PRTH-101: An investigational treatment for thoracic solid tumors targeting discoidin domain receptor (DDR1) and the tumor microenvironment (TME).

Abstract

e20510 Background: Many tumors are resistant to existing targeted therapies and chemotherapies, with high treatment failure rates in collagen-rich solid tumors. Collagen blocks T cell access to tumors, precluding effective anti-tumor responses. DDR1 binds collagen and is overexpressed in many solid tumors, including thymic epithelial cancers (TEC) and non-small cell lung cancer (NSCLC). Data show that high DDR1 expression in NSCLC is associated with poor prognoses and lack of response to immunotherapy, and low PD-L1 status is associated with T cell exclusion and worse responses. Immunotherapy for TEC leaves much room for improvement and treatment of PD-L1-negative NSCLC remains challenging. PRTH-101, a first-in-class, humanized monoclonal antibody, blocks the DDR1:collagen interaction and disrupts tumor collagen, facilitating T cell infiltration in tumors and tumor reduction in preclinical studies. Methods: PRTH-101 is being tested in an open-label Phase 1 clinical trial at doses of 8 to 1600 mg every 3 weeks, as a single agent and combined with pembrolizumab. In the dose escalation, multiple tumor types were enrolled. In the expansion phase, advanced TEC and NSCLC patients are being enrolled and treated with a provisional Phase 2 dose of 1200 mg PRTH-101, based on pharmacokinetics and target engagement, alone or with pembrolizumab. DDR1 density in tumors is evaluated by immunohistochemistry. Results: To date, 72 patients have been treated with PRTH-101, alone or with pembrolizumab; no dose-limiting toxicities have been seen. Most patients had progressed on multiple prior lines of therapy, including immunotherapy. Target engagement data correlate well with PK data. In TEC, 1 partial response (PR) by RECIST in a PD-L1-negative tumor (1200 mg combination therapy), and a PR (1600 mg monotherapy) by modified RECIST were seen; 72% of TEC patients had stable disease (SD), with median progression-free survival (mPFS) of 5.7 months for all patients and 8 months for those receiving more than one cycle. By MRI, tumors have also shown tumor cavitation and reduced vascularity. In NSCLC, a PR was seen in a PD-L1-negative tumor (1200 mg PRTH-101 alone after not tolerating first dose of pembrolizumab), and SD for 15 months was seen in a PD-L1-positive tumor (24 escalated to 80 mg, monotherapy). All tumors tested expressed DDR1, and patients with high-expressing tumors (≥25 th percentile) showed significantly longer PFS than patients with low-expressing tumors. Conclusions: PRTH-101 shows evidence of activity in this early phase clinical trial, with outcomes correlating with DDR1 expression. Analysis of the data by monotherapy and combination therapy in the context of PD-L1 expression, suggests that PRTH-101 contributes to or is responsible for PFS in these patients. Further clinical evaluation of PRTH-101 alone and with pembrolizumab in patients with TEC and NSCLC is planned. Clinical trial information: NCT05753722 .