BeyPro1: A phase II single-arm study for the treatment after recurrence of advanced melanoma patients harboring the ^V600BRAF mutation and pretreated with vemurafenib, with the association of vemurafenib plus fotemustine.

Abstract

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.