Final results of phase Ib/II study of durvalumab and guadecitabine in advanced clear cell renal cell carcinoma (ccRCC) and biomarker analysis.

696 Background: Hypomethylating agents (HMA) can augment the anti-tumor immune response. Guadecitabine (G) is a novel HMA shown to induce a dose-dependent decrease of global DNA and gene-specific methylation in pre-clinical models. Methods: This is phase Ib/II clinical trial of Guadecitabine (G) and Durvalumab (D) in advanced ccRCC. Phase Ib tested two doses of G, de-escalated from 60 mg/m2 to 45 mg/m2 in combination with standard dose of D. Followed by two cohorts in phase II. Cohort 1 (C1, CPI naïve) allowed up to one prior line of treatment and Cohort 2 (C2, CPI refractory) enrolled patients with up to two prior systemic therapies including at least one CPI. Primary endpoint in phase 1b was safety, primary endpoint in phase II was overall response rate (ORR) and secondary endpoint of progression free survival (PFS) and overall survival (OS) and biomarkers evaluation. Results: Fifty-seven patients were enrolled, 42 were in C1 and 15 in C2. One dose limiting toxicity (DLT) of grade 3 neutropenia was noted with G 60 mg/m2. The combination of G 45 mg/m2 on days 1-5 along with D at 1500 mg on day 8, was deemed safe and the recommended phase II dose. Asymptomatic neutropenia was the most common adverse event (AE). Other AEs included thyroid dysfunction, diarrhea, pneumonitis, myalgia, and hepatotoxicity. No treatment-related deaths were reported. The ORR for C1 and C2 were 26% and 7% respectively. The median PFS for C1 and C2 were 18.4 and 3.9 months respectively. Median OS was not reached. Flow cytometry on peripheral blood (PB) collected before treatment demonstrated myeloid-derived suppressor cells (MDSC) to be inversely associated with response, showing the highest levels in progressive disease (PD) and the lowest in partial response (PR). Responders to treatment had the highest expression of IFN γ, IL-17 and RORyt in CD8+ T cells and lower Foxp3 expression in CD4+ T cells compared to non-responders. We observed a significant increase in serum CXCL9/CXCL10 with the study combination (p 0.00003 and p 0.000005 respectively) and this increase correlated with better clinical outcome. Conclusions: The combination of D and G has an acceptable toxicity profile and promising efficacy mainly PFS in CPI naïve ccRCC patients, that is worth further investigation in larger randomized clinical trial. Clinical trial information: NCT03308396 .