NP-G2-044 (fascin inhibitor) + anti–PD-1 drives 50% CR-heavy responses in PD-1–resistant CSCC

NP-G2-044 is an oral, first-in-class fascin inhibitor designed to activate intratumoral dendritic cells (DCs) and enhance IL-12/IFN-γ–dependent antitumor immunity, potentially re-sensitizing tumors to PD-1 blockade; it was evaluated with anti–PD-1 in the Phase 2 NP-G2-044-P2-01 basket trial in ICI-refractory or acquired-resistant advanced/metastatic solid tumors (NCT05023486). Across 45 efficacy-evaluable patients, CR/PR occurred in 7 tumor types, including 5 composite CRs and several highly durable benefits (3 off-treatment disease-free >1 year; 3 with PFS >2 years), while the CSCC expansion (n=6) reported ORR 50% (3/6) with 3 CRs by mixed modalities and confirmed DCR 100% (6/6)—numerically similar to first-line anti–PD-1 monotherapy ORRs (~47% with cemiplimab; ~32–50% with pembrolizumab depending on line of therapy), but notable here because all patients were ICI-resistant (where expected post–PD-1 salvage responses are typically low and no uniform SOC exists). Safety in 56 treated patients was mostly grade 1/2; study drug–related grade 3 AEs occurred in 8.9% and grade 4 in 1.8% with “no new safety signals,” and paired immune profiling suggested on-mechanism immune activation (↑intratumoral activated DCs and proliferating CD8+ T cells).