At therapeutic concentrations AM0010 stimulates the cytotoxicity, survival and proliferation of CD8 T cells. IL-10 receptors and PD-1 are expressed on activated and exhausted CD8 T cells, providing a rationale for combining AM0010 and an anti-PD-1. AM0010 alone had partial tumor responses (PR) in 4 of 16 pts with poor to intermediate risk RCC. In dose escalation, 4 of 8 RCC patients receiving AM0010 plus pembrolizumab in 3rd line, had a PR. The mPFS was 16.7 months.
29 pts with metastatic RCC were enrolled on AM0010 (10 or 20 ug/kg daily SC) and nivolumab (3mg/kg, q2wk IV). Two had favorable, 20 had intermediate and 4 had poor IMDC risk (3 data not available). Pts. had a median of 1 prior therapy (range 1-3), and at least one VEGFR-TKI. Tumor responses were assessed following irRC. Immune related cytokines in the serum, activation of blood derived T cells and clonal identity of peripheral T cell were measured.
AMO010 plus nivolumab or pembrolizumab was well tolerated. TrAEs were reversible and transient. 14 patients on 20ug/kg AM0010 daily SC and nivolumab had at least 1 G3/4 TrAE, including anemia (10), thrombocytopenia (5), hypertriglyceridemia (5). Two pts had a reversible cytokine release syndrome with splenomegaly and increased immune mediated red blood cell phagocytosis most likely precipitated by T-cell activation, as both pts had objective tumor responses. Patients treated with 10ug/kg AM0010 and anti-PD-1 did not have hematologic G3/4 TrAEs. As of May 1 2017, PRs were observed in 9 of 26 evaluable pts (35%). An additional 12 pts have stable disease (46%), 7 of those have a tumor reduction > 30% (in progress). The mPFS and mOS has not been reached, the mFU is 7.7 months (range 0.5-13.7). AM0010 + anti-PD1 increased Th1 cytokines in the serum, proliferation of PD1+ Lag3+ CD8 T cells and oligoclonal expansion of novel T cell clones in the blood. The expansion of invigorated T cells and the clonal expansion correlated with tumor responses.
AM0010 in combination with anti-PD-1 is well-tolerated in RCC pts, the recommended phase 2 dose is 10ug/kg. The efficacy and the observed CD8 T cell activation is promising and encourages the continued study of AM0010 in combination with nivolumab.
Clinical trial identification
Legal entity responsible for the study
A. Hung: Stock employment. P. Van Vlasselaer: Employment stock ledership. M. Oft: Employment. All other authors have declared no conflicts of interest.