Phase 1/2 ARV-6723 oral PROTAC HPK1 degrader ± pembrolizumab (PD-1 mAb) in solid tumors

This first-in-human, open-label Phase 1/2 study sponsored by Arvinas evaluates ARV-6723 as monotherapy and combined with pembrolizumab (Merck/MSD’s anti–PD-1 monoclonal antibody) in adults with advanced/metastatic, unresectable solid tumors that have progressed after prior therapy. ARV-6723 is an oral PROTAC designed to degrade HPK1 (hematopoietic progenitor kinase 1), an intracellular negative regulator of immune-cell activation; the goal is to reprogram the tumor microenvironment and improve anti-tumor immunity, including potentially in immune checkpoint inhibitor–resistant settings. The Phase 1a/1b parts dose-escalate ARV-6723 alone and with fixed-dose pembrolizumab (IV or SQ), followed by Phase 1 dose optimization and Phase 2 tumor-specific expansion testing ARV-6723 alone, ARV-6723 + pembrolizumab, and an investigator’s-choice SOC arm. The commercial/scientific angle is the use of targeted protein degradation (rather than enzymatic inhibition) to modulate an immune signaling node, which may create combination leverage with PD-1 blockade. For most refractory advanced solid tumors, today’s care is sequential systemic therapy (histology- and biomarker-driven chemo, targeted therapy when actionable, and checkpoint inhibitors/IO combinations in selected diseases), so this tests whether HPK1 degradation can add response depth or restore sensitivity beyond PD-1 alone.