Flipped versus traditional nivolumab plus ipilimumab dosing in patients with melanoma brain metastases

Nivolumab plus ipilimumab (NIVO+IPI) is a standard option for melanoma with brain metastases. "Flipped" dosing (nivolumab 3mg/kg + ipilimumab 1mg/kg; NIVO3 +IPI1) reduces toxicity relative to traditional dosing (nivolumab 1mg/kg + ipilimumab 3mg/kg; NIVO1 +IPI3) in extracranial disease, but its efficacy in patients with brain metastases is not established.

We retrospectively analyzed 189 patients with cutaneous,mucosal, acral or unknown-primary melanoma and brain metastases treated with NIVO + IPI at two Swedish university hospitals, comparing NIVO3 + IPI1 (n = 54) and NIVO1 + IPI3 (n = 135). Outcomes were treatment exposure, global, intracranial and extracranial objective response rate (ORR), progression free survival (PFS), overall survival (OS) and safety. OS and PFS were analysed using Cox regression adjusted for age, ECOG status, baseline LDH, brain disease burden and number of extracranial metastatic sites.

Baseline characteristics were comparable, though local brain-directed therapy before NIVO + IPI was more frequent with flipped dosing (29.6% vs 14.8%, p = 0.019). More patients completed all four induction doses with flipped dosing (50.0% vs 30.4%, p = 0.011). Grade 3-4 immune-related adverse events occurred in 29.6% vs 43.0% (p = 0.090). Intracranial ORR was 44.4% vs 30.2% (p = 0.065), extracranial ORR 60.9% vs 53.4% (p = 0.409) and global ORR 42.6% vs 29.2% (p = 0.080). In adjusted analysis, flipped dosing was associated with longer PFS (aHR 0.56, 95% CI 0.38-0.83, p = 0.004) and OS (aHR 0.54, 95% CI 0.35-0.83, p = 0.005).

In this real-world cohort of melanoma patients with brain metastases, flipped NIVO + IPI dosing was associated with more patients completing induction and longer OS and PFS. A prospective evaluation is warranted.