68Ga-PFD3 PET Imaging for the Diagnosis and Evaluation of Small Cell Lung Cancer

Small cell lung cancer (SCLC) constitutes approximately 15% of all lung cancers and is characterized by its aggressive biology, rapid growth, and early, widespread metastasis. It is highly lethal, with a 5-year survival rate of less than 7% for patients with extensive-stage disease. The current standard of care relies on the clinical staging of patients as either limited-stage (LS-SCLC) or extensive-stage (ES-SCLC), which fundamentally dictates therapeutic strategies. LS-SCLC, where disease is confined to a single radiation port, is potentially curable with concurrent chemoradiotherapy. Conversely, ES-SCLC, with metastases beyond a single radiation field, is treated primarily with systemic chemotherapy. Accurate staging is therefore critical for optimal patient management.

\[18F\]-FDG PET/CT is a cornerstone for staging SCLC due to its high sensitivity in detecting metabolically active tumor sites, including occult metastases. This capability has significantly improved the accuracy of distinguishing LS-SCLC from ES-SCLC, thereby guiding appropriate use of definitive radiotherapy. However, the clinical utility of \[18F\]-FDG-PET/CT is hampered by its suboptimal specificity. FDG avidity is common in inflammatory processes and other malignancies, leading to false-positive interpretations, particularly in lymph nodes. This limitation can result in overstaging, causing a subset of patients with truly limited-stage disease to be incorrectly classified as extensive-stage. Consequently, these patients may be denied potentially curative radiotherapy and receive only palliative chemotherapy, representing a significant missed therapeutic opportunity. There is a clear unmet need for a more specific imaging agent for SCLC.

Delta-like ligand 3 (DLL3) is a cell-surface protein that is rarely expressed in healthy adult tissues but is overexpressed in over 80% of SCLC cases, as well as in other high-grade neuroendocrine tumors (e.g., neuroendocrine prostate cancer, neuroendocrine tumors of the gastrointestinal tract). Its highly restricted expression profile makes DLL3 an exceptionally promising target for both diagnosis and therapy. Several DLL3-targeted therapeutic agents, such as antibody-drug conjugates (e.g., rovalpituzumab tesirine) and bispecific T-cell engagers, are in development or clinical trials. Therefore, an imaging probe for detecting DLL3 expression could not only aid in diagnosis and staging but also serve as a biomarker to select patients most likely to benefit from these targeted therapies-a concept known as patient stratification for theranostics.

To translate this target into imaging, the probe must have favorable pharmacokinetics. Nanobodies, derived from camelid single-domain antibodies, are approximately 15 kDa in size, significantly smaller than conventional monoclonal antibodies (\~150 kDa). This small size confers several advantages for imaging: superior tissue penetration, rapid clearance from the bloodstream, and reduced immunogenicity. PFD3 is a novel probe constructed by conjugating a DLL3-specific nanobody with a chelator for 68Ga radiolabeling. This design offers dual advantages: first, the high affinity and specificity of the nanobody for DLL3 ensure targeted accumulation in tumors, minimizing off-target binding. Second, the nanobody's pharmacokinetics result in a shorter in vivo residence time compared to monoclonal antibody-based probes, enabling same-day imaging protocols with enhanced patient convenience and potentially improved safety profiles due to more predictable radiopharmaceutical retention. Furthermore, the growing pipeline of DLL3-directed therapeutics makes the development of an accompanying diagnostic tool like PFD3 clinically relevant for both patient selection and treatment monitoring.

Given this background, this study aims to evaluate the safety and imaging performance of \[68Ga\]Ga-PFD3 PET/CT in human subjects with SCLC. Furthermore, a head-to-head comparison between \[68Ga\]Ga-PFD3 PET/CT and the widely used \[18F\]-FDG PET/CT will be conducted to determine the relative diagnostic performance of this novel, target-specific tracer.

• Imaging performance of [68Ga]Ga-PFD3 PET/CT [Time frame: Baseline]
• Progression-free survival [Time frame: From baseline PET/CT imaging to disease progression or death, assessed up to 12 months post-imaging]
• Overall Survival [Time frame: Through study completion, an average of 13 months]