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

• Published in: Journal of clinical oncology Vol. 41; no. 16_suppl; p. 2523
• Main Authors: Patnaik, Amita, Barve, Minal A., Kummar, Shivaani, Schenk, Erin Lynn, LoRusso, Patricia, Yeku, Oladapo O., Fu, Siqing, Jahchan, Nadine, Myers, Matthew, Liang, Linda, Deegan, Denise, Jackson, Lynnae, Li, Yunfeng, Reyno, Len, Chamberlain, Marc Charles
• Format: Journal Article
• Language: English
• Published: American Society of Clinical Oncology 01.06.2023
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2023.41.16_suppl.2523

2523Background: 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.