Checkpoint inhibition (CPI) is a standard therapeutic approach in metastatic renal cell carcinoma (RCC). However, not all patients respond to CPI, and the immune suppressive characteristics of the RCC tumor microenvironment may contribute to treatment failure. Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) is a transmembrane protein expressed on a subset of myeloid cells with M2-like anti-inflammatory properties that has previously been associated with disease recurrence after nephrectomy and poor outcomes when expressed at high levels. PY314 is a humanized monoclonal antibody targeting TREM2 that depletes tumor-associated macrophages. In this study, the combination of PY314 and pembrolizumab was investigated in patients with CPI-refractory RCC. Eligible patients had clear cell RCC with disease progression on prior CPI either in combination or sequentially with VEGF-TKI. Patients were treated with PY314 10 mg/kg in combination with pembrolizumab 200 mg IV every 21 days. The primary objective was to assess safety and tolerability and secondary objectives included pharmacokinetics and anti-tumor activity by RECIST v1.1. Seventeen patients were enrolled with a median age of 67 years, 82% male, 100% had prior CPI, and 76% had received three or more prior lines of therapy. The combination of PY314 and pembrolizumab demonstrated an acceptable safety profile with 47.1% any grade treatment-related adverse events (AE) (including only 5.9% grade ≥ 3), the most common being fatigue, pyrexia, nausea, and infusion-related reactions. One patient achieved a partial response (6%), and four patients had stable disease (24%) as their best response. The median PFS was 1.4 months (95% CI 1.2- 3.8). The combination of PY314 and pembrolizumab was safe, but the limited anti-tumor effect observed suggests that TREM2 targeting in conjunction with PD-1 blockade may not overcome resistance to prior CPI. Further investigation is warranted to determine if improved efficacy can be achieved in IO-naïve settings. Trial Registration: NCT04691375.
Investigational new drugs. 2024 Feb 19 [Epub ahead of print]
Kathryn E Beckermann, Amita Patnaik, Ira Winer, Winston Tan, Babar Bashir, Christos E Kyriakopoulos, Randy F Sweis, Marc Chamberlain, Brian I Rini
Vanderbilt University Medical Center, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA., START South Texas Accelerated Research Therapeutics, San Antonio, TX, 78229, USA., Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, 48201, USA., Mayo Clinic, Jacksonville, FL, 32224, USA., Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA, 19107, USA., University of Wisconsin Carbone Cancer Center, Madison, WI, 53705, USA., Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA., Starlight/Lantern Pharma, 7700 Windrose Ave. Office 3-187, Piano, TX, USA., Vanderbilt University Medical Center, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA. .