Abstract CT503: A phase I/Ib study of the safety and preliminary efficacy of NZV930 alone and in combination with spartalizumab and/or taminadenant in patients (pts) with advanced malignancies
Authors: Fu Siqing , Banerji Udai , Bedard Philippe L. , Ferrándiz Aitana Calvo , Chiappori Alberto , Desai Jayesh , Jamal Rahima , Perez Desamparados Roda , Yamamoto Noboru , Vieira Erica , Wong Gabrielle , Subramanian Kulandayan K. , Wang Shunguang , Mueller Britta , Otero Javier A. , Koo Si-Lin 
Published: June 2022

Abstract
Background: The over-expression of CD73 has been linked to many cancers. NZV930, an investigational, CD73-targeting monoclonal antibody (mAb), forms bidentate structures with the CD73 dimer, shutting down the catalytic activity of cell surface and soluble CD73. Taminadenant is an investigational A2AR antagonist and spartalizumab is an anti-PD-1 mAb. Preclinical studies provide compelling antitumor activity when combining CD73, A2AR, and PD-1 blockade.
Methods: This first-in-human study (NCT03549000) comprised dose-escalation and dose-expansion parts. Here, we present the dose-escalation results of the four treatment (tx) arms: NZV930 single agent (SA; 60-1000 mg Q2W), NZV930 (200-600 mg Q2W) + spartalizumab (400 mg Q4W) or taminadenant (80-240 mg Q2W), or in combination with spartalizumab (400 mg Q4W) + taminadenant (80-240 mg BID). Eligible pts had selected malignancies, and disease progression following standard therapy. Primary objectives included assessing safety and tolerability and determining the recommended dose for expansion (RDE) of NZV930 SA and its combinations. Secondary objectives were to determine efficacy, characterize the pharmacokinetics (PKs) of NZV930 SA and its combinations, and assess the immunogenicity of spartalizumab and NZV930. Biomarker tumor samples were obtained at screening, C2D1, and C4D1.
Results: As of June 10, 2021, 105 pts were enrolled for dose escalation, including pts with CRC (n=63), ovarian cancer (n=15), pancreatic cancer (n=11), NSCLC (n=8), TNBC (n=5), RCC (n=2), and prostate cancer (n=1). Most pts (81%) had been treated with ≥3 lines of prior therapy. In total, 98 pts discontinued, mainly due to disease progression (72%); six were ongoing. At least one tx-related adverse event (TRAE) was reported by 89 pts (85%); these were mostly grade 1-2. A triad of headache, fever, and nausea/emesis was observed after the first infusion of NZV930. Most common TRAEs (≥30%) were headache (67%), nausea and vomiting (32% each), and pyrexia (30%). At least one grade ≥3 TRAE was reported in 15 pts (14%); headache (4%) was most common, accounting for 4/7 DLTs (all grade ≥3). There were no tx-related deaths. Overall, no responses were reported; 12 pts (11%) had stable disease and 69 pts (66%) had progressive disease. NZV930 has good PK properties, with target-mediated drug disposition at lower doses, which normalize to typical IgG-like PKs at higher doses. Biomarker data confirm CD73 target engagement in plasma. Adenosine pathway modulation in tumors and plasma was seen post-NZV930 tx.
Conclusions: NZV930 reduced adenosine levels in plasma and tumors. The RDE of NZV930 SA or in combination with spartalizumab and/or taminadenant is 600 mg Q2W with a step-up dosing regimen. NZV930 SA and its combinations exhibited a tolerable safety profile in multiple advanced solid tumors and showed good PK properties.
Citation Format: Siqing Fu, Udai Banerji, Philippe L. Bedard, Aitana Calvo Ferrándiz, Alberto Chiappori, Jayesh Desai, Rahima Jamal, Desamparados Roda Perez, Noboru Yamamoto, Erica Vieira, Gabrielle Wong, Kulandayan K. Subramanian, Shunguang Wang, Britta Mueller, Javier A. Otero, Si-Lin Koo. A phase I/Ib study of the safety and preliminary efficacy of NZV930 alone and in combination with spartalizumab and/or taminadenant in patients (pts) with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT503.