Abstract Purpose: LOGIC 2 (NCT02159066), a multicenter, open-label, two-part, phase II study, assessed encorafenib plus binimetinib combined with a third targeted agent after tumor progression on encorafenib plus binimetinib in patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma. Patients and Methods: Adults with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma who were BRAF inhibitor/MEK inhibitor (BRAFi/MEKi) treatment–naïve or pretreated received encorafenib plus binimetinib (part I/run-in). Based on the genomic testing at disease progression following encorafenib plus binimetinib, patients were assigned to one of four treatment arms to receive encorafenib plus binimetinib with an appropriate molecularly targeted agent (ribociclib, infigratinib, capmatinib, or buparlisib; part II). The primary endpoint was best overall response; safety, biomarkers, pharmacokinetics, and other efficacy endpoints were also assessed. Results: In part I/run-in, 75 BRAFi/MEKi-naïve patients and 83 BRAFi/MEKi-pretreated patients were treated; in part II, 58 patients were treated (ribociclib, n = 38; infigratinib, n = 1; capmatinib, n = 13; buparlisib, n = 6). The overall confirmed response rate was 73.3% [95% confidence interval (CI), 61.9–82.9] in BRAFi/MEKi-naïve patients, 25.3% (95% CI, 16.4–36.0) in pretreated patients, 2.6% (95% CI, 0.1–13.8) in the ribociclib arm, and 0% in the other three arms. Adverse events were manageable and consistent with the known safety profile of each drug. Conclusions: LOGIC 2 supports the use of encorafenib plus binimetinib for treatment-naïve and previously treated, locally advanced, unresectable or metastatic BRAFV600-mutant melanoma. However, adding a third targeted agent following disease progression did not show meaningful efficacy; further research is needed to identify other therapeutic targets to circumvent resistance.