PRESERVE-003: Phase 3, two-stage, randomized study of ONC-392 versus docetaxel in metastatic non-small cell lung cancers that progressed on PD-1/PD-L1 inhibitors.

TPS9146 Background: For NSCLC without driver mutation, the PD-1/PD-L1 inhibitor as the first-line (monotherapy or in combination with platinum-based doublet agents) or second-line therapy after chemotherapy significantly improved overall survival. However, there remain a significant number of patients who do not have response or have an initial response followed by disease progression to PD-1/PD-L1 inhibitor therapy. CTLA-4 is a proven immunotherapy target in solid tumor, unfortunately no monotherapeutic efficacy has been shown in NSCLC by marketed anti-CTLA-4 antibodies, including ipilimumab and tremelimumab. These anti-CTLA4 mAbs cause severe toxicity that prevents adequate dosing in cancer patients. In contrast, ONC-392 keeps high-level CTLA-4 on Treg cells through a recycling mechanism and makes Treg cells a better target for antibody-dependent cellular cytotoxicity, particularly in the tumor microenvironment where macrophages are more abundant. The selective elimination of Treg cells in the tumor microenvironment and maintenance of CTLA-4 expression in Treg cells in the peripheral tissues by ONC-392 form the cellular and molecular basis for more potent tumor rejection and low toxicity in animal studies. Our first in human studies have demonstrate safety and clinical activities of ONC-392 in patients with NSCLC and other solid tumors. Methods: This is a seamless 2-stage, randomized, open-label, active-controlled, Phase 3 study of ONC-392 for treatment of NSCLC patients who progressed on PD-1/PD-L1 inhibitor (NCT05671510). Approximately 600 patients will be enrolled. Stage I, the dose-confirmation stage, will assess the efficacy and safety of two ONC-392 dosing regimens (3 mg/kg Q3W and 6 mg/kg Q3W with 2 loading doses of 10 mg/kg Q3W) in comparison to docetaxel 75 mg/m2 Q3W. A total of 120 patients will be randomized 1:1:1 in Stage I into one of two ONC-392 dose cohorts or docetaxel cohort. An interim analysis will be conducted at the end of Stage I when 120 patients are enrolled. Stage 2 will start when ONC-392 dose is determined and approximately 480 patients will be randomized 1:1 to receive ONC-392 or docetaxel treatment. All enrolled patients who are randomized to the ONC-392 arms will receive ONC-392 at the randomized dose for up to 17 cycles in approximately 1 year or until discontinuation criteria are met. Patients who are randomized to the docetaxel arm will receive docetaxel 75 mg/m 2 Q3W until disease progression per RECIST 1.1. The primary endpoint is overall survival. The treatment effect will be estimated using a Cox Proportional Hazard model stratified by the randomization stratification factors to calculate the estimated hazard ratio and its 95% CIs. Kaplan-Meier (i.e., product-limit) estimates of median OS time will be presented by treatment arm with two-sided 95% CIs. The analyses will be based on the ITT Population. Clinical trial information: NCT05671510 .