P-22 Phase III Study (Danis-2) of the Anti–tgf-Β Monoclonal Antibody NIS793 with Nab-Paclitaxel/gemcitabine Vs Nab-Paclitaxel/gemcitabine Alone in Patients with First-Line Metastatic Pancreatic Ductal Adenocarcinoma

Despite improving outcomes, current therapies for metastatic pancreatic ductal adenocarcinoma (mPDAC) have a modest impact on overall survival (OS) and new therapies are needed. PDAC is characterized by an abundance of intratumoral fibrosis, which may contribute to the lack of treatment efficacy and act as a mechanical barrier to effective penetration of therapeutics. TGF-β has a multifactorial role in tumorigenesis and maintaining an immunosuppressive tumor microenvironment (TME). Emerging evidence points to the role of TGF-β as a pivotal activator of cancer-associated fibroblasts that lead to the development of fibrotic networks. In preclinical models, TGF-β blockade alters the TME to facilitate an antitumor response, reduce stromal fibrosis, and augment the benefit of chemotherapy, providing rationale for combining TGF-β–targeting agents with chemotherapy. NIS793 is a potent, selective, human IgG2 monoclonal antibody (mAb) antagonist of TGF-β. This study investigates NIS793 in combination with nab-paclitaxel/gemcitabine (NG) vs NG alone in treatment-naïve patients with mPDAC. This is a phase III, randomized, double-blind, multicenter, two-arm study (NCT04935359) consisting of two stages: an initial safety run-in period followed by two-arm randomization. Eligible patients include adults with previously untreated mPDAC and an ECOG performance status ≤1. Patients with a tumor histology other than adenocarcinoma or with microsatellite instability-high tumors are ineligible. The aim of the safety run-in period is to assess the safety and tolerability of NIS793 + NG and confirm the recommended dose for the randomized phase of this study. Data will be analyzed once at least six evaluable patients have received NIS793 (intravenous [IV] 2100 mg every 2 weeks) + nab-paclitaxel (IV 125 mg/m2 on Days 1, 8, and 15) + gemcitabine (IV 1000 mg/m2 on Days 1, 8, and 15) for one 28-day cycle. Patients (N=480) will be randomized 1:1 to NIS793 + NG or placebo + NG. Treatment will continue until unacceptable toxicity, disease progression, discontinuation by investigator or patient choice, death, or withdrawal of consent. The primary objective is to evaluate the OS of patients receiving NIS793 + NG vs NG alone; secondary objectives include assessing progression-free survival, the overall response rate, disease control rate, duration of response, and time to response (assessed locally per RECIST v1.1), as well as safety and tolerability, immunogenicity, pharmacokinetics, and patient-reported outcomes such as health-related quality of life. Efficacy will be assessed at screening, every 8 weeks for 1 year, and then every 12 weeks until disease progression. Blood samples will be taken at baseline and during treatment for pharmacokinetic and immunogenicity assessments. This study is ongoing and will enroll patients from approximately 149 sites across 28 countries. The first patient was treated on October 20, 2021. NCT04935359. Novartis Pharmaceticals. Novartis Pharmaceuticals.