The fourth "
Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination
Therapies, News in
Immunotherapy, and Tumor Microenvironment and
Biomarkers. Until recently systemic
therapy for metastatic
melanoma patients was ineffective, but recent advances in
tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New
therapies, such as
mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic
melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of
receptor tyrosine kinases (BRAF,
MEK, and VEGFR), the
phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT,
mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including
radiotherapy and surgery are still valid approaches in treatment of advanced
melanoma that can be integrated with novel
therapies. Intrinsic, adaptive and acquired resistance occur with targeted
therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/
MEK inhibitors (e.g.,
dabrafenib/
trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial
therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted
therapy for patients with metastatic
melanoma. Immune-modulating
antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1
ligand 1 (PD-L1) pathway
blocking antibodies that result in durable responses in a subset of
melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with
melanoma as well. These agents are being studied in combination with targeted
therapies in attempt to produce longer-term responses than those more typically seen with targeted
therapy. Other combinations with cytotoxic
chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted
therapy and
immunotherapy. Both combination targeted
therapy approaches and different
immunotherapies were discussed. Similarly to the previous meetings, the importance of
biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on
biomarkers supports novel concepts toward integrating
biomarkers into contemporary clinical management of patients with
melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different
tumors represents a bridge to impact on prognosis and response to
therapy in
melanoma.