Efficacy of PEGylated human IL-10 (AM0010) in combination with anti-PD-1 blockade in patients (pts) with metastatic renal cell carcinoma (mRCC): A phase 1b trial

Abstract

Background: IL-10 is anti-inflammatory and stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are expressed on activated and exhausted CD8 T cells, providing a rationale for combining AM0010 and an anti-PD1 antibody. 4 of 16 heavily pre-Treated pts with poor- or intermediaterisk mRCC, achieved a PR with AM0010 alone. Methods: 38 pts with metastatic RCC were enrolled from 2/20/2015 to 11/18/16 on AM0010 (10 or 20 ug/kg daily SC) and nivolumab (n=29; 3mg/kg, q2wk IV) or pembrolizumab (n=9; 2mg/kg, q3wk IV). Three had favorable and 30 had intermediate or poor-risk by IMDC (5 data not available). Pts had a median of 1 prior therapy (range: 1-3), and at least one VEGFR-TKI. One patient with prior AM0010 was included the safety population only. Tumor responses were assessed by irRC. Serum cytokines, blood derived T cells, clonal identity of peripheral T cells, and tumor DNA sequence and mRNA profiling were assayed. Results: AMO010 plus nivolumab (nivo) or pembrolizumab (pembro) was well tolerated. TrAEs were reversible and transient. G3/4 TrAE in patients on AM0010 and 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 precipitated by T-cell activation, as both pts had a PRs. Patients treated with 10ug/kg AM0010 and nivo or pembro did not have G3/4 anemia or thrombocytopenia. As of August 11 2017, PRs were observed in 14 of 34 evaluable pts (41%). An additional 13 pts had stable disease (38%), 8 of those had a tumor reduction of more than 30% following irRC (in progress). Median PFS and median OS have not been reached, at median FU of 13.5 months (range: 0.5-29.83) for the nivolumab arm. mRNA analysis was used to distinguish patients with CR/PR/SD from progressive disease. Responding patients had a higher degree of CD8+ T cell invigoration. Conclusions: The combination of AM0010 with nivo or pembro is well-Tolerated in mRCC pts; the recommended phase 2 dose is 10ug/kg. The observed efficacy is very promising and further studies of AM0010 and nivo or pembro in mRCC are in preparation. Clinical trial identification: NCT02009449 Legal entity responsible for the study: ARMO BioSciences Funding: ARMO BioSciences Disclosure: A. Hung, P. Van Vlasselaer: Employee of ARMO BioSciences.M. Oft: Founder and employee of ARMO BioSciences. All other authors have declared no conflicts of interest.