Ipilimumab in combination with nivolumab may be an effective second-line therapy in patients with PD-1 blockade–refractory metastatic melanoma, according to a novel study published by VanderWalde et al in Nature Medicine. In a phase II trial, researchers randomly assigned 92 pretreated patients to receive either the combination of ipilimumab plus nivolumab or ipilimumab alone; the primary endpoint of the trial was progression-free survival. Patients who received the immunotherapy combination demonstrated a 37% improvement in progression-free survival (hazard ratio = 0.63, 90% confidence interval = 0.41–0.97) vs those who received ipilimumab monotherapy. Further, the patients who received the combination therapy had an objective response rate of 28% compared with 9% among those who received ipilimumab monotherapy. However, grade 3 or higher treatment-related adverse event rates were more common in the combination therapy group (57%) vs the monotherapy group (35%). The researchers concluded that ipilimumab in combination with nivolumab may be effective at reversing primary resistance to PD-1 blockade therapy.