Background: Denosumab (deno) is an antibody directed against Receptor Activator of NF Kappa-b ligand (RANKL) with established indications as a bone anti-resorptive agent in several cancers. Pre-clinical studies and several case series suggest anti-RANKL can enhance the anti-tumor effect of immune checkpoint inhibitors possibly via modulation of Treg and M2 macrophages. We did a multicentre phase Ib/II trial (NCT03161756) to investigate the safety and efficacy of deno in combination with nivolumab (nivo) or ipilimumab-nivolumab (ipi-nivo). Methods: Patients (pts) with unresectable stage III or IV melanoma were recruited to either Arm A (nivo-deno) or Arm B (ipi-nivo-deno) as first-line therapy. In Arm A pts received nivo 3 mg/kg IV q2 weekly for 4 doses and deno 120 mg SC on D1, D8, D15, D29 and then maintenance nivo 480 mg IV with deno 120 mg SC q 4 weekly. In Arm B pts received combined ipi 3mg/kg with nivo 1 mg/kg IV 3 weekly for 4 doses with deno 120 mg SC on D1, D8, D15, D29 followed by 4 weekly maintenance nivo 480 mg with deno 120 mg. Co-primary endpoints were median PFS and grade 3-4 treatment related adverse events (TRAE) of interest. Secondary endpoints were objective response rate (ORR) and overall survival (OS). Results: 27 pts (15 males, median age 67 years, 48% (13/27) stage IVM1c, 26% elevated LDH, 31% BRAF^V600 mutant) were enrolled in Arm A and 24 of 25 evaluable pts (16 males, median age 62, 46% (11/24) stage IVM1c, 13% (3/24) stage IVM1d, 30% elevated LDH and 33% BRAF^V600 mutant) were enrolled in Arm B. Median follow up was 30.8 months (m) for Arm A and 24.8 m for Arm B. The RECIST 1.1 ORR was 56% (n=15/27, 15% [4/27] complete responses [CR] and 41% [11/27] partial response [PR]) for Arm A and 71% (17/24, 25% [6/24) CR and 46% [11/24] PR) for Arm B. The median PFS in both arms has not been reached with 12 month PFS rates of 59% (95%CI: 43-81) and 63% (95%CI: 46-88) for Arms A & B, respectively. Grade 3-4 TRAE were 11% (3/27) in Arm A and 71% (17/24) in Arm B. Common TRAE (≥10%) in Arm A was rash (52%), pruritus (30%), fatigue (26%), nausea (19%), diarrhoea/colitis (15%), arthralgia (11%), vitiligo (11%), hyperthyroidism (11%). Common TRAE (≥10%) in Arm B included rash (63%), fatigue (54%), diarrhoea/colitis (54%), hepatitis (46%), hyperthyroidism (29%), pneumonitis (29%), pruritus (25%), increased GGT (17%), hypothyroidism (17%), hypocalcaemia (13%). Arm B G3-4 TRAE included diarrhoea/colitis (25%), pneumonitis (17%) and hepatitis (13%). Conclusions: Nivo-deno and ipi-nivo-deno had numerically similar G3-4 TRAE compared to nivo and ipi-nivo. The median PFS, 12 month PFS and ORR for nivo-deno and ipi-nivo-deno are encouraging compared with CHECKMATE 067. Clinical trial information: NCT03161756.