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

被引：17

作者：

Bauer, Todd M. ^{[1
]}

Santoro, Armando ^{[2
,3
]}

Lin, Chia-Chi ^{[4
]}

Garrido-Laguna, Ignacio ^{[5
]}

Joerger, Markus ^{[6
]}

Greil, Richard ^{[7
]}

Spreafico, Anna ^{[8
]}

Yau, Thomas ^{[9
]}

Goebeler, Maria-Elisabeth ^{[10
]}

Huetter-Kroenke, Marie Luise ^{[11
,12
,13
,14
]}

Perotti, Antonella ^{[15
]}

Juif, Pierre-Eric ^{[16
]}

Lu, Darlene ^{[17
,18
]}

Barys, Louise ^{[16
]}

Cremasco, Viviana ^{[17
,18
]}

Pelletier, Marc ^{[17
,18
]}

Evans, Helen ^{[16
]}

Fabre, Claire ^{[16
]}

Doi, Toshikiko ^{[18
]}

机构：

[1] Sarah Cannon Res Inst, Nashville, TN USA

[2] Humanitas Univ, Dept Biomed Sci, Pieve Emanuele, Italy

[3] IRCCS Humanitas Res Hosp, Humanitas Canc Ctr, Rozzano, Lombardia, Italy

[4] Natl Taiwan Univ Hosp, Dept Oncol, Taipei, Taiwan

[5] Univ Utah Hlth, Huntsman Canc Inst, Div Oncol, Salt Lake City, UT USA

[6] Kantonsspital St Gallen, Dept Oncol & Hematol, St Gallen, Switzerland

[7] Paracelsus Med Univ Salzburg, Lab Immunol & Mol Canc Res SCRI LIMCR, Dept Internal Med Haematol Med Oncol Haemostaseol, Oncol Ctr,Salzburg Canc Res Inst, Salzburg, Austria

[8] Princess Margaret Hosp, Div Med Oncol & Hematol, Dept Med, Canc Ctr, Toronto, ON, Canada

[9] Queen Mary Hosp, Dept Med, Hong Kong, Peoples R China

[10] Univ Hosp Wurzburg, Comprehens Canc Ctr Mainfranken, Early Clin Trials Unit, Wurzburg, Bayern, Germany

[11] Univ Ulm, Dept Internal Med 3, Ulm, Baden Wurttembe, Germany

[12] Charite Univ Med Berlin, Dept Hematol Oncol & Tumor Immunol, Berlin, Germany

[13] Free Univ Berlin, Berlin, Germany

[14] Humboldt Univ, Berlin, Germany

[15] Osped San Raffaele, Dept Med Oncol, Milan, Lombardia, Italy

[16] Novartis Inst BioMed Res Basel, Basel, Switzerland

[17] Novartis Inst BioMed Res Inc, Cambridge, MA USA

[18] Novartis Inst BioMed Res Inc, Cambridge, MA USA

来源：

JOURNAL FOR IMMUNOTHERAPY OF CANCER | 2023年 / 11卷 / 11期

关键词：

SAFETY;

D O I：

10.1136/jitc-2023-007353

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background NIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-beta). 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-beta/NIS793 complexes and depleted active TGF-beta in peripheral blood. Gene expression analyses in tumor biopsies demonstrated decreased TGF-beta 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-beta pathway inhibition.

引用

页数：13

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