Drug resistance imposes severe limitations to the efficacy of targeted therapy in BRAF-mutated metastatic melanoma.,Although this issue has been mitigated by the development of combination therapies with BRAF plus MEK inhibitors, drug resistance inevitably occurs with time and results in clinical recurrences and untreatable disease.,Hence, there is strong need of developing new combination therapies and non-invasive diagnostics for the early identification of drug-resistant patients.,We report here that the development of drug resistance to BRAFi is dominated by a dynamic deregulation of a large population of miRNAs, leading to the alteration of cell intrinsic proliferation and survival pathways, as well as of proinflammatory and proangiogenic cues, where a prominent role is played by the miR-199b-5p/VEGF axis.,Significant alterations of miRNA expression levels are detectable in tumor biopsies and plasma from patients after disease recurrence.,Targeting these alterations blunts the development of drug resistance.
Melanoma was again a focus of attention at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, in particular the use of combination treatment strategies involving immunotherapies and/or targeted agents.,New data on targeted therapies confirmed previous findings, with combined BRAF inhibitor (vemurafenib) plus MEK inhibitor (cobimetinib) improving progression-free survival (PFS) compared to vemurafenib monotherapy in patients with BRAFV600 mutation-positive tumors (CoBRIM trial).,Positive results were also seen with combined dabrafenib and trametinib in patients with BRAF V600E/K metastatic melanoma and encorafenib plus binimetinib in BRAFV600-mutant cutaneous melanoma.,Even more interesting news centered on the use of combination immunotherapy, in particular the randomized, double-blind CheckMate 067 study in which median PFS with nivolumab plus ipilimumab was 11.5 months, compared to 2.9 months with ipilimumab alone (HR 0.42) and 6.9 months with nivolumab alone (HR 0.57).,Of interest, in patients with ≥5% PD-L1 expression, median PFS was 14 months with the combination or with nivolumab alone compared with 3.9 months in the ipilimumab group, while in the PD-L1 negative cohort, the combination remained superior to both monotherapies.,Given that combination therapy was accompanied by a high occurrence of side-effects, this raises the suggestion that combination therapy might be reserved for PD-L1 negative patients only, with PD-L1 positive patients achieving the same benefit from nivolumab monotherapy.,However, overall survival data are awaited and the equivalence of single agent to the combination remains unconvincing.,Interesting data were also reported on the combination of T-VEC (talimogene laherparepvec) with ipilimumab, and the anti-PD-1 agent MEDI4736 (durvolumab) combined with dabrafenib plus trametinib.,Emerging data also suggested that predictive markers based on immunoprofiling and mismatch repair deficiency may be of clinical use.,In conclusion, the use of combination approaches to treat patients with melanoma, as well as other cancers, is no longer a just a wish for the future but is today a clinical reality with a rapidly growing evidence-base.,Moreover, the most exciting consideration is that this is far from the end of the story, but rather a fantastic introduction.