Activity of NP-G2-044 (fascin inhibitor) + anti–PD-1 in ICI-resistant advanced/metastatic solid tumors with expansion in cutaneous squamous cell carcinoma (CSCC).

e21557 Background: Most patients do not respond to anti–PD-1 therapy, and many responders develop acquired resistance. In CSCC, response rates are ~50%, and acquired resistance occurs in ~35% of initial responders, highlighting the need to convert ICI-refractory or acquired-resistant tumors into responders. NP-G2-044 is a first-in-class fascin inhibitor that activates intratumoral dendritic cells (DCs), enhancing antigen uptake/activation, increasing tertiary lymphoid structures, and promoting IL-12/IFN-γ–dependent antitumor immunity that can synergize with PD-1 blockade; fascin inhibition also suppresses new metastasis formation. Methods: NP-G2-044-P2-01 is a Phase 2 study evaluating NP-G2-044 orally QD in combination with anti-PD-1 therapy across multiple tumor-specific expansion cohorts, in patients with ICI-refractory disease or acquired resistance without molecular biomarker selection. The primary endpoint is confirmed ORR per RECIST 1.1 with secondary endpoints including DCR, DOR, and PFS. Safety was assessed by CTCAE. Results: 45 patients with primary ICI-refractory disease or acquired ICI resistance were evaluable for efficacy. CR and PR were observed across 7 tumor types, including 5 composite CRs (RECIST, clinical, or pathological) in cervical, endometrial, CSCC, pancreatic, and gastroesophageal junction adenocarcinomas. 3 patients are off treatment and disease-free for > 1 year, and 3 patients are with PFS > 2 years. Median MFI was 14 months. In the CSCC cohort (efficacy population N = 6), responses included 1 RECIST CR, 1 clinical CR (residual deep scarring only), and 1 pathological CR, for ORR 50% (3/6) and confirmed DCR 100% (6/6). In the clinical CR case, tumor-informed ctDNA was detectable at baseline, cleared after 8 weeks of treatment, and has remained negative for > 2 years; the patient remains in clinical CR one year after stopping therapy. TEAEs (n = 56) were predominantly grade 1/2; common TEAEs (≥20%) were fatigue, nausea, ALT increased, AST increased, and vomiting. Study drug–related AEs were mostly grade 1/2 (66%), with grade 3 in 8.9% and grade 4 in 1.8%, with no new safety signals. Mechanistic analyses using multiplex immunofluorescence and immunophenotyping showed increased intratumoral CD8⁺ T-cell infiltration and proliferation, along with increased intratumoral activated DCs, consistent with a strong immunomodulatory response. Conclusions: NP-G2-044 plus anti–PD-1 demonstrated pan-tumor activity in ICI-resistant advanced/metastatic solid tumors with durable benefit, including responses persisting after treatment cessation. In advanced/metastatic ICI-resistant CSCC, the regimen achieved 50% ORR and 100% disease control with durable CRs. These data support fascin inhibition as a novel DC-activating immunotherapy backbone for immune-resistant CSCC. Clinical trial information: NCT05023486 .