Dr Beckermann on Targeting TREM2 in the Treatment of 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 role of TREM2 in the treatment of patients with clear cell renal cell carcinoma (ccRCC), highlighting a phase 1a/1b study (NCT04691375).

This first-in-human, multicenter, open-label trial evaluated PY314 in combination with pembrolizumab (Keytruda) and enrolled patients with locally advanced, unresectable, and/or metastatic solid tumors, including ccRCC, who had shown refractoriness to or relapsed after standard-of-care treatment. The study outcomes revealed limited efficacy of the combination regimen in patients with ccRCC, with only 1 patient achieving a partial response and several others experiencing stable disease. Despite these modest clinical responses, the primary end point of the study—assessing safety and tolerability—was met.

Reflecting on the presented data, Beckermann acknowledges remaining uncertainties regarding the role of TREM2 in the immune-suppressive tumor microenvironment (TME). Although TREM2 might not independently overcome prior immune checkpoint inhibition, the phase 1a/1b trial findings underscored the potential for exploring alternative TREM2-targeted treatment approaches, such as upfront combination strategies or different modalities, she explains. The study emphasized the feasibility of investigating safe combination therapies within immunotherapy-refractory diseases, according to Beckermann. Although PY314's performance did not warrant further advancement of this agent in the refractory setting, Beckermann reports that she is optimistic regarding ongoing efforts to deepen the field’s understanding of the TME and pursue innovative avenues to enhance treatment responses.

Looking ahead, investigators are actively exploring novel strategies to modify the TME and synergize established therapies to achieve durable clinical outcomes, she continues. For instance, ongoing investigations involve a triplet regimen targeting the adenosine receptor in the frontline treatment of patients with metastatic kidney cancer, Beckermann says. Given kidney cancer's metabolic characteristics and its tendency to create an immunosuppressive environment rich in ATP, this treatment approach aims to counteract immune evasion and enhance therapeutic efficacy, Beckermann states. These endeavors exemplify a broader commitment to advancing precision medicine in oncology, with a focus on optimizing treatment strategies and improving patient outcomes through innovative drug development and therapeutic combinations, she concludes.