47: A Phase 1b Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PY314 In Combination with Pembrolizumab in Subjects with Advanced Solid Tumors, RCC cohort

Background: Checkpoint inhibition (CPI) is a standard therapeutic approach in metastatic renal cell carcinoma (RCC), inducing T cell activation. 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 been associated with disease recurrence after nephrectomy and poor outcomes when expressed at high levels. PY314 is a humanized monoclonal antibody targeting TREM2 to deplete tumor-associated macrophages. In this study , the combination of PY314 and pembrolizumab was investigated in patients with CPI-refractory RCC.

Methods: The primary objective was to assess the safety and tolerability of PY314 10 mg/kg in combination with pembrolizumab 200 mg IV every 21 days, and secondary objectives included pharmacokinetics and anti-tumor activity. Eligible patients had RCC with clear cell histology with disease progression on prior CPI, either in combination or sequentially with VEGF-TKI.

Results: Seventeen patients were enrolled, median age of 67, 82% male, all patients 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% treatment related adverse events (AE), the most common being fatigue, pyrexia, nausea, and infusion-related reaction. Among the 17 patients receiving PY314 and pembrolizumab, one patient achieved a partial response (6%), and four patients had stable disease (24%) as the best response (median duration of response 15 weeks, range 15-69).

Conclusions: The combination of PY314 and pembrolizumab was safe however, 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 necessary to determine if improved efficacy can be achieved in IO-naïve settings.