BXCL701: First-in-class oral activator of systemic innate immunity combined with pembrolizumab, in patients with metastatic castration-resistant prostate cancer (mCRPC) of small-cell neuroendocrine carcinoma (SCNC) phenotype—Phase 2a interim results.

Abstract

126 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP 8/9 & DPP 4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 & IL-1ß, bridging innate & adaptive immunity. BXCL701 is evaluated in a phase 1b/2 study in combination with pembrolizumab, in mCRPC patients with SCNC phenotype (and in adenocarcinoma). SCNC is highly proliferative and aggressive and does not express androgen receptor or PSA. Here are reported the interim results of the phase 2a after enrollment of 16 patients for the SCNC cohort. Methods: Phase 2a patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, required to have progression by PCWG3 on ≥1 prior line of cytotoxic chemotherapy (patients who either have refused chemotherapy or are considered unsuitable for chemotherapy may be eligible following discussion with the sponsor). Patients received pembrolizumab (200 mg IV q21-days) + BXCL701 0.2 mg BID for a week with step-up to 0.3 mg BID on days 8-14, and 0.3 mg BID on days 1-14 of subsequent cycles. Primary endpoint is Composite Response defined as RECIST 1.1 ± PSA50 ± CTC count conversion. Study uses a Simon 2-stage minimax design with 15 evaluable patients in stage 1 and 13 in stage 2. Baseline markers and changes in relevant immune effector cells also evaluated. Results: As of 9/27/21, 16 patients with SCNC were enrolled (10 evaluable, 6 in active treatment): at the 7/08/21 data extract, 9 of the evaluable patients had prior chemotherapy and a median of 2 prior lines of therapy (range 1-4); 33% have bone only disease. Median follow-up duration is 9 weeks (range 1-27)/ 3 cycles. Although follow-up was short, anti-tumor activity was observed. 3/ 10 evaluable patients showed responses—1 RECIST-defined confirmed PR + 1 unconfirmed PR (both 18 weeks/ 6 cycles) + 1 CTC conversion—amounting to a 30% Composite Response rate, meeting protocol-defined expansion criteria from stage 1 to stage 2. BXCL701 + pembrolizumab demonstrated acceptable tolerability without evidence of increased immune-related AEs compared to historic controls with checkpoint inhibitors. AEs consistent with cytokine activation were observed (hypotension, fever, fatigue). Conclusions: Oral BXCL701 in combination with pembrolizumab demonstrates encouraging anti-tumor activity in very late-line, refractory mCRPC SCNC for which there is currently no standard of care. BXCL701 BID dosing continues to demonstrate an acceptable safety profile. Additional interim phase 2a study results will be presented. Clinical trial information: NCT03910660.