Durable responses in ICI-refractory or acquired resistance: Phase 2 study of NP-G2-044 combined with anti-PD-1 therapy.

2513 Background: Although immune checkpoint inhibitors (ICIs) have transformed cancer treatment, many patients still develop primary or acquired resistance. NP-G2-044 is a first-in-class, oral fascin inhibitor that disrupts cancer cell motility, invasion, and metastasis while promoting intratumoral dendritic cell (DC) activation and CD8+ T-cell proliferation. Preclinical studies indicate NP-G2-044 synergizes with anti-PD-1 therapy to convert nonresponsive tumors into responsive ones. Early-phase clinical data support the feasibility of NP-G2-044 at pharmacologically active doses and its potential to prevent metastasis when used as monotherapy. Methods: In this open-label Phase 2 trial (NCT05023486), patients with advanced or metastatic solid tumors and documented primary or acquired resistance to anti-PD-(L)1 therapy received NP-G2-044 plus standard-of-care anti-PD-1. Efficacy was assessed using RECIST, with the primary endpoint being objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), duration of response, disease control rate (DCR), and safety. Results: Forty-five patients were enrolled, with 33 evaluable for efficacy. No dose-limiting toxicities were observed. Objective responses occurred in 7/33 patients (21%) [95 % CI 9 - 38.9%], including 4 complete responses (CRs)—2 by RECIST in cervical and endometrial cancers, and 2 pathological CRs in pancreatic and gastroesophageal junction adenocarcinomas—and 3 partial responses (cutaneous squamous cell carcinoma, non-small cell lung cancer, and cholangiocarcinoma). Three patients have been cancer-free for over 7 months, and 5 have remained on therapy for more than 15 months. The DCR was 76%, and 55% of patients showed no new metastases during the study. One-year PFS is projected at 30%. The most common adverse events were diarrhea, fatigue, nausea, and transaminitis (~30%), which was transient, reversible, and preceded tumor response. Mechanistic analyses using multiplex immunofluorescence and immunophenotyping revealed enhanced intratumoral cytotoxic T-cell infiltration, proliferation, and granzyme B expression, along with an increase in activated DCs—consistent with a strong immunomodulatory effect. Conclusions: NP-G2-044, in combination with anti-PD-1 therapy, appears to have clinical activity across multiple cancer types, overcoming both primary and acquired ICI resistance while producing durable responses. Ongoing expansion cohorts and biomarker analyses aim to refine patient selection. These findings underscore NP-G2-044’s potential to address metastatic disease and improve cancer immunotherapy outcomes, offering a promising therapeutic option for patients with limited alternatives. Clinical trial information: NCT05023486 .