Abstract CT017: First-in-human PET imaging with the PD-L1 antibody 89Zr-atezolizumab
Authors: Bensch Frederike , Veen Elly van der , Jorritsma Annelies , Hooge Marjolijn Lub-de , Boellaard Ronald , Oosting Sjoukje , Schröder Carolien , Hiltermann Jeroen , Wekken Anthonie van der , Groen Harry , Fine Bernard , McKnight Nathan , Bohorquez Sandra Sanabria , Williams Simon , Veronese Luisa , Mancao Christoph , Brouwers Adrienne H. , Vries Elisabeth de 
Published: July 2017

Abstract
Background: Programmed death-ligand 1 (PD-L1) expression has been associated with response to PD-1/PD-L1 inhibition, but responses are also seen in patients with PD-L1 negative tumors when assessed immunohistochemically (IHC) with various antibodies. To help understand these findings, we performed a first-in-human positron emission tomography (PET) imaging study with the anti-PD-L1 antibody atezolizumab labeled with zirconium-89 (89Zr) prior to treatment with atezolizumab to assess normal organ distribution and evaluate tumor tracer uptake in relation to PD-L1 IHC in archival and post-tracer tumor specimen and ultimately to treatment response. Methods: Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), bladder cancer (BC) or triple-negative breast cancer (TNBC) received 10 mg unlabeled atezolizumab plus 37 MBq 89Zr-atezolizumab (~1 mg) followed by up to 4 PET scans (1 hour, days 2, 4 and 7 post-injection (pi)). Next, after obtaining a tumor biopsy for PD-L1 IHC 8-10 days after tracer injection, patients received atezolizumab (1200 mg) i.v. once every 3 weeks until disease progression (NCT02453984 and NCT02478099). Response was assessed every 6 weeks with RECIST1.1. Normal organ tracer uptake was calculated as percentage of the injected dose/kg (%ID/kg) 4 and 7 days pi, tumor tracer uptake as maximum standardized uptake value (SUVmax) and %ID/kg 7 days pi. Tumor biopsy PD-L1 expression was assessed in tumor cells (TC) and tumor infiltrating immune cells (IC) by HistoGeneX IHC with the SP142 assay (Ventana). Results: In this ongoing trial, 16/25 patients completed the PET series and received atezolizumab at least until the first response assessment. The median follow-up of these patients is 16 weeks (6-40+, NSCLC=6, BC=8, TNBC=2). The highest normal organ 89Zr-atezolizumab uptake was seen in the spleen (16.3±3.6 %ID/kg 4 days and 17.9±3.6 %ID/kg 7 days pi), and uptake in other lymphatic organs (single normal lymph nodes and tonsil) and sites of (chronic) inflammation (e.g. chronic sinusitis and bursitis) were detected. Uptake in liver, kidney and intestine was similar to other antibodies with 7.3±1.6, 5.5±2.0 and 4.7±2.4 %ID/kg, respectively, 7 days pi. Tumor SUVmax ranged between 1.6 and 46.0 (1.8-12.4 %ID/kg), with an up to 9-fold difference within patients, and 4-fold difference between patients. In 4 biopsied lesions with IC/TC 0, 89Zr-atezolizumab uptake calculated as SUVmax was 10.0±3.6 (7.1±1.6 %ID/kg). At this time only 4 biopsies had a IHC score of 2+ on either IC or TC, and there were no biopsies with a score of 3+, limiting the ability to determine correlation of PD-L1 IHC to imaging data. Conclusion: 89Zr-atezolizumab imaging showed high uptake in normal spleen, other normal lymphoid organs and regions of inflammation. Uptake in tumor lesions was heterogeneous within and between patients and even PD-L1 IHC 0 tumors showed clear tracer uptake.
Citation Format: Frederike Bensch, Elly van der Veen, Annelies Jorritsma, Marjolijn Lub-de Hooge, Ronald Boellaard, Sjoukje Oosting, Carolien Schröder, Jeroen Hiltermann, Anthonie van der Wekken, Harry Groen, Bernard Fine, Nathan McKnight, Sandra Sanabria Bohorquez, Simon Williams, Luisa Veronese, Christoph Mancao, Adrienne H. Brouwers, Elisabeth de Vries. First-in-human PET imaging with the PD-L1 antibody 89Zr-atezolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT017. doi:10.1158/1538-7445.AM2017-CT017