Intracranial outcomes with ipilimumab and nivolumab in melanoma brain metastases following progression on anti-PD-1 therapy.

9555 Background: Ipilimumab + nivolumab (ipi/nivo) is effective for melanoma brain metastases (MBM), but the efficacy of ipi/nivo in MBM in patients (pts) whose melanoma has progressed on anti-PD-1 is unknown. Methods: We conducted a retrospective analysis of pts with progressive MBM who received ipi/nivo at Memorial Sloan Kettering Cancer Center following prior anti-PD-1. Cohort A included pts with ≥1 untreated MBM (≥5mm) without local interventions (such as neurosurgery, radiotherapy). Cohort B included pts who had received local interventions for all MBMs before starting ipi/nivo. The primary endpoint was intracranial (IC) progression free survival (PFS). IC response was assessed based on clinical radiological interpretation for Cohort A. Kaplan-Meier methods were used to estimate time-to-event outcomes. Results: Fifty-seven pts were identified: 28 and 29 in Cohort A and B, respectively. All pts had received prior anti-PD-1, 42% prior ipi, a median of 2 (IQR: 1, 3) prior lines, and 21% (12/57) of pts prior treatment was in the adjuvant setting only. 79% (45/57) of pts had cutaneous, 14% (8/57) acral, 5% (3/57) unknown primary and 2% (1/57) mucosal melanoma. Median age was 64 (IQR: 58, 71) and 55 (IQR: 47, 70) years in Cohort A and B, respectively. Cohort A had median lesion size (largest measurable MBM) of 1.0cm (IQR: 0.60, 2.12), and 64% (18/28) of pts had >5 lesions; Cohort B had a median lesion size 1.5cm (IQR: 1.10, 2.00) and 28% (8/29) of pts had >5 lesions. 14% (8/57) of pts received concurrent steroid (equivalent of ≥dexamethasone 4mg daily) upon starting ipi/nivo, and leptomeningeal disease was present in 14% (4/28) and 7% (2/29) of Cohort A and B, respectively. The IC response rate was 11% (3/28, 2 were complete (CR)) in Cohort A.Both patients with CR were asymptomatic with ≤ 2 lesions and no prior CTLA-4 exposure. Most (20/28, 71%) in Cohort A had best response of progressive disease (PD); all that had a best response of stable disease (SD; 5/28, 18%) sustained that response for less than 6 months. Median IC-PFS was 1.7 (95% CI: 1.3,4.4) and 7.6 (95% CI: 3.6, -) months, and median overall survival (OS) was 6.7 (95% CI: 3.6,10) and 24 (95% CI: 11, -) months in Cohort A and B. 24-month OS was 19% (95% CI: 8.1,45) and 51% (95% CI: 35,75) in Cohort A and B. 30% (8/27) and 66% (19/29) of pts had subsequent systemic therapy, and 48% (13/27) and 52% (15/29) subsequent local therapy in Cohorts A and B. Conclusions: Ipi/nivo has limited efficacy in patients with progressive MBM post-PD-1 therapy in the absence of local therapy. These results highlight the unmet clinical need for more effective therapies to address progressive MBM post-PD-1 therapy, an increasingly relevant clinical scenario particularly in light of the growing use of adjuvant and neoadjuvant anti-PD-1.