Abstract 1137: Determination of a recommended Phase 2 dose (RP2D) for SRF388, a first-in-class IL-27-blocking antibody, in patients with advanced solid tumors

• Published in: Cancer research (Chicago, Ill.) Ill.), 2022-06, Vol.82 (12_Supplement), p.1137-1137
• Main Authors: Hill, Jonathan A., White, Kerry F., Rausch, Matthew, Chung, Jou-Ku, Patnaik, Amita, Naing, Aung, Morgensztern, Daniel, Mantia, Charlene M., Tannir, Nizar M., Smith, Lon S., Bowers, Beth, Alika, Alex, Harshman, Lauren C., Lee, Benjamin H.
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-1137

SRF388 is a first-in-class, anti-IL-27 antibody developed to enhance immune responses within the tumor microenvironment. Preclinical studies have demonstrated that IL-27 pathway blockade can inhibit tumor growth in mouse models of liver cancer and lung cancer metastases. There is also evidence that IL-27 pathway inhibition is accompanied by activation of the innate and adaptive arms of the immune system. An ongoing Phase I trial has shown good tolerability at all dose levels tested and preliminary monotherapy antitumor activity with SRF388 (NCT04374877). Here, we describe the preclinical and clinical data used to select a RP2D and characterize cytokine and chemokine changes observed in patients after treatment with SRF388. To guide selection of the RP2D, the relationship between maximal effective dose (MaxED), pharmacokinetics (PK), and whole blood inhibition of IL-27-mediated phosphorylation of STAT1 by SRF388 was evaluated in a mouse model of liver cancer. The concentration of SRF388 associated with optimal antitumor activity was ~20-fold above the concentration needed for complete inhibition (> 90%) of whole blood phosphorylated STAT1 (pSTAT1). These PK and activity relationships were also defined in patients during the dose-escalation phase of the trial and integrated with safety and efficacy data to select a monotherapy RP2D. In patients, PK were linear, no dose-limiting toxicities were reported, complete pSTAT1 inhibition was achieved throughout the first cycle at 0.3 mg/kg, and 1 patient experienced a confirmed partial response per RECIST version 1.1 at a dose of 10 mg/kg. In the MaxED mouse model, the area under the concentration versus time curve (AUC) associated with significant antitumor activity was 1720 day*μg/mL. In patients, the corresponding target AUC was achieved clinically at 10 mg/kg after a single dose of SRF388. Changes in the concentration of several serum cytokines and chemokines were observed after SRF388 treatment including an increase in IL-27, a phenomenon described for other anti-cytokine antibodies due to altered clearance of the cytokine-antibody complex. Changes in a subset of other serum cytokines/chemokines correlated with a reduction in target lesion size. Taken together, these data support the selection of a monotherapy RP2D of 10 mg/kg intravenously every 4 weeks for SRF388. These data highlight how complementary strategies utilizing preclinical and clinical biomarker evaluations can be employed to establish a monothera