TY - JOUR
T1 - Phase I/Ib, open-label, multicenter, dose-escalation study of the anti-TGF-β monoclonal antibody, NIS793, in combination with spartalizumab in adult patients with advanced tumors
AU - Bauer, Todd M
AU - Santoro, Armando
AU - Lin, Chia-Chi
AU - Garrido-Laguna, Ignacio
AU - Joerger, Markus
AU - Greil, Richard
AU - Spreafico, Anna
AU - Yau, Thomas
AU - Goebeler, Maria-Elisabeth
AU - Hütter-Krönke, Marie Luise
AU - Perotti, Antonella
AU - Juif, Pierre-Eric
AU - Lu, Darlene
AU - Barys, Louise
AU - Cremasco, Viviana
AU - Pelletier, Marc
AU - Evans, Helen
AU - Fabre, Claire
AU - Doi, Toshikiko
N1 - © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2023/11/29
Y1 - 2023/11/29
N2 - BACKGROUND: NIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-β). This first-in-human study investigated NIS793 plus spartalizumab treatment in patients with advanced solid tumors.METHODS: Patients received NIS793 (0.3-1 mg/kg every 3 weeks (Q3W)) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 plus spartalizumab (NIS793 0.3-30 mg/kg Q3W and spartalizumab 300 mg Q3W or NIS793 20-30 mg/kg every 2 weeks [Q2W] and spartalizumab 400 mg every 4 weeks (Q4W)). In dose expansion, patients with non-small cell lung cancer (NSCLC) resistant to prior anti-programmed death ligand 1 or patients with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE).RESULTS: Sixty patients were treated in dose escalation, 11 with NIS793 monotherapy and 49 with NIS793 plus spartalizumab, and 60 patients were treated in dose expansion (MSS-CRC: n=40; NSCLC: n=20). No dose-limiting toxicities were observed. The RDE was established as NIS793 30 mg/kg (2100 mg) and spartalizumab 300 mg Q3W. Overall 54 (49.5%) patients experienced ≥1 treatment-related adverse event, most commonly rash (n=16; 13.3%), pruritus (n=10; 8.3%), and fatigue (n=9; 7.5%). Three partial responses were reported: one in renal cell carcinoma (NIS793 30 mg/kg Q2W plus spartalizumab 400 mg Q4W), and two in the MSS-CRC expansion cohort. Biomarker data showed evidence of target engagement through increased TGF-β/NIS793 complexes and depleted active TGF-β in peripheral blood. Gene expression analyses in tumor biopsies demonstrated decreased TGF-β target genes and signatures and increased immune signatures.CONCLUSIONS: In patients with advanced solid tumors, proof of mechanism of NIS793 is supported by evidence of target engagement and TGF-β pathway inhibition.TRIAL REGISTRATION NUMBER: NCT02947165.
AB - BACKGROUND: NIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-β). This first-in-human study investigated NIS793 plus spartalizumab treatment in patients with advanced solid tumors.METHODS: Patients received NIS793 (0.3-1 mg/kg every 3 weeks (Q3W)) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 plus spartalizumab (NIS793 0.3-30 mg/kg Q3W and spartalizumab 300 mg Q3W or NIS793 20-30 mg/kg every 2 weeks [Q2W] and spartalizumab 400 mg every 4 weeks (Q4W)). In dose expansion, patients with non-small cell lung cancer (NSCLC) resistant to prior anti-programmed death ligand 1 or patients with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE).RESULTS: Sixty patients were treated in dose escalation, 11 with NIS793 monotherapy and 49 with NIS793 plus spartalizumab, and 60 patients were treated in dose expansion (MSS-CRC: n=40; NSCLC: n=20). No dose-limiting toxicities were observed. The RDE was established as NIS793 30 mg/kg (2100 mg) and spartalizumab 300 mg Q3W. Overall 54 (49.5%) patients experienced ≥1 treatment-related adverse event, most commonly rash (n=16; 13.3%), pruritus (n=10; 8.3%), and fatigue (n=9; 7.5%). Three partial responses were reported: one in renal cell carcinoma (NIS793 30 mg/kg Q2W plus spartalizumab 400 mg Q4W), and two in the MSS-CRC expansion cohort. Biomarker data showed evidence of target engagement through increased TGF-β/NIS793 complexes and depleted active TGF-β in peripheral blood. Gene expression analyses in tumor biopsies demonstrated decreased TGF-β target genes and signatures and increased immune signatures.CONCLUSIONS: In patients with advanced solid tumors, proof of mechanism of NIS793 is supported by evidence of target engagement and TGF-β pathway inhibition.TRIAL REGISTRATION NUMBER: NCT02947165.
KW - Adult
KW - Humans
KW - Antibodies, Monoclonal/adverse effects
KW - Antineoplastic Agents/therapeutic use
KW - Carcinoma, Non-Small-Cell Lung/drug therapy
KW - Kidney Neoplasms/drug therapy
KW - Lung Neoplasms/drug therapy
KW - Transforming Growth Factor beta
U2 - 10.1136/jitc-2023-007353
DO - 10.1136/jitc-2023-007353
M3 - Original Article
C2 - 38030303
SN - 2051-1426
VL - 11
JO - JOURNAL FOR IMMUNOTHERAPY OF CANCER
JF - JOURNAL FOR IMMUNOTHERAPY OF CANCER
IS - 11
ER -