Vincenzo Ottaviano

BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. More recently, the combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown improved progression-free survival, compared to dabrafenib monotherapy, in a Phase II study and has received approval by the US Food and Drug Administration. However, even when treated with the combination, most patients develop mechanisms of acquired resistance, and some of them do not achieve tumor regression at all, because of intrinsic resistance to therapy. Along with the development of BRAF inhibitors, immunotherapy made an important step forward: ipilimumab, an anti-CTLA-4 monoclonal antibody, was approved for the treatment of metastatic melanoma; anti-PD-1 agents achieved promising results in Phase I/II trials, and data from Phase III studies will be ready soon. The availability of such drugs, which are effective regardless of BRAF status, has made the therapeutic approach more complex, as first-line treatment with BRAF inhibitors may not be the best choice for all BRAF-mutated patients. The aim of this paper is to review the systemic therapeutic options available today for patients affected by BRAF V600-mutated metastatic melanoma, as well as to summarize the mechanisms of resistance to BRAF inhibitors and discuss the possible strategies to overcome them. Moreover, since the molecular analysis of tumor specimens is now a pivotal and decisional factor in the treatment strategy of metastatic melanoma patients, the advances in the molecular detection techniques for the BRAF V600 mutation will be reported.

TPS9109 Background: BRAF-inhibitor Vemurafenib achieves high response rate and a statistically significant improvement in overall survival (OS) in patients (pts) with unresectable stage III and IV melanoma. However, clinical resistance to this agent eventually arises in most pts. In a Phase I study of Vemurafenib, among 48 pts with progressive disease (PD), 18 pts were treated beyond progression (TBP) > 30 days after local therapy of PD lesions: median OS had not been reached at a median follow-up of 15.5 months from initiation of Vemurafenib, with a median treatment duration beyond initial PD of 3.5 months. Conversely, in pts who were not TBP, median OS was 1.4 months (Kim et al. ASCO 2011). In a series of 112 patients treated with BRAF-inhibitors (Chan et al. ASCO 2013), 36/92 were TBP: median OS from commencement of BRAF-inhibitors in those TBP was longer than those not TBP (15.0 vs 6.5 months, p<0.001), as was OS from PD (7.4 vs 1.9 mo, p=0.001). These findings suggest that one possible approach to improve the prognostic outlook in pts progressing during Vemurafenib treatment may be continuing the drug in combination with chemotherapy: resistance is not caused by acquisition of secondary BRAF mutations but rather by up-regulation in some cell populations of other proliferative signals with the creation of heterogeneous cell populations partly resistant to BRAF inhibition, and a cytotoxic drug such as Fotemustine (FTM) might act on those proliferating clones. FTM was chosen because it has shown an effect on brain metastases: in a phase III study (Avril et al. JCO 2004) comparing FTM with dacarbazine, the median time of occurrence of brain metastases was longer in the FTM group (22.7 months) than in the dacarbazine group (7.2 months). Methods: Thirty pts progressing while on Vemurafenib were enrolled in the study between January and October 2013. The primary objective is to assess the activity of Vemurafenib plus FTM in pts harboring the V600BRAF mutation and recurred while on treatment with Vemurafenib. The primary endpoint is PFS. Treatment with FTM plus Vemurafenib will be continued until PD or unacceptable toxicity. Clinical trial information: NCT01983124.