Noninvasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer
Sai Kiran Sharma1,2, Jacob Pourat1,2, Dalya Abdel-Atti1,2
1Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T; SC16LD6.5) is a first-in-class DLL3-targeted antibody-drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, although orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC. We developed 89Zr-labeled SC16 antibody as a companion diagnostic agent to facilitate selection of patients for treatment with Rova-T based on a noninvasive interrogation of the in vivo status of DLL3 expression using PET imaging. Despite low cell-surface abundance of DLL3, immunoPET imaging with 89Zr-labeled SC16 antibody enabled delineation of subcutaneous and orthotopic SCLC tumor xenografts as well as distant organ metastases with high sensitivity. Uptake of the radiotracer in tumors was concordant with levels of DLL3 expression and, most notably, DLL3 immunoPET yielded rank-order correlation for response to SC16LD6.5 therapy in SCLC patient-derived xenograft models. Cancer Res; 77(14); 3931-41. ©2017 AACR.
Insights
A novel PET imaging agent targeting DLL3 (a biomarker for small cell lung cancer) successfully identified tumors and metastases. This diagnostic tool correlates with treatment response to Rovalpituzumab teserine (Rova-T).
Area of Science:
- Oncology
- Molecular Imaging
- Biomarker Development
Background:
- DLL3 is a therapeutic target in small cell lung cancer (SCLC) and neuroendocrine carcinomas.
- Rovalpituzumab teserine (Rova-T) is an antibody-drug conjugate targeting DLL3, showing promise in SCLC treatment.
- DLL3 expression, though low on the cell surface, can serve as an imaging biomarker for SCLC.
Purpose of the Study:
- To develop a companion diagnostic agent for Rova-T therapy selection.
- To validate DLL3 as an in vivo imaging biomarker for SCLC using PET imaging.
- To assess the utility of 89Zr-labeled SC16 antibody for noninvasive DLL3 detection.
Main Methods:
- Development of 89Zr-labeled SC16 antibody for immunoPET imaging.
- Imaging of subcutaneous and orthotopic SCLC xenografts and metastases.
- Correlation of radiotracer uptake with DLL3 expression levels and treatment response in patient-derived xenograft models.
Main Results:
- 89Zr-labeled SC16 immunoPET successfully delineated SCLC tumors and metastases with high sensitivity, despite low DLL3 cell-surface abundance.
- Radiotracer uptake in tumors was concordant with in vivo DLL3 expression levels.
- DLL3 immunoPET showed a rank-order correlation with response to Rova-T therapy in SCLC models.
Conclusions:
- 89Zr-labeled SC16 antibody immunoPET is a sensitive method for noninvasively imaging DLL3 expression in SCLC.
- This DLL3-targeted PET imaging agent can serve as a companion diagnostic for Rova-T therapy.
- ImmunoPET imaging of DLL3 holds potential for patient selection and monitoring treatment response in SCLC.
