Background: Ipi+Nivo is now FDA approved in the US to treat pts with melanoma. We report our clinical experience of toxicity in pts enrolled in the Ipi+Nivo EAP. Methods: 64 pts were treated on the Ipi+Nivo EAP from Dec. 2014 through Jan. 2016 at MSKCC. Ipi (3mg/kg) and nivo (1mg/kg) were administered q3 weeks for 4 doses. Afterwards, pts were offered Nivo (3mg/kg) q2wks or off-protocol pembrolizumab (2 mg/kg) q3wks until unacceptable toxicity, disease progression (POD), or complete response. Clinically significant immune-related adverse events (irAEs) were defined as CTCAE v4.0 grade ≥ 2 or grade 1 events requiring systemic steroids. Results: 15 pts (39.1%) received all 4 doses of Ipi+Nivo; 11 pts (17.2%) received 3 doses, 20 pts (31.3%) received 2 doses, and 8 pts (12.5%) received 1 dose. Minimum follow up after last Ipi+Nivo treatment was 1 month. 31 pts (79.5%) stopped early for toxicity, 7 (18.0%) for POD and 1 (2.6%) for death due to other causes. The median number of anti-PD-1 doses administered was 1 (range 0-16); 31 pts (48.4%) did not receive any anti-PD-1 therapy after ipi/nivo. 58/64 pts (90.6%) had ≥ 1 clinically significant irAE (median = 2, range 0-6) and 46/64 pts (71.9%) required ≥ 1 course of systemic steroids. 14/64 pts (21.9%) required infliximab for steroid-refractory diarrhea and 2 pts (3.1%) required mycophenolate for treatment of steroid-refractory transaminitis. 40 pts (62.5%) had ≥ 1 emergency room (ER) visit while on study (range 0-5); 30 pts (47.6%) had ≥ 1 admission to the hospital. The majority of both ER visits (61%) and hospital admissions (70%) were related to irAEs. Clinically significant irAEs on anti-PD-1 monotherapy were uncommon. 8/33 pts (24%) had an asymptomatic grade ≥ 2 increase in lipase and 5 pts (15%) had endocrine dysfunction. Conclusions: Treatment with Ipi+Nivowas associated with a high rate of clinically significant irAEs, ER visits, and systemic immunosuppression to treat irAEs. Only 39% of pts were able to receive all 4 doses of Ipi+Nivo, with the majority stopping early for toxicity. Patients and oncologists should be aware of need for careful monitoring and the likelihood of irAEs requiring therapy. Clinical trial information: NCT02186249