Results of a phase 1 study of SRF388, a first-in-human, first-in-class, high-affinity anti-IL-27 antibody in advanced solid tumors.
Authors: Patnaik Amita , Morgensztern Daniel , Mantia Charlene , Tannir Nizar M. , Harshman Lauren C , Hill Jonathan , White Kerry , Chung Jou-Ku , Bowers Beth , Sciaranghella Gaia , Lee Benjamin , Choueiri Toni K. , Smith Lon S. , Naing Aung 
Published: June 2021

2551 Background: IL-27 is an immunosuppressive cytokine, consisting of two subunits p28 and EBI3, that upregulates immune checkpoint receptors (eg, PD-L1, TIGIT) and downregulates proinflammatory cytokines such as IFNγ, TNFα, and IL-17. SRF388 is a first-in-class, fully human IgG1 antibody to IL-27 that blocks the interaction between IL-27 and its receptor, thereby promoting immune activation in the tumor microenvironment. The IL-27 pathway is activated in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), and high circulating levels of EBI3 are associated with inferior outcomes in both. Circulating EBI3 levels may serve as a predictive biomarker of SRF388 activity. Methods: Patients with advanced solid tumors refractory to standard therapy were enrolled in a phase 1 dose-escalation study (accelerated single patient followed by standard 3+3) to establish the preliminary safety of SRF388 as a monotherapy and to identify a dose suitable for expansion (NCT04374877). SRF388 was administered intravenously every 4 weeks. Tumor response was assessed by RECIST v1.1. SRF388 pharmacokinetic (PK) and pharmacodynamic (PD) [phospho-STAT (pSTAT) inhibition] analyses were performed. Results: As of January 26, 2021, 12 patients have received SRF388 at doses ranging from 0.003 to 10 mg/kg with 2 patients undergoing intra-patient dose escalation. Median age was 68 years, 67% were female, and ECOG PS was 0/1 (42%/58%). Median number of prior therapies was 2 (range 1–9), and 75% were anti-PD-(L)1 experienced (n = 9). The only treatment-related adverse events observed across dose levels were low-grade fatigue (n = 1, 8%), nausea (n = 1, 8%) and excess salivation (n = 1, 8%). No dose-limiting toxicities (DLTs) or ≥ Grade 3 related toxicity have occurred. Mean time on study is 12.5 weeks (range 4–40). One patient with RCC who received prior anti-PD-1 has prolonged stable disease for > 9 months. SRF388 PK are linear with estimated T1/2 ranging from 6–19 days. There is evidence of accumulation and no anti-drug antibody development to date. Maximal inhibition of the IL-27 signaling pathway as measured by > 90% pSTAT inhibition in whole blood was achieved starting at 0.3 mg/kg. Given combined evidence of near-complete pathway inhibition and preclinical human equivalent dose modeling projecting biologically active doses, additional slots were opened for RCC and HCC starting at 1 mg/kg. Conclusions: Preliminary results of IL-27 pathway blockade with a first-in-class therapeutic demonstrates that SRF388 is well tolerated at doses that achieve maximal inhibition of downstream pSTAT signaling through the dosing period. Expansions are planned in HCC and RCC. Updated data including the recommended phase 2 dose, clinical outcomes, PK/PD and correlative analyses will be presented. Clinical trial information: NCT04374877.