Background: Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma. While many patients receive less than 4 doses due to treatment-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and if fewer doses of I/N can achieve similar survival outcomes. Methods: We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2020 who were treated with standard I/N. Cox regression of progression free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response assessment after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging or physical examination. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 3 or 4 vs 1 or 2 doses of I/N adjusted by age, gender, pre-treatment LDH level, BRAF mutation status, primary melanoma site, time to initial assessment, brain metastasis, and liver metastasis. Results: 199 patients were identified and considered evaluable in our study. Median follow up was 28.8 months. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.23, 95% CI 0.14-0.39; p<0.001) and OS (HR: 0.19, 95% CI 0.10-0.38; p<0.001) compared to progressive disease (PD) [Table]. Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS (HR: 0.17, 95% CI 0.11-0.26; p<0.001) and OS (HR: 0.13, 95% CI 0.07-0.23; p<0.001) [Table]. The survival risk comparing 3 or 4 vs 1 or 2 doses of I/N were HR 0.82 (95% CI 0.45-1.53; p=0.540) for PFS and HR 0.56 (95% CI 0.24-1.30; p=0.175) for OS. Conclusions: Clinical benefit response (CBR) after 1 or 2 doses of I/N may be predictive of long-term survival in advanced stage melanoma. Patients who have CBR after 1 or 2 doses of I/N may achieve a similar survival benefit with fewer doses of I/N. Longer follow up and prospective studies are warranted to validate our findings.