Dr Beckermann on the Investigation of PY314 Plus Pembrolizumab in ccRCC

Kathryn Beckermann, MD, PhD, genitourinary medical oncologist, assistant professor, medicine, Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, discusses the background of and outcomes observed in a phase 1a/1b study (NCT04691375) of PY314 in combination with pembrolizumab (Keytruda) in patients with clear cell renal cell carcinoma (ccRCC).

This open-label, multicenter, first-in-human study included patients with locally advanced, unresectable, and/or metastatic solid tumors, including ccRCC, who were refractory to or relapsed after treatment with standard-of-care treatment. Previous research indicated the presence of a subset of macrophages potentially linked to recurrence post-nephrectomy in patients with ccRCC, Beckermann begins. These macrophages, believed to possess immune-suppressive qualities, express a protein known as TRIM2, she says, adding that this discovery formed part of the rationale behind the research. Investigators hypothesized that targeting this macrophage subset within the immune-suppressive tumor microenvironment could enhance responses to both immunotherapy and standard checkpoint inhibition, Beckermann explains.

Investigators initiated a phase 1 dose-finding clinical trial assessing the TRIM2 molecule PY314 in combination with pembrolizumab, wherein a safe dose of the combination was determined, she expands. At the 2023 International Kidney Cancer Symposium, Beckermann presented data from an expansion cohort of this trial, which comprised patients with ccRCC who had been refractory to prior therapies.

Investigators observed limited efficacy with the combination in this trial, she continues. Within this highly refractory patient population, only 1 patient achieved a partial response, and several patients experienced stable disease, Beckermann reports, adding that the median progression-free survival was 1.4 months. However, the primary end point of the study was met, with the combination deemed safe and tolerable, she explains.

Regarding adverse effects associated with the combination, investigators primarily observed immune-related toxicities that were consistent with the toxicity expectations for a checkpoint inhibitor, according to Beckermann. Infusion-related reactions were noted, but overall, the safety profile of the combination was manageable, with symptoms such as fever, fatigue, and nausea commonly reported, Beckermann concludes.