Journal Article

Imaging with 89ZrZr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial

Kirov, Assen, Rekhtman, Natasha, Morris, Michael J, Aly, Rania G, Poirier, John T, Lyashchenko, Serge K, Rudin, Charles M, Bodei, Lisa, Baine, Marina K, O'Donoghue, Joseph, Mauguen, Audrey, Schoder, Heiko, Agee, Matthew, Tendler, Salomon, Kesner, Adam, Dunphy, Mark P, Weber, Wolfgang A, Choudhury, Noura J, Lewis, Jason S

2024

Overview

Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0–2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37–74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3–6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23–81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3–6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adult / Aged / Aged, 80 and over / Allergies / Androgens / Antibodies / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - chemistry / Antibodies, Monoclonal, Humanized / Benzodiazepinones / Biopsy / Chromatography / Computed tomography / Deferoxamine / Deferoxamine - chemistry / Drug dosages / Female / Hematology, Oncology, and Palliative Medicine / Humans / Immunoconjugates - pharmacokinetics / Immunohistochemistry / Intracellular Signaling Peptides and Proteins / Ligands / Lung cancer / Lung Neoplasms - diagnostic imaging / Lung Neoplasms - drug therapy / Lung Neoplasms - immunology / Lung Neoplasms - pathology / Male / Malignancy / Medical imaging / Membrane Proteins - immunology / Membrane Proteins - metabolism / Metastasis / Middle Aged / Neoplasm Grading / Neuroendocrine tumors / Neuroendocrine Tumors - diagnostic imaging / Neuroendocrine Tumors - drug therapy / Neuroendocrine Tumors - immunology / Neuroendocrine Tumors - pathology / Non-small cell lung carcinoma / Patients / Positron emission tomography / Positron Emission Tomography Computed Tomography / Prostate cancer / Prostatic Neoplasms - diagnostic imaging / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - immunology / Prostatic Neoplasms - pathology / Radioisotopes / Radiopharmaceuticals / Small cell lung carcinoma / Zirconium