Targeting Fibroblast Activation Protein with [177Lu]Lu-FAP-2286 in Patients with Advanced Solid Tumors in the Phase I LuMIERE Trial.
177Lu-FAP-2286 was well tolerated in patients with advanced solid tumors, with a recommended phase II dosage of 9.25 GBq.
Where it sits
this study against the rest of the vipivotide corpusSummary and findings
This study evaluated the safety of [177Lu]Lu-FAP-2286 in patients with advanced solid tumors and identified the recommended phase II dosage. A total of 27 patients received varying doses of the treatment. The study reported dosage-limiting toxicities and treatment-emergent adverse events.
Abstract
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 [177Lu]Lu-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, nonrandomized, 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 [68Ga]Ga-FAP-2286 (68Ga-FAP-2286, also known as [68Ga]Ga-HKG301) PET/CT imaging on all target lesions [maximum standardized uptake value (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 (DLT) and treatment-emergent adverse events (TEAE). 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 to be 9.25 GBq. Preliminary Response Evaluation Criteria in Solid Tumors efficacy findings demonstrated a partial response in 1 patient and stable disease in 10 patients (maintained for at least two assessments in 6 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.
Background
The paper addresses the potential of targeting fibroblast activation protein (FAP) with radiopharmaceutical therapy in advanced solid tumors. Previous studies have indicated that FAP is a promising target for cancer treatment, but safety and dosage information for new therapies is often lacking. This study is significant as it investigates a new treatment option in a heavily pretreated patient population.
Methods
This is a phase I/II, multicenter, open-label, nonrandomized study. It included 35 patients who were selected based on positive 68Ga-FAP-2286 PET/CT imaging. The study evaluated four escalating activity levels of 177Lu-FAP-2286 (3.70, 5.55, 7.40, and 9.25 GBq) administered intravenously every 6 weeks for up to 6 cycles. The primary outcome measures were dosage-limiting toxicities (DLT) and treatment-emergent adverse events (TEAE).
Results
The primary endpoint revealed two DLTs: one patient at 5.55 GBq with grade 4 lymphopenia and another at 9.25 GBq with grade 3 hemoptysis. All-cause grade ≥3 TEAEs were reported in 11 patients (40.7%). The RP2D was established at 9.25 GBq, with preliminary efficacy showing a partial response in 1 patient and stable disease in 10 patients, maintained in 6 for at least two assessments.
Interpretation
The findings suggest that 177Lu-FAP-2286 is generally well tolerated, with some significant adverse events noted. While the study provides initial safety data, the effect size and clinical significance of the treatment response are limited by the small sample size and the nature of the patient population. Further studies are required to confirm these findings and assess long-term outcomes.
Key findings
- Two DLTs observed: one grade 4 lymphopenia at 5.55 GBq and one grade 3 hemoptysis at 9.25 GBq.
- All-cause grade ≥3 TEAEs reported for 11 patients (40.7%).
- RP2D for 177Lu-FAP-2286 monotherapy determined to be 9.25 GBq.
- Partial response in 1 patient and stable disease in 10 patients, with 6 maintaining stable disease for at least two assessments.
Limitations
- open-label, nonrandomized design
- small sample size (n=27)
- short follow-up duration
- limited efficacy data