Phase I Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Dosimetry, and Preliminary Activity of [177Lu]Lu-NNS309 in Patients With Pancreatic, Lung, Breast and Colorectal Cancers

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Overview

[177Lu]Lu-NNS309 (also called FXX489) is an investigational FAP-targeted radioligand therapy being developed for solid tumors including pancreatic ductal adenocarcinoma (PDAC), non–small cell lung cancer (NSCLC), breast cancer, and colorectal cancer. A first‑in‑human, phase 1 open‑label, multicenter study (CFXX489A12101; NCT06562192) began on October 15, 2024 and is currently recruiting, with dose escalation ongoing as of April 2025. Eligibility requires uptake on the companion PET tracer [68Ga]Ga‑NNS309. Planned enrollment is 124 patients, with estimated study completion in June 2030. (novartis.com)

Mechanism of action

• Target: Fibroblast activation protein (FAP) expressed on cancer‑associated fibroblasts in many epithelial tumors; minimal expression in most normal tissues. (aacrjournals.org)
• Modality: A DOTA‑chelated lutetium‑177 radioligand that delivers β‑particle radiation to FAP‑expressing stromal cells with a proposed “cross‑fire” effect damaging adjacent tumor cells. (aacrjournals.org)
• Ligand properties: FXX489 was optimized using mRNA display and FAP co‑crystal structures to increase tumor retention and improve the tumor/kidney ratio versus earlier FAP ligands; it binds human and mouse FAP with sub‑10‑pM affinity and shows high selectivity over related proteases such as DPP4. (aacrjournals.org)

Clinical development status

• Trial design: Phase 1, dose escalation followed by expansion in PDAC, NSCLC, HR+/HER2‑ ductal and lobular breast cancer, triple‑negative breast cancer, and colorectal cancer. Patients are first imaged with [68Ga]Ga‑NNS309 PET/CT; eligible patients then receive [177Lu]Lu‑NNS309 on 4‑ or 6‑week schedules. Bayesian model–based escalation with dosimetry informs recommended dose(s). The study is currently enrolling in dose escalation. (aacrjournals.org)
• Sponsor/site information and timelines: Novartis Pharmaceuticals; recruiting with a target of 124 participants; study start October 15, 2024; estimated primary completion June 25, 2030. (novartis.com)

Efficacy

• As of October 7, 2025, there are no peer‑reviewed human efficacy results reported for [177Lu]Lu‑NNS309. The ongoing phase 1 trial lists preliminary antitumor activity as a secondary objective; no response‑rate data have been disclosed. Preclinical data cited by AACR abstracts report antitumor activity in translational models (e.g., PDAC, NSCLC), but these are not clinical outcomes. (aacrjournals.org)

Safety

• No human safety results have been published yet. The phase 1 study’s primary objectives include safety and tolerability assessment, organ/tumor dosimetry, and identification of recommended dose(s); results are pending while dose escalation is ongoing. (aacrjournals.org)

Further reading

• AACR abstract (mechanism/ligand optimization): “FXX489, a FAP targeting ligand with best‑in‑class potential for radioligand therapy.” Cancer Research 2025;85(8_Suppl_2):ND07. (aacrjournals.org)
• AACR abstract (clinical trial design/status): “Phase I open‑label, multi‑center study to evaluate the safety, tolerability, dosimetry, and preliminary activity of FXX489 ([177Lu]Lu‑NNS309).” Cancer Research 2025;85(8_Suppl_2):CT112. (aacrjournals.org)
• Novartis trial listing (NCT06562192) with status, eligibility, timelines. (novartis.com)

Note: No human efficacy or safety outcomes have been publicly reported for [177Lu]Lu‑NNS309 as of the dates cited above. (aacrjournals.org)

Last updated: Oct 2025

Overview

[68Ga]Ga‑NNS309 is an investigational PET imaging agent designed to visualize fibroblast activation protein (FAP) expression, typically on cancer‑associated fibroblasts across many epithelial tumors. It is being clinically paired with the therapeutic radioligand [177Lu]Lu‑NNS309 (also called FXX489 when referring to the underlying ligand) in a first‑in‑human Phase 1 trial where [68Ga]Ga‑NNS309 PET is used to select patients and characterize imaging properties before treatment with [177Lu]Lu‑NNS309. As of October 7, 2025, no peer‑reviewed human imaging results specific to [68Ga]Ga‑NNS309 have been published. (novartis.com)

Mechanism of action

• Target: Fibroblast activation protein (FAP), highly expressed on cancer‑associated fibroblasts and limited in most normal tissues. (aacrjournals.org)
• Ligand: NNS309 (also referenced as FXX489) is a peptide‑based FAP ligand optimized for very high affinity (<10 pM in preclinical assays) and selectivity versus related proteases; it was engineered to improve tumor retention compared with earlier FAP ligands. The same ligand can be labeled with diagnostic 68Ga for PET or therapeutic 177Lu for radioligand therapy. (aacrjournals.org)
• Imaging rationale: [68Ga]Ga‑NNS309 binds FAP in the tumor stroma, enabling PET visualization of FAP‑expressing lesions and informing eligibility and dosimetry planning for the therapeutic counterpart. (novartis.com)

Clinical status

• Ongoing trial: NCT06562192 is a Phase 1, open‑label, multicenter study (start October 15, 2024; planned completion June 26, 2030; target n=124) in PDAC, NSCLC, HR+/HER2‑ and triple‑negative breast cancer, and colorectal cancer. All measurable lesions must show uptake on [68Ga]Ga‑NNS309 PET/CT or PET/MRI to proceed to [177Lu]Lu‑NNS309 treatment. Sites in the United States include MGH, UCLA, Stanford, MD Anderson, University of Washington, and BAMF Health. (novartis.com)
• Conference reports: AACR 2025 abstracts describe the program and preclinical data supporting FAP targeting and improved tumor retention for the NNS309/FXX489 ligand; they also outline the clinical design requiring [68Ga]Ga‑NNS309 uptake for eligibility. (aacrjournals.org)

Efficacy

• Human efficacy data for [68Ga]Ga‑NNS309 imaging (e.g., lesion detection rates, uptake metrics) have not been published as of this date. The ongoing Phase 1 study is designed to characterize imaging properties of [68Ga]Ga‑NNS309 and to assess preliminary antitumor activity of [177Lu]Lu‑NNS309 in patients selected by [68Ga]Ga‑NNS309 PET. (novartis.com)

Safety

• No standalone human safety results for [68Ga]Ga‑NNS309 have been published yet. The Phase 1 protocol includes evaluation of safety and radiation dosimetry for [68Ga]Ga‑NNS309 in addition to the therapeutic agent. (novartis.com)

Further reading

• Phase 1 study description and participating sites for [68Ga]Ga‑/ [177Lu]Lu‑NNS309 (NCT06562192). (novartis.com)
• AACR 2025 clinical abstract: Phase I study design for FXX489 ([177Lu]Lu‑NNS309) requiring [68Ga]Ga‑NNS309 PET uptake. (aacrjournals.org)
• AACR 2025 invited abstract: Preclinical profile of FXX489/NNS309 as a high‑affinity, selective FAP ligand with improved tumor retention. (aacrjournals.org)
• Reagent overview indicating NNS309 (FXX489) can be labeled with 68Ga and 177Lu. (targetmol.com)

Note: Several peer‑reviewed articles exist on FAP‑targeted radiotheranostics in general, but program‑specific, peer‑reviewed human data for [68Ga]Ga‑NNS309 have not yet appeared as of October 7, 2025. (pubmed.ncbi.nlm.nih.gov)

Last updated: Oct 2025

Inclusion Criteria:

* Age ≥ 18 years old

* Patients with one of the following indications:

* Locally advanced unresectable or metastatic PDAC with disease progression following, or intolerance to cytotoxic chemotherapy, unless patient was ineligible to receive such therapy

* Locally advanced unresectable or metastatic NSCLC without any actionable genomic alterations with disease progression following, or intolerance to chemotherapy and immunotherapy, unless patient was ineligible to receive such therapy, or locally advanced unresectable or metastatic NSCLC with an actionable genomic alteration with disease progression following, or intolerance to targeted therapy, unless patient was ineligible to receive such therapy

* Locally advanced unresectable or metastatic HR+/HER2- ductal or lobular BC with disease progression following, or intolerance to, at least 2 lines of therapy, unless patient was ineligible to receive such therapy

* Locally advanced unresectable or metastatic TNBC with disease progression following, or intolerance to, at least 2 lines of therapy, unless patient was ineligible to receive such therapy

* (Dose escalation part only) Locally advanced or metastatic unresectable CRC with disease progression following, or intolerance to cytotoxic chemotherapy, unless patient was ineligible to receive such therapy. Patients with known microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) status must also have had disease progression following, or intolerance to immune checkpoint inhibitor therapy, unless patient was ineligible to receive such therapy

* Patients must have lesions showing 68Ga-NNS309 uptake

Exclusion Criteria:

* Absolute neutrophil count (ANC) \< 1.5 x 109/L, hemoglobin \< 9 g/dL, or platelet count \< 100 x 109/L

* QT interval corrected by Fridericia's formula (QTcF) ≥ 470 msec

* Creatinine clearance \< 60 mL/min

* Unmanageable urinary tract obstruction or urinary incontinence

* Radiation therapy within 4 weeks prior to the first dose of \[177Lu\]Lu-NNS309

Other protocol-defined inclusion/exclusion criteria may apply.