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

Abstract

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.

Keywords: Drug Therapy, Combination; Immunotherapy; Non-Small Cell Lung Cancer; Programmed Cell Death 1 Receptor; Therapies, Investigational.

Figure 1

Waterfall plot for best overall response for dose expansion (n=119) (investigator assessed). A change in formulation (NIS793 originally provided as ^aliquid for infusion and subsequently as ^blyophilisate for infusion), which occurred at the first dose level of the study, and proven to be safe, with no difference in the formulation. During dose-escalation, one patient with non-measurable disease as per RECIST V.1.1 was recruited (per protocol). MSS-CRC, microsatellite stable colorectal cancer; NSCLC, non-small cell lung cancer; PD, progressive disease; PR, partial response; Q3W, every 3 weeks; Q4W, every 4 weeks; RECIST V.1.1, Response Evaluation Criteria in Solid Tumors version 1.1; SD, stable disease; UNK, unknown; uPR; unconfirmed partial response.

Figure 2

Geometric mean and arithmetic mean (SD) of concentration-time profiles of NIS793 by treatment and cycle. MSS-CRC, microsatellite-stable colorectal cancer; NSCLC, non-small cell lung cancer; Q2W, every 2 weeks; Q3W, every 3 weeks; Q4W, every 4 weeks.

Figure 3

Serum TGF-β concentration over time on study treatment. (A) Active TGF-β1 and 3 ligands were detected in all but one patient prior to initial dose of NIS793. Post-NIS793 dosing, all serum samples were below limit of quantification, demonstrating that free, active TGF-β was greatly reduced (B) Total TGF-β concentration over time on study treatment. ^aTGF-β assay measures isoform 1. A change in formulation (NIS793 originally provided as ^bliquid for infusion and subsequently as ^clyophilisate for infusion), which occurred at the first dose level of the study, and proven to be safe, with no difference in the formulation. The timing for collection was slightly different when referring to C3, depending on whether the dosing regimen was NIS793 Q2W or Q3W. BL, baseline; C, Cycle; D, Day; EOT, end of treatment; LLOQ, lower limit of quantification; MSS-CRC; microsatellite-stable colorectal cancer; NSCLC, non-small cell lunger cancer; Q2W, every 2 weeks; Q3W, every 3 weeks; Q4W, every 4 weeks; TGF-β, transforming growth factor beta.

Figure 4

NIS793 proof of mechanism in the tumor. (A) Levels of TGF-β pathway and immune activation at baseline were assessed using two gene expression signatures for TGF-β (one from Genentech and one from Novartis) and an IFN-γ gene signature, respectively, derived from bulk RNA sequencing, (B) on-treatment modulation of gene signatures versus baseline for paired tumor biopsies from 11 patients is shown using five readouts for TGF-β activity (PMEPA1 gene expression and 4 gene signatures capturing fibroblast, TGF-β and EMT activity), as well as two gene signatures for IFN-γ activity, derived from bulk RNA sequencing. The average log₂ fold change of those gene signatures across all paired samples in the box plot on the right, and (C) CD8 detection derived from immunohistochemistry per cent marker area at baseline and on treatment is shown in the heat map with percent change shown as a bar graph. CD8, cluster of differentiation 8; CMS, consensus molecular subtypes; EMT, epithelial-to-mesenchymal transition; FC, fold change; GNT, Genentech; IFNγ, interferon gamma; NVS, Novartis; PMEPA1, prostate transmembrane protein, androgen induced 1; Q2W, every 2 weeks; Q3W, every 3 weeks, Q4W, every 4 weeks; TGF-β, transforming growth factor beta.