Ipilimumab improves survival in patients with advanced melanoma.,The activity and safety of ipilimumab outside of a clinical trial was assessed in an expanded access programme (EAP).,Ipilimumab was available upon physician request for patients aged 16 or over with pretreated stage III (unresectable)/IV melanoma, for whom no other therapeutic option was available.,Patients received ipilimumab 3 mg/kg every 3 weeks for four doses.,Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression.,Tumour assessments were conducted at baseline and week 12.,Patients were monitored for adverse events (AEs) within 3 to 4 days of each scheduled visit.,Of 855 patients participating in the EAP in Italy, 833 were evaluable for response.,Of these, 13% had an objective immune response, and the immune-related disease control rate was 34%.,Median progression-free survival and overall survival were 3.7 and 7.2 months, respectively.,Efficacy was independent of BRAF and NRAS mutational status.,Overall, 33% of patients reported an immune-related AE (irAE).,The frequency of irAEs was not associated with response to ipilimumab.,Outside of a clinical trial setting, ipilimumab is a feasible treatment option in patients with pretreated metastatic melanoma, regardless of BRAF and NRAS mutational status.,Data from this large cohort of patients support clinical trial evidence that ipilimumab can induce durable disease control and long-term survival in patients who have failed to respond to prior treatment.
Resistance to BRAF inhibitors is an emerging problem in the melanoma field.,Strategies to prevent and overcome resistance are urgently required.,The dynamics of cell signalling, BrdU incorporation and cell-cycle entry after BRAF inhibition was measured using flow cytometry and western blot.,The ability of combined BRAF/MEK inhibition to prevent the emergence of resistance was demonstrated by apoptosis and colony formation assays and in 3D organotypic cell culture.,BRAF inhibition led to a rapid recovery of phospho-ERK (pERK) signalling.,Although most of the cells remained growth arrested in the presence of drug, a minor population of cells retained their proliferative potential and escaped from BRAF inhibitor therapy.,A function for the rebound pERK signalling in therapy escape was demonstrated by the ability of combined BRAF/MEK inhibition to enhance the levels of apoptosis and abrogate the onset of resistance.,Combined BRAF/MEK inhibition may be one strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas.