Positron emission tomography (PET) is an imaging method that employs injected radioactive tracers to visualize and measure changes in metabolic processes, physiologic processes (e.g., blood flow), and even disease associated antigens. The tracers emit gamma rays that are detected by scanners to form images that can be combined with computed tomography or magnetic resonance scans to generate a 3D image. Because PET can show how tissues are working at a cellular level, this method can often detect disease onset before other imaging methods can. PET has become widely used for detecting the extent of cardiac damage following a heart attack and for pinpointing metastases in several cancers, notably lung, lymphoma, colorectal, melanoma, and head and neck. Now, sensitive antigen-specific tracers are further extending PET usefulness in other settings, including prostate cancer and Alzheimer’s disease (AD).
In oncology, PET imaging using the fluorodeoxyglucose (FDG) tracer has been widely used for diagnosing many cancers. Tumor cells require higher levels of glucose than healthy ones, leading the glucose-based tracer to accumulate at high levels in malignant tissues, making them detectable via PET. However, this method has been inadequate for detecting occult disease (i.e., a small tumor showing no signs or symptoms of its existence) especially in men with prostate cancer who exhibit low PSA (prostate specific antigen) levels (under 2ng/mL).
New, more sensitive, tumor antigen-targeting tracers, such as the Gallium-68 PSMA-11 (prostate specific membrane antigen) tracers first developed by the University of Heidelberg, are now further extending the usefulness of PET in the prostate cancer setting. The use of PSMA PET/CT has greatly increased since its introduction in 2014, especially in Australia, where it has become a standard within the treatment paradigm of prostate cancer. Most Australian nuclear medicine departments have their own gallium generators, making the tracer quick, easy and inexpensive to manufacture and deliver. Thus, PSMA PET/CT scans are available at all public university hospitals and many private healthcare providers at an affordable cost equivalent to about $500.
Until now, PSMA PET/CT scans have lagged in the United States due to more limited availability and higher expense, with costs ranging from $1,250 to $9,225. But with several PSMA PET/CT imaging agents that show superiority over conventional imaging methods gaining or close to FDA approval, this diagnostic tool is expected to become a standard in the United States as well over the next several years.
In December 2020, the FDA approved the use of Gallium-based PSMA PET/CT in prostate cancer management, but only at the University of California, Los Angeles and University of California, San Francisco. A few other major medical centers are using the procedure, but only on an investigational basis as part of a clinical trial; each center must apply for its own approval. Telix Pharmaceuticals filed an NDA in September 2020 for TLX591-CDX, a radiopharmaceutical cold kit for preparation of the Gallium-68 PSMA-11 PET tracer; approval of that product by the FDA could help increase the use of PSMA PET/CT in the United States.
Moreover, several new PSMA PET imaging agents are being investigated as potential diagnostic / monitoring / staging tools for prostate cancer patients. In December 2020, the FDA granted Priority Review to an NDA from Lantheus Holdings, the parent company of Lantheus Medical Imaging and Progenics Pharmaceuticals, for their PyL (Fluorine-18 DCFPyL) PSMA-targeted prostate cancer PET Imaging agent; a decision from the FDA is expected in late May 2021. PyL PET enables the visualization of both localized prostate cancer as well as distant bone and soft tissue metastases with high specificity and sensitivity.
The PyL NDA is supported by data from two pivotal studies, OSPREY and CONDOR. Results from the OSPREY study demonstrated an improvement in specificity and positive predictive value of PyL PET imaging over conventional imaging methods in men with high-risk prostate cancer, and also showed the sensitivity of PyL PET imaging in detecting metastases in a variety of prostate cancer disease states. The CONDOR study, conducted in patients with recurrent prostate cancer and non-informative baseline PSA findings, showed PyL PET imaging’s ability to correctly detect and localize prostate cancer lesions with high specificity, including in patients with low PSA values. Moreover, the study showed that the intended disease management plans for 63.9% of the participating men changed as a result of their imaging findings, suggesting the value of PyL PET to improve patient management. Such changes included moving a patient from salvage local therapy to systemic therapy (or vice versa), or from watchful waiting to treatment (or vice versa).
PET has also been increasingly used as both a research and clinical tool for diagnosing certain brain diseases including dementia, stroke, and traumatic brain injury. Notably, PET imaging has become an important component of AD diagnosis and an essential tool in clinical trials evaluating potential new treatments for the condition. In 2012, Avid Radiopharmaceuticals, now part of Eli Lilly, gained approval for AMYVID, the first PET imaging agent used for estimating the density of beta amyloid plaques, one of the two hallmarks of AD pathology. Two other amyloid imaging agents from GE Healthcare and Piramal Imaging have since received approval. In December 2020, Lilly initiated its New IDEAS study to compare the three approved PET amyloid plaque imaging agents in their ability to detect and measure beta amyloid, as well as to expand insights to under-represented ethnic populations at higher-than-average risk of AD.
Researchers have now turned to another hallmark of AD pathology, the TAU protein and the neurofibrillary tangles that can be found in the brains of AD patients, as a target for drug development and potential biomarker. In May 2020, Lilly/Avid received FDA approval for TAUVID (fluoraucipir F18 injection) as the first PET agent for imaging TAU tangles in the brain. Results of two clinical studies in normal and cognitively impaired, terminally ill patients showed high sensitivity (92-100%), moderate-to-good specificity (52-92%) for TAUVID and good agreement between scan readers (0.87), across 241 patients. Together, PET imaging with both AMYVID and TAUVID are expected to allow a more comprehensive evaluation of AD patients, leading to improved diagnosis, disease monitoring, and treatment decisions.