic. Genetic mutations found in cancer cells have opened up a new field of therapeutic options. Step one was the discovery of the frequency of the B-Raf mutation. Such findings have opened up the possibility of targeted therapy for many patients.

Reinhard opens the discussion by asking Prof Dirk Schadendorf if and which B-Raf inhibitors he uses in daily clinical practice. Genetic analysis of the tumor has changed clinical practice over the past 5 years. The understanding of pathways driving the tumor proliferation, which are critical oncogenic drivers, has increased significantly. We now know that the MAP-kinase pathways mutations in N-Ras and B-Raf (in 15-20% and about 40% of our patients, respectively) are critical for maintaining the melanoma growth. Selective B-Raf inhibitors like vemurafenib and dabrafenib are now standard in our melanoma treatment algorithms, since pivotal clinical studies have shown improvement in survival. This is the first time in decades that we have seen that in melanoma. Both drugs have been approved and are being used by oncologists at centers and in the periphery. Future lies in combining drugs targeting the N-Ras and B-Raf mutations. We are e.g. awaiting results from clinical trials with combinations of B-Raf- and MEK-inhibitors. In this manner we are hoping to maximize suppression of the pathway and improve on clinical parameters such as progression free survival (PFS), overall survival. First data from the COMBI-d study, a Phase III study comparing the combination of dabrafenib and trametinib to dabrafenib monotherapy as first-line therapy for B-Raf positive melanoma, show improved PFS and early evidence of improved overall survival. That will become the next standard.

Reinhard states that B-Raf mutations are also seen in many other tumor types, and asks James if he or his colleagues are using B-Raf inhibitors for treating other tumor types. Yes, James responds, in an investigational setting in colorectal and lung cancer for instance. B-Raf mutations in these cancers are, however, a lot rarer than for melanoma (5-10%). At least in colorectal cancer the B-Raf mutations do not seem to behave, in response to treatment, as they do in melanoma. This is interesting in its own right, but trials have thus far been disappointing for colorectal cancer. There is however some interesting early (preclinical) evidence that combining B-Raf inhibitors with anti-EGFR might have greater activity / synergy, and we are looking forward to seeing some clinical data in that area. The fact that certain mutations occur in different cancers, thus does not mean they have the same effect. That is true for B-Raf, but can similarly be true for other mutations, like N-Ras, K-Ras. If we can successfully target a mutation in melanoma, it will not automatically also work in other cancers with similar mutations. This is likely because the signaling pathways are highly complex and the effects are largely context dependent. Reinhard counters that there are some examples of the contrary. True, says James, that makes it so interesting. James describes that in melanoma KIT mutations are relatively rare, but they are also very diverse. Early trial data show that you can get very different responses from different melanoma to KIT inhibitors. This probably reflects both the mutation as the context of the mutation. Reinhard agrees, a malignancy is always a combination of events, complexing the treatment. Dirk states that context is important, but what to think of heterogeneity? Is that important for response? James thinks it might. Heterogeneity exists in many different forms. He believes heterogeneity may form a basis for creating resistance to therapy, by basic selection mechanisms. So yes, heterogeneity may be a big problem.

Reinhard asks Dirk which may be the resistance alternating mutations to B-Raf inhibitors? From investigating ‘B-Raf resistant tumors’ it is found that over 66% have new alterations in their MAP-kinase signaling pathway, which was originally shut down by the B-Raf inhibitor. Alterations are seen in MEK-1, MEK-2, B-Raf amplification is seen, etc. Thus, the pathway is not sufficiently shut down and we have to work on further suppression of the pathway. E.g. by combining drugs or using higher dosages, to avoid escape from suppression. Such approaches need to be tested in vitro, in animal models, and then in clinical trials. Reinhard finishes this discussion by pointing at the Advances in Melanoma Resource Centre website, where links to many papers relating to this issue can be found.





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