A new tracer for use in PET imaging can detect more metastases in patients with cancer than the standard tracer, leading to predictions of a “paradigm shift” in this field.

The new tracer, 68Ga-FAPI, detected more metastases in patients with lung cancer than the standard tracer, 18F-FDG, which has been in use for years.

The study by Chinese researchers was published in Radiology.

The team imaged 34 lung cancer patients with both 68Ga-FAPI and 18F-FDG. Performance was similar for primary tumors and for lung, liver, and adrenal gland metastases. However, FAPi imaging detected more metastases in the lymph nodes (356 vs 320), brain (23 vs 10), bone (109 ves 91), and pleura (66 vs 35). However, neither modality outperformed MRI for brain metastases, the researchers note.

An accompanying editorial concluded that 68Ga-FAPI PET/CT scanning marks “an important paradigm shift to more specific identification and characterization of a variety of cancers.”

“This may also mark the arrival of a new era in nuclear medicine where molecular imaging helps visualize and characterize the entire tumor burden in one setting,” write editorialists Francine Jacobson, MD, and Annick Van den Abbeele, MD, from Harvard University and Brigham and Women’s Hospital and the Dana Farber Cancer Center, in Boston, Massachusetts.

A new tracer for use in PET imaging can detect more metastases in patients with cancer than the standard tracer, leading to predictions of a “paradigm shift” in this field.

The study by Chinese researchers was published in Radiology.

The team imaged 34 lung cancer patients with both 68Ga-FAPI and 18F-FDG. Performance was similar for primary tumors and for lung, liver, and adrenal gland metastases. However, FAPi imaging detected more metastases in the lymph nodes (356 vs 320), brain (23 vs 10), bone (109 vs 91), and pleura (66 vs 35). Neither modality outperformed MRI for brain metastases, the researchers note.

An accompanying editorial concluded that 68Ga-FAPI PET/CT scanning marks “an important paradigm shift to more specific identification and characterization of a variety of cancers.”

“This may also mark the arrival of a new era in nuclear medicine where molecular imaging helps visualize and characterize the entire tumor burden in one setting,” write editorialists Francine Jacobson, MD, and Annick Van den Abbeele, MD, from Harvard University and Brigham and Women’s Hospital and the Dana Farber Cancer Center, in Boston, Massachusetts.

This study was the one of the latest in a fast-growing body of literature reporting that tracers targeting fibroblast activation protein (FAP) with a small molecule inhibitor (FAPi) outperform fluoro-D-glucose (FDG) tracers, not just in lung cancer but across a broad range of cancers, including breast, hepatic, gastrointestinal, head-neck, gynecologic, and many other tumor types.

The possibilities aren’t limited to imaging, either. Several companies are planning trials to target FAP with radiopharmaceuticals.

FAP is associated with wound repair and is highly expressed by the fibroblasts tightly packed in with cancer cells, particularly in stroma-dense tumors. FAP is rarely expressed by healthy tissue.

The underlying idea is to deliver a radionuclide to cancer-associated fibroblasts, using either a positron emitter, such as gallium-68 (68Ga), for PET imaging or a beta particle or other short-radiation emitter to kill nearby cancer cells as part of treatment.

Targeting FAP holds the promise of PET imaging that is more selective for cancer than FDG. FDG resolution depends on glucose uptake, which is high in active tumors but is also high in inflamed tissues as well as in the brain, gastrointestinal tract, and other areas. Uptake by background tissue can make it difficult to distinguish tumors from their surroundings. FDG uptake can also be lower in small and indolent tumors.

On the therapy side, there’s hope that FAP targeting will lead to radiopharmaceuticals that work across tumor types, not just in specific cancers.

High Interest in FAP

Overall, FAP “is a target of high interest for the whole medical oncology community. The preliminary data are good, but this will take a while” to get to market, said Jeremie Calais, MD, a nuclear medicine specialist and FAP researcher at the University of California, Los Angeles.

Interest in FAP as a radiopharmaceutical target is being driven by the success of two agents that have served as a kind of proof of concept, Calais said.

The first is Novartis’s 177Lu-PSMA-617, which was granted priority review by the US Food and Drug Administration in September 2021 following phase 3 results that showed a progression-free survival benefit of about 5 months when added to standard of care for metastatic castration-resistant prostate cancer, as well as an overall survival benefit of 4 months.

PSMA-617 binds prostate cancer cells that express prostate-specific membrane antigen. The lutetium-177 (177Lu) bombards them with beta particles and gamma radiation.

FAP researchers are also encouraged by the success of 177Lu dotatate (Lutathera), from Advanced Accelerator Applications, which delivers the radionucleotide to gastroenteropancreatic neuroendocrine tumors that express somatostatin receptors.

FDA approved this agent in 2018 in part on the basis of phase 3 results that found a 20-month progression-free survival of 65.2% when Lutathera was added to octreotide for metastatic disease, vs 10.8% when it wasn’t.

Novartis is now looking into developing FAP targeted radiopharmaceuticals, along with Clovis and Point Biopharma, among others.

“That’s the key goal” of industry research, “more so than FAP as a diagnostic tool,” Calais commented to Medscape Medical News. There’s “huge potential” if it works out, Calais said, in part because it won’t be limited to one tumor type.

Clovis recently launched a phase 1/2 trial of its candidate, 177Lu-FAP-2286, for advanced/metastatic solid tumors.

In the company’s “luMIERE” trial, subjects will be infused with 68Ga-FAP-2286 to image the tumor. Once uptake is confirmed, they’ll be infused with 177Lu-FAP-2286 for treatment.

The two-step process ― uptake confirmation, then treatment ― is dubbed “theranostics” and is the standard approach for radiopharmaceutical therapy, Calais said.

His own team is working to confirm that imaging accurately reflects FAP expression in tumors by comparing pre-op imaging results with FAP expression on surgical specimens. So far, his team has found that they are strongly correlated.

FAPi PET imaging research is much farther along than therapeutic applications, with almost 200 research articles listed on PubMed in 2021, up from just three in 2018. One 2019 paper reported “remarkably high uptake and image contrast” across 28 cancers in 80 patients, including breast, esophagus, lung, pancreatic, head-neck, and colorectal tumors.

Imaging studies so far have tended to be small, with many currently focused on identifying the optimal molecule for targeting FAP and the best positron emitter to combine with it.

FAPi tracers are not available yet commercially, so researchers are creating them themselves. One team recently reported it’s recipe for automated synthesis using commercially available synthesis modules.

Sofie, a maker of FDG and other tracers, hopes to change that and is working to bring FAP tracers to market. The company announced in November 2021 a phase 2 study of 68Ga FAPI-46 to image pancreatic ductal adenocarcinoma. It’s the first step in a broader development program for oncologic and non-oncologic indications, Sofie said in a press release.

Calais sees potential for indications where FAPi has already outperformed FDG in the literature, particularly for gastrointestinal cancers. He doesn’t think it will ever replace FDG for indications such as lymphoma, where it “works perfectly well.”

“On the other hand, you have lesions located in a tissue that has some background level” of FDG uptake. “These things are okay with FDG, but I think maybe FAP can help” because of the improved signal-to-noise ratio, Calais commented. Unlike FDG, “you mostly never see background uptake with FAP imaging agents,” he said.

Other pluses include quicker distribution throughout the body than FDG, so scan times are shorter, and also patients do not need to fast beforehand.

Calais predicts that FAPi tracers will reach the market within 5 years.

Radiology. Published online January 4, 2022. Abstract, Editorial

M. Alexander Otto is a physician assistant with a master’s degree in medical science, and an award-winning medical journalist who has worked for several major news outlets before joining Medscape. He is an MIT Knight Science Journalism fellow. Email: [email protected]

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