A phase 2 clinical trial of first-in-class fascin inhibitor NP-G2-044 as monotherapy and in combination therapy with anti-PD-1 immunotherapy in patients with advanced solid tumor malignancies.
Authors: Frank Yung-Chin Tsai, Michael J. Birrer, Jason R Brown, Sanjay Chandrasekaran, Vincent Chung, Richard C. Frank, Edward Graeme Garmey, Shirish M. Gadgeel, Thomas J. George, Shadia Ibrahim Jalal, Andrew Stewart Poklepovic, Jennifer Margaret Segar, Alexander I. Spira, Jue Jillian Zhang, Anup Kasi
Journal: Journal of Clinical Oncology (2024)

3112 Background: Fascin is the main actin cross-linker in filopodia and its elevated levels are correlated with increased risk of cancer metastasis, disease progression and mortality. Pre-clinical evidence shows that deletion of the fascin gene (FSCN1) delays tumor development, slows tumor growth, reduces metastatic colonization and increases overall survival. NP-G2-044 is a novel, small molecule antagonist of fascin that blocks tumor metastasis, inhibits cancer growth and increases antigen uptake by intra-tumoral dendritic cells. In a previously presented phase 1 clinical trial, the drug was well tolerated and demonstrated signals of anti-tumor and anti-metastatic activity. Methods: This open-label study was designed to establish the recommended phase 2 dose (RP2D) of orally administered NP-G2-044 administered as both monotherapy (MT) and in combination (CT) with anti-PD-1 immunotherapy (IO). Efficacy was assessed by RECIST 1.1 and iRECIST [CT patients (pts.) only]. Following MT-RP2D identification, additional treatment-refractory pts. with advanced/metastatic gynecologic (GYN) malignancies were evaluated at the MT-RP2D. The CT-RP2D was established by a 3+3 design followed by an expansion cohort in pts. experiencing stable disease (SD) or progressive disease (PD) on prior anti-PD(L)-1 therapy. Results: MT-RP2D of 2100mg QD was selected based on a 16-pt. comparative review of PK, safety, and efficacy between two highest doses previously identified in phase 1. No DLTs or drug-related SAEs were observed among MT-RP2D pts. Median PFS for 12 GYN pts. receiving the MT-RP2D was 20 weeks and greater than 70% of these pts did not develop new metastases while on study. One pt. (treatment-refractory ovarian cancer) continues on study with SD exceeding 24 months. A CT-RP2D of 1600 mg. QD was selected and enrollment is ongoing. Among 29 enrolled CT pts. evaluated to-date, no DLTs were observed. Multiple tumor bulk reductions were observed among CT pts. incl one confirmed RECIST PR (53% reduction in tumor bulk) for a pt. with cutaneous squamous cell cancer who progressed on prior anti-PD(L)-1 therapy. Most common TEAEs observed for CT were diarrhea, fatigue and nausea with the safety monitoring is ongoing. Conclusions: The first-in-class fascin inhibitor, NP-G2-044, appears safe and well tolerated administered both as MT and in CT with IO. Signals of anti-cancer and anti-metastatic activity were observed with both mono and combination therapy. A phase 3 randomized clinical trial evaluating NP-G2-044 in combination with chemo in pts. with platinum-resistant ovarian cancer is in development with enrollment anticipated to start later this year. Additionally, a phase 2 study to further evaluate NP-G2-044 in combination with anti-PD-1 therapy in IO-naïve pts is planned. Clinical trial information: NCT05023486 .