P2.07-058 First-In-Human Study of JNJ-64041757, a Live Attenuated Listeria Monocytogenes Immunotherapy, for Non-Small Cell Lung Cancer

JNJ-64041757 (JNJ-757) is a live attenuated, double-deleted (LADD) Listeria monocytogenes (Lm)-based immunotherapy engineered to induce adaptive immune responses against the tumor-associated antigen mesothelin. The goals of Part 1 of this first-in-human (FIH) study were to establish the recommended phase 2 dose (RP2D), characterize the safety profile, and evaluate the immunological activity of JNJ-757 in patients with adenocarcinoma of the lung. This is an ongoing FIH trial in patients with advanced adenocarcinoma non-small cell lung cancer (Stage IIIb or IV) who have progressed after standard therapy (ClinicalTrials.gov: NCT02592967). Patients were treated at 1 of 2 dose levels (108 CFU or 109 CFU), infused over 1 hour every 3 weeks until disease progression or unacceptable toxicity. Dose limiting toxicities (DLTs) were evaluated during the first cycle. Disease response was assessed every 3 cycles according to RECIST 1.1. Post-infusion blood, urine, fecal, and saliva samples were evaluated for the presence of JNJ-757. Immunological activity of JNJ-757 was assessed by evaluation of peripheral cytokines and immune cells as well as ELISPOT analysis to defined antigens. Nine subjects were enrolled; 6 at 108 CFU and 3 at 109 CFU. There were no DLTs in either dosing cohort, and 109 CFU was identified as the RP2D. Most adverse events (AEs) were of grade 1/2 severity, with fatigue, headache, nausea, and vomiting as the most reported events. One drug-related AE of grade ≥3 severity (hypokalemia, grade 3) was reported in the 108 CFU cohort. Best response was stable disease. Four patients had received at least 7 cycles (range, 1 to 14 cycles). JNJ-757 was quickly cleared after infusion, with 7/9 patients showing negative blood cultures at 2 hours; all were negative after 24 hours. Correlative studies demonstrated activation of both innate and adaptive immune responses. Natural killer cell and T cell activation were observed 24 hours after infusion, coinciding with elevated cytokine production (i.e., IFN-γ, TNF-α). Specific T cell responses against Listeria listeriolysin O and mesothelin antigens were documented in a subset of patients, consistent with the mechanism of LADD to prime new immune responses. The RP2D of JNJ-757 is 109 CFU, with a safety profile consistent with other LADD Lm-based agents such as CRS-207. Both innate and mesothelin-specific adaptive immune responses were demonstrated in multiple patients. Recruitment in the trial continues to further characterize the safety profile and immune response, and a phase 1b/2 trial with JNJ-757 and nivolumab is planned.