A phase 1a dose-escalation study of PY159, a monoclonal antibody targeting TREM1 (triggering receptor expressed on myeloid cells 1).

Abstract

2523 Background: This study aimed to characterize the safety of PY159 (an agonist antibody to TREM1 that reprograms immunosuppressive intratumoral myeloid cells) as a single agent and in combination with pembrolizumab in subjects with advanced refractory solid tumors, including subjects refractory to immune checkpoint inhibitors. Methods: Two strata were evaluated, PY159 as a single agent and in combination with pembrolizumab, using an accelerated 3+3 dose escalation study design. Dosing was intravenous once every 3 weeks. Disease assessment by RECIST 1.1 was performed every 6 weeks. The single-agent stratum included 7 dose levels of PY159 (range, 0.01–10 mg/kg). The combination stratum included 4 dose levels of PY159 (range, 0.3–10 mg/kg). Pharmacokinetics were evaluated at specified time points. Archival tumor tissue was analyzed for TREM1 expression by immunohistochemistry. Based on preclinical immunohistochemistry data, HR+ HER2– and triple-negative breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, non-small cell lung cancer, and gynecologic cancers were studied. Results: Thirty-seven subjects (median age 65 years; range 29–86 years; 22 female and 15 male) with an ECOG PS <2 were enrolled and all but 5 were RECIST-evaluable (3 withdrew consent, 1 sustained a TEAE, and 1 had a DLT, an asymptomatic grade-3 transaminitis). Twenty subjects received single-agent PY159 and 17 received PY159 in combination with pembrolizumab. Four subjects experienced a grade-3 TRAE, 14 a low-grade immune-related reaction, 18 an SAE (related in 2), and 14 an immune-related adverse event (arthralgias). There were no SUSARs. Five subjects sustained high-grade TRAE resulting in discontinuation. TREM1 levels in the tumors ranged from 0 to 15%. Pharmacokinetic parameters were linear beyond the 0.3 mg/kg dose, dose proportional with a half-life of 8–9 days, and unaffected by pembrolizumab. Radiographic response included 2 partial responses (1 each in an ovarian and pancreatic cancer subject) and stable disease in 9 subjects, ranging from 12 to 96+ weeks. Two subjects continue receiving PY159. Conclusions: PY159 was well tolerated, with an acceptable safety profile, as a single agent and in combination with pembrolizumab. A dose for expansion was derived and enrollment of subjects with 7 prespecified cancers is ongoing. Clinical trial information: NCT04682431 .