Background: New drug combinations are required in advanced clear cell renal cancer (RCC). These potentially include MET inhibition with savolitinib (S) or CTLA-4 inhibition with tremelimumab (T). In this study these agents were given alone or in combination with the PD-L1 inhibitor durvalumab (D). Methods: A multinational open-label randomised phase II study assigning patients to one of D, S, DT or DS was performed. Patients with RCC, who had previously received VEGF targeted therapy but not immune checkpoint inhibitors or MET inhibitors were included. Confirmed response rate (cRR) was the primary endpoint. A response rate of at least 50% was required for further exploration. The S arm was closed early due to a lack of efficacy. DNA alterations were measured using Foundation One and PD-L1 analysis was performed with SP263. This abstract details the pre-planned 12-month interim analyses after the cohort completed randomisation. Results: Between 2017 and 2021, 139 patients were randomised (D N=39, S N=22, DT N=39, DS N=39). The median age was 62 years (range: 28 – 85). cRRs for the 4 arms were D=10%, S=5%, DT=28%, DS=13%, which did not meet the primary objective. cRRs in the MET-driven patients (N=17) were D=0% (0/7), S=0% (0/2), DT=50% (1/2), DS=17% (1/6). cRRs in PD-L1+ves for DT and D were 14% (1/7) and 33% (2/6) respectively. 12-month progression-free survival (PFS) rates were D=26% (80% confidence interval [CI]: 17% - 36%), S=21% (80% CI: 10% - 35%), DT=33% (80% CI: 24% - 43%), DS=17% (80% CI: 10% - 26%). Median overall survival for D=26.1 (80% CI: 16.2 – 32.0) months, S=23.1 (80% CI: 20.6 – 29.7) months, DT=21.9 (80% CI: 16.3 – 31.5) months, DS=16.1 (80% CI: 10.3 – 18.8) months. There was 1 treatment related death in the DT arm. Of the 136 patients who received treatment, grade 3 or more treatment related adverse events occurred in D=10% (4/39), S=26% (5/19), DT=23% (9/39), DS=23% (9/39). Conclusions: This randomised phase II study did not demonstrate significant efficacy for S alone or in combination with D in RCC. The addition of T to D did not demonstrate clearly superior efficacy to D in this setting. Clinical trial information: NCT02819596.