Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: A network meta-analysis.

Immune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity. A comprehensive search for RCTs of immune checkpoint inhibitors and targeted therapies was conducted to August 2016. Using a network meta-analysis approach, treatments were compared with each other and ranked based on their effectiveness (as measured by the impact on progression-free survival [PFS]) and acceptability (the inverse of high grade toxicity). Twelve RCTs enrolling 6207 patients were included. Network meta-analysis generated 15 comparisons. Combined BRAF and MEK inhibitors were associated with longer PFS as compared to anti-CTLA4 (HR: 0.22; 95% confidence interval [CI]: 0.12-0.41) and anti-PD1 antibodies alone (HR: 0.38; CI: 0.20-0.72). However, anti-PD1 monoclonal antibodies were less toxic than anti-CTLA4 monoclonal antibodies (RR: 0.65; CI: 0.40-0.78) and their combination significantly increased toxicity compared to either single agent anti-CTLA4 (RR: 2.06; CI: 1.45-2.93) or anti-PD1 monoclonal antibodies (RR: 3.67; CI: 2.27-5.96). Consistently, ranking analysis suggested that the combination of targeted therapies is the most effective strategy, whereas single agent anti-PD1 antibodies have the best acceptability. The GRADE level of evidence quality for these findings was moderate to low. The simultaneous inhibition of BRAF and MEK appears the most effective treatment for melanomas harboring BRAF V600 mutation, although anti-PD1 antibodies appear to be less toxic. Further research is needed to increase the quality of evidence.

Pasquali S ，Chiarion-Sileni V ，Rossi CR ，Mocellin S ... -  《-》

Systemic treatments for metastatic cutaneous melanoma.

Pasquali S ，Hadjinicolaou AV ，Chiarion Sileni V ，Rossi CR ，Mocellin S ... -  《Cochrane Database of Systematic Reviews》

Place des anti-PD1 dans la prise en charge des mélanomes cutanés.

ANTI-PD1 ROLE IN TREATMENT OF CUTANEOUS MELANOMA: The treatment of metastatic melanoma dramatically changed over the last years. Two therapeutic revolutions emerged in parallel, targeted anti-BRAF and anti-MEK therapies, for patients BRAFV600 mutated and immunotherapy with immune checkpoint blockers using anti-CTLA-4 then anti-PD1 monoclonal antibodies. Indeed, melanoma immunotherapy was a golden objective for many years but in spite of important efforts using cytokines (interferon, interleukin) and different vaccine approaches no objective improvement of patients 'prognosis was obtained. Ipilimumab, authorized in 2011, was the first drug which showed a benefit of overall survival in patients with metastatic melanoma in spite a low response rate (10-15) and the occurrence of about 25% of serious toxicity. Anti-PD1 appear as a new generation of immune checkpoint blockade with response rates between 30 to 40% of the patients, a proven overall survival benefit as compared with chemotherapy or ipilimumab and less toxicity than ipilimumab. Two molecules, pembrolizumab and nivolumab were recently approved in monotherapy, for metastatic melanoma. Several questions remain unresolved: the respective indications of anti-PD1 and targeted therapies in first line therapy in patients with BRAF mutant melanoma, the benefit of combining immunotherapy with radiotherapy or with targeted therapies, the optimal treatment duration, and the benefit of the anti-PD1 in the adjuvant setting. The combination of ipilimumab and nivolumab, recently approved by the FDA but not yet in Europ, shows an improvement of the objective response rates (50-57%) and progression free survival compared with nivolumab but is associated with an higer incidence of serious adverse events (more than 50%).

Mateus C ，Libenciuc C ，Robert C 《-》

Therapeutic efficacy of combined BRAF and MEK inhibition in metastatic melanoma: a comprehensive network meta-analysis of randomized controlled trials.

Mai R ，Zhou S ，Zhong W ，Rong S ，Cong Z ，Li Y ，Xie Q ，Chen H ，Li X ，Liu S ，Cheng Y ，Huang Y ，Zhou Y ，Zhang G ... -  《Oncotarget》

Comparative efficacy and safety of combination therapies for advanced melanoma: a network meta-analysis.

An Q ，Liu Z 《BMC CANCER》