Phase II study (daNIS-1) of the anti-TGF-β monoclonal antibody (mAb) NIS793 with and without the PD-1 inhibitor spartalizumab in combination with nab-paclitaxel/gemcitabine (NG) versus NG alone in patients (pts) with first-line metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Bai Li-Yuan , Macarulla Teresa , Grell Peter , Chee Cheng Ean , Krishnamurthy Anuradha , Wong Mark Ka , Michael Michael , Milella Michele , Prager Gerald , Springfeld Christoph , Collignon Joelle , Siveke Jens , Santoro Armando , Lin Chia-Chi , Peltola Katriina Johanna , Bostel Geraldine , Jankovic Dragana , Altzerinakou Maria-Athina , Fabre Claire , Sivakumar Shivan 
Published: June 2022

TPS4183 Background: Overall survival remains low for pts with mPDAC despite approved therapies, highlighting the need for further innovative treatment options. Intra-tumoral fibrosis that characterizes PDAC has been associated with a state of immune exclusion and may constitute a mechanical obstacle to the intra-tumoral penetration of chemotherapy as well as contribute to the lack of efficacy of immunotherapy. TGF-β plays a key role in regulating the tumor microenvironment and emerging evidence points to its role as a pivotal activator of cancer-associated fibroblasts, leading to the development of fibrotic networks. Preclinical data in murine models have shown that TGF-β blockade augmented the antitumor activity of both NG and anti-PD-1 therapy, leading to tumor regression. These data provide the rationale for combining TGF-β-targeting agents with immunotherapy and chemotherapy. NIS793 is a human IgG2 mAb that binds to TGF-β. This study investigates NIS793 with and without spartalizumab (PD-1 antagonist) combined with NG in treatment naïve mPDAC. Methods: This is a phase II open-label, randomized, multicenter study (NCT04390763) beginning with a safety run-in period followed by randomization. Eligible pts are adults with previously untreated mPDAC and ECOG performance status score ≤1. Pts are excluded if they have a microsatellite-unstable tumor. The safety run-in data will be analyzed after ≥6 pts have received NIS793 (intravenously [IV] 2100 mg Q2W) + spartalizumab (IV 400 mg Q4W) + nab-paclitaxel (IV 125 mg/m2 on Days 1, 8 and 15) + gemcitabine (IV 1000 mg/m2 on Days 1, 8 and 15) for 1 cycle (28 days) to assess the safety and tolerability of the combination. In the randomized part, pts will be randomized 1:1:1 to NIS793 + spartalizumab + NG (n = 50) or NIS793 + NG (n = 50) or NG (n = 50). Treatment will continue until unacceptable toxicity, disease progression, discontinuation by investigator’s/pt’s choice, or withdrawal of consent. The primary objective is to evaluate the progression-free survival per RECIST 1.1, of NIS793 + NG ± spartalizumab versus NG alone. Secondary objectives include safety and tolerability, antitumor activity, overall survival, change in tumoral CD8 and PD-L1 status, and characterization of immunogenicity and pharmacokinetics. Efficacy will be assessed locally per RECIST v1.1 and iRECIST at screening, every 8 weeks for 1 year and then every 12 weeks until disease progression. Blood and tumor samples will be taken at baseline and during study treatment for pharmacokinetic, immunogenicity and biomarker assessments. This study is ongoing and will enroll pts from 31 sites across 14 countries. The first pt was treated on October 22, 2020. Enrollment for the randomized part of the study started on August 09, 2021. Clinical trial information: NCT04390763.