Sonic hedgehog inhibitor suppresses carcinoma associated fibroblasts to prime Gemcitabine/Nab-Paclitaxel and anti-CTLA4 immunotherapy as sequential first-line combination therapy in a Phase 1b/2 study in PDAC: NUMANTIA trial

Abstract Metastatic pancreatic ductal adenocarcinoma (PDAC) remains deadly, with minimal improvement in prognosis over the past 20 years despite expansion of our chemotherapeutic arsenal. The complex tumor microenvironment (TME) of PDAC in the advanced stage, which often accompany clinical diagnosis, likely contributes to the limited efficacy of current standard of care chemotherapy. Informed by mechanistic preclinical studies, we evaluated the impact of inhibition of Hedgehog (Hh) signaling to prime PDAC TME and leverage anti-tumor efficacy of Gemcitabine plus nab-Paclitaxel (GnP) together with anti-CTLA-4 immune check point inhibitor (ICI, zalifrelimab). Hh inhibition using NLM-001 (an oral small molecule inhibitor of Smo) aimed to polarize the PDAC TME, including cancer associated fibroblasts (CAFs) and intratumoral immune profile, and to foster an immunosuppressive milieu that engages ICI. In this Phase 1b/2, open label, single arm study, patients with metastatic PDAC received standard GnP every 28-day cycles. In addition, NLM-001 was given at 800 mg daily on days -4 to -1 and days 10 to 13 of the GnP cycles 1 to 3, 6 to 8, 11 to 13 onwards (3 cycles on, followed by 2 rest cycles). Anti CTLA-4 inhibitor, zalifrelimab, was administered at 1mg/kg on day 15 of cycle 1 and every 6 weeks thereafter. The primary end point was to assess efficacy by objective response rate (ORR) as per RECIST v1.1. Treatment was overall well tolerated in the 28 patients enrolled. Most frequent grade 3-4 adverse events (AEs) were neutropenia (46.4%), asthenia (21.4%), and neurotoxicity (14.3%). No patient discontinued treatment due to toxicity. ORR was 50% [95% CI, 29.1-70.9] and disease control rate was 95.5% [95% CI, 86.8 - 100.0]. Median progression-free survival (PFS) was 7.3 months 95.5% [95% CI, 5.564 – 9.041] and median overall survival (OS) was 11.5 months [95% CI, 10.23 –12.73]; 1-year PFS was 18.2% [95% CI, 2.1 – 34.3] and 1-year OS was 50% [95% CI, 29.0 – 710]. Patients who achieved ctDNA clearance at cycle 4 had a significant better PFS (10.7 vs 6.0 months; p<0.0001). Paired biopsies immunolabeling and spatial transcriptomic analyses showed polarization of the TME, with increased CD4 + and CD8 + T cells infiltration, down trending Tregs, and decreased αSMA/FAP ratio. Hedgehog inhibitor NLM-001 in combination with gemcitabine/nab-paclitaxel and zalifrelimab was safe and well tolerated and showed encouraging objective responses in the first line treatment of advanced PDAC. Clinical Trial Registration EudraCT: 2020-004932-52; NCT04827953 .