PURPOSE: Fibroblast activation protein (FAP) is an attractive target for radiopharmaceutical therapy. Phase I of the LuMIERE study (ClinicalTrials.gov, NCT04939610) investigated the safety of 177LuLu-FAP-2286 (177Lu-FAP-2286) in heavily pretreated patients with advanced solid tumors and identified the recommended phase II dosage (RP2D). PATIENTS AND METHODS: LuMIERE is a prospective, open-label, non-randomized, phase I/II, multicenter study. Phase I followed a Bayesian optimal interval design evaluating four escalating activity levels of 177Lu-FAP-2286 (3.70, 5.55, 7.40, and 9.25 GBq). Patients were selected by positive 68GaGa-FAP-2286 (68Ga-FAP-2286, also known as 68GaGa-HKG301) PET/CT imaging on all target lesions (SUVmax ≥1.5× SUVmean of mediastinal blood pool). 177Lu-FAP-2286 was administered intravenously every 6 weeks for ≤6 cycles. The primary endpoint was dosage-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs). RESULTS: Of 35 patients imaged with 68Ga-FAP-2286, 27 received 177Lu-FAP-2286 (3.70 GBq, n=3; 5.55 GBq, n=6; 7.40 GBq, n=7; 9.25 GBq, n=11). Two DLTs were observed: one patient who received 5.55 GBq of 177Lu-FAP-2286 experienced Grade 4 lymphopenia and one patient who received 9.25 GBq experienced Grade 3 hemoptysis; these were the only treatment-related Grade ≥3 TEAEs. All-cause Grade ≥3 TEAEs were reported for 11 patients (40.7%). The RP2D for 177Lu-FAP-2286 monotherapy was determined as 9.25 GBq. Preliminary RECIST efficacy findings demonstrated partial response in one patient and stable disease in 10 patients (maintained for at least two assessments in six patients). CONCLUSIONS: 177Lu-FAP-2286 was well tolerated in patients with advanced solid tumors. The safety and preliminary efficacy findings support its continued development in phase II.
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