Background: Pegilodecakin (PEGylated hIL-10, AM0010) alone produced 25% partial responses (PR) in heavily pre-treated (median prior therapies 3) RCC pts. IL-10 receptors and PD1 are expressed on activated and exhausted CD8+ T cells. IL-10 stimulates the cytotoxicity and proliferation of CD8+ T cells. This provides a rationale for combining pegilodecakin with anti-PD-1. Methods: Between 2/20/2015 and 11/18/16, 38 pts with metastatic RCC (87% clear cell) were enrolled in a phase Ib trial and received pegilodecakin at 10 (n = 6) or 20 ug/kg (n = 32, QD SC) and nivo (n = 29; 3mg/kg, q2wk IV) or pembro (n = 9; 2mg/kg, q3wk IV). Pts had intermediate- or poor-risk disease by IMDC criteria (94%) and a median of 1 prior therapy (range: 1-3), including at least one VEGFR-TKI. Results: Pegilodecakin + nivo or pembro was well tolerated. TrAEs were reversible and transient. G3/4 TrAE in pts who received pegilodecakin (20 ug/kg) + nivo or pembro included anemia (10), thrombocytopenia (7), and hypertriglyceridemia (6). Two pts had a reversible cytokine release syndrome with splenomegaly and increased immune mediated red blood cell phagocytosis (HLH) most likely due to T-cell activation, as both pts had PRs. Pts on 10ug/kg pegilodecakin + nivo or pembro did not have G3/4 anemia or thrombocytopenia. As of 1/29/2018, response evaluation by irRC yielded 14 PRs of 34 evaluable pts (41%) including 3 complete response [CRs] (9%); 15 additional pts had stable disease (44%), 8 of whom had a tumor reduction of more than 30%. By RECIST, ORR and disease control rate (DCR) were 53% and 81%. Median progression-free survival (PFS) was 16.7 mos with pegilodecakin + pembro, and was not reached for pegilodecakin + nivo at a median follow up of 13.8 mos (range: 0.5-19.8). The 1y- overall survival for pegilodecakin + anti-PD-1 is 89%. Pegilodecakin strongly expanded previously undetectable T cell clones in the blood, which correlated with tumor response. Nanostring expression profiling separated pts with CR/PR from progressive disease. Conclusions: Pegilodecakin with nivo or pembro is well-tolerated in mRCC pts; the recommended phase 2 dose is 10ug/kg. The efficacy and the observed CD8+ T cell activation are very encouraging. Clinical trial information: NCT02009449