A systematic review and network meta‐analysis of immunotherapy and targeted therapy for advanced melanoma

Immune and BRAF‐targeted therapies have changed the therapeutic scenario of advanced melanoma, turning the clinical decision‐making a challenging task. This Bayesian network meta‐analysis assesses the role of immunotherapies and targeted therapies for advanced melanoma. We retrieved randomized controlled trials testing immune, BRAF‐ or MEK‐targeted therapies for advanced melanoma from electronic databases. A Bayesian network model compared therapies using hazard ratio (HR) for overall survival (OS), progression‐free survival (PFS), and odds ratio (OR) for response rate (RR), along with 95% credible intervals (95% CrI), and probabilities of drugs outperforming others. We assessed the impact of PD‐L1 expression on immunotherapy efficacy. Sixteen studies evaluating eight therapies in 6849 patients were analyzed. For OS, BRAF‐MEK combination and PD‐1 single agent ranked similarly and outperformed all other treatments. For PFS, BRAF‐MEK combination surpassed all other options, including CTLA‐4‐PD‐1 dual blockade hazard ratio (HR: 0.56; 95% CrI: 0.33–0.97; probability better 96.2%), whereas BRAF single agent ranked close to CTLA‐4‐PD‐1 blockade. For RR, BRAF‐MEK combination was superior to all treatments including CTLA‐4‐PD‐1 (OR: 2.78; 1.18–6.30; probability better 97.1%). No OS data were available for CTLA‐4‐PD‐1 blockade at the time of systematic review, although PFS and RR results suggested that this combination could also bring meaningful benefit. PD‐L1 expression, as presently defined, failed to inform patient selection to PD‐1‐based immunotherapy. BRAF‐MEK combination seemed an optimal therapy for BRAF‐mutated patients, whereas PD‐1 inhibitors seemed optimal for BRAF wild‐type patients. Longer follow‐up is needed to ascertain the role of CTLA‐4‐PD‐1 blockade. Immunotherapy biomarkers remain as an unmet need.