NEW YORK – As the burgeoning radiopharmaceutical market advances at a rapid pace, oncologists and drugmakers are homing in on a promising target, the fibroblast activation protein (FAP), which they say could bring theranostics to a wide variety of solid tumors.
At one cancer center in India, the benefit seen across solid tumors with a FAP-inhibiting radiopharmaceutical provides insight into why drugmakers are investing in this theranostic class.
During the annual meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) this week, Kumaraswamy Kallur, the director of nuclear medicine at the HealthCare Global (HCG) Hospital in Bengaluru, India, shared findings from his cancer center's initial experience with both diagnostic and therapeutic radiopharmaceuticals targeting FAP across multiple solid tumors.
The HCG hospital began conducting PET scans using FAP-targeted imaging agents in 2019, according to Kallur, and since then it has conducted close to 16,000 of these scans. At the SNMMI meeting, Kallur walked through his center's experience using the scan to identify patients with FAP-positive tumors and treat them with a radionuclide comprising the FAP-targeting ligand FAP 9 — which Kallur's department at HCG developed in-house — linked to therapeutic radioisotopes actinium-225 or lutetium-177, instead of the gallium-68 isotope used for imaging.
FAP has been shown to cause increased cancer cell migration, promote angiogenesis, and lead to chemotherapy resistance, Kallur said. Accordingly, high FAP expression can mean a poorer prognosis for patients with a wide variety of cancer types.
"Based on this, we wanted to see how we could apply theranostics in FAP," he said. In 2019, Kallur and his colleagues got the go-ahead from HCG's ethics committee to evaluate FAP inhibitors linked to either a diagnostic radioactive isotope or a therapeutic radioactive isotope for patients with advanced solid tumors.
Patients could have any type of metastatic cancer to be eligible for the study, though their cancers had to have progressed on chemotherapy, immunotherapy, or any other targeted therapy. To be eligible for the therapeutic FAP-targeting radioligand, the patients' tumors had to be confirmed as FAP-positive via imaging.
Kallur and colleagues also incorporated a post-theranostic treatment regimen through which they administered additional systemic therapies a week following the FAP-targeting radiopharmaceutical. "Because by that time [after the lutetium-based theranostic], we've now caused some destruction in tumor microenvironment, creating a hot tumor where the tumors are more susceptible to immunotherapy or chemotherapy," he said, highlighting the case of one advanced colorectal cancer patient who did not receive chemotherapy after the FAP-targeted therapy and did not seem to derive much benefit from the theranostic alone. Additionally, patients could receive repeat FAP-targeting radioligand therapy eight to 10 weeks later if their tumors were still FAP-positive in imaging scans.
"We did not see any significant or serious adverse reactions," he said, noting there was a low red blood cell count, but it was likely associated with the chemotherapy administered after FAP inhibitor (FAPI) therapy.
Patients with a wide range of solid tumor types received treatment on Kallur's study, including those with tongue, liver, bile duct, kidney, pancreatic, esophageal, lung, neuroendocrine, prostate, colon, and ovarian cancers, among others. Kallur said he is also waiting for the results from a patient with dendritic cell sarcoma, a rare soft-tissue tumor, for which there is no available treatment.
Kallur shared data from HCG's initial experience treating 69 patients with lutetium-linked FAPI and 28 with actinium-linked FAPI.
The median survival time for patients treated with the lutetium FAPI was 22.3 months, and for patients treated with actinium 225-linked FAPI, the median survival time was 12 months. The lutetium-linked FAP 9 had what Kallur called a "residence time" or seven to 10 days, meaning that's how long it was retained in the tumor.
"Why was it less in actinium? It's because this cohort of patients was very, very sick compared to the lutetium FAPI cohort," Kallur said, preempting questions about the discrepancy.
Separate from the documented survival data, Kallur pointed out observed palliative effects with the radiopharmaceuticals. Almost all patients experience an improvement in their pain levels, he said, and their tumor-associated fevers went away. In several patients, he said the palliative effect was almost immediate with significant pain reduction noted within 24 hours.
Going forward, Kallur and colleagues are developing two other ligands, FAPI-18 and FAPI-27, and designing three more clinical studies, in which to evaluate them. They are also keeping an eye on the FAP ligands, including FAPI-46, that Dulles, Virginia-based Sofie Biosciences is assessing in diagnostic radiopharmaceutical studies.
Sofie is just one of several companies that have thrown their hats in the ring with FAP-targeting radiopharmaceuticals. Singapore-based Yantai LNC Biotechnology, for instance, is evaluating 177Lu-LNC1004, its own FAP-targeted radiopharmaceutical, in a Phase I trial involving solid tumor patients who are screened for FAP expression using Sofie's gallium-based FAPI-46 PET imaging agent.
The year-old company Ratio Therapeutics has plans to bring FAP-targeted radiopharmaceuticals to the clinic, too.
And in recent years, perhaps the biggest pharmaceutical player in the radiopharmaceutical space, Novartis, has inked licensing deals to bring smaller biotechs' FAP-targeted radiopharmaceuticals into its pipeline. The firm inked a deal with Sofie in 2021, through which it acquired the right to develop the FAPI-46 and FAPI-74 ligands for therapeutic uses. In that same deal, Novartis and Sofie agreed to share the rights to develop those ligands for imaging uses.
Then, toward the end of 2022, when Clovis Oncology filed for bankruptcy, Novartis scooped up that firm's FAP-targeting radioligand candidate, FAP-2286, too. In April 2023, Novartis expanded that licensing deal to acquire worldwide rights to 3B Pharmaceuticals' whole FAP-targeting technology platform, which had included the FAP-2286 ligand Clovis sold to Novartis.
Now, Novartis is the sole sponsor of the ongoing Phase I clinical trial, LuMIERE, in which it is evaluating the lutetium-linked 188Lu-FAP-2286 as a treatment for patients with FAP-positive solid tumors, as determined according to the gallium-linked FAP PET imaging agent, 68Ga-FAP-2286.
HCG's Kallur mentioned Novartis' trial in his SNMMI presentation, noting that, in the dose-escalation portion of LuMIERE, Novartis is just now enrolling patients to receive dosages of up to 200 millicuries (mci) of lutetium-177, whereas his center has administered up to 285 mci doses for the lutetium-based therapeutics, with an average dose of 250 mci. Novartis has yet to report any efficacy data from the LuMIERE trial.