177Lu-FAP-2286 in patients with advanced or metastatic solid tumors: Initial data from a phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity (LuMIERE)

Introduction: Fibroblast activation protein (FAP) is a membrane protease that is highly expressed by cancer-associated fibroblasts in many epithelial tumors and by tumor cells in some mesenchymal tumors. With limited expression in normal adult tissues, FAP is an attractive candidate for peptide-targeted radiotherapies, such as FAP-2286. FAP-2286 is a cyclic peptide that potently and selectively binds FAP covalently linked to a tetraazacyclododecane tetraacetic acid (DOTA) cage capable of carrying a therapeutic or imaging radionuclide. LuMIERE (NCT04939610) is an ongoing, multicenter, open-label phase 1/2 study investigating the safety and tolerability, pharmacokinetics, dosimetry, and preliminary activity of ¹⁷⁷Lu-FAP-2286 in adult patients with FAP-expressing tumors identified based on uptake of the imaging agent ⁶⁸Ga-FAP-2286.

Methods: Adult patients eligible for phase 1 have advanced/metastatic solid tumors, refractory to or progressed after prior treatment, with no satisfactory alternative treatment options. Patients with measurable disease by RECIST v1.1 are selected for ¹⁷⁷Lu-FAP-2286 treatment based on uptake of ⁶⁸Ga-FAP-2286 in all measurable target lesions by positron emission tomography (PET). Patients receive an intravenous (IV) dose of ¹⁷⁷Lu-FAP-2286 at the beginning of each 6-week cycle, up to a maximum of 6 cycles. Dose escalation and determination of the maximum tolerated dose (MTD) is based on a Bayesian optimal interval (BOIN) design. The starting dose is 3.7 GBq (100 mCi), with escalation increments of 1.85 GBq (50 mCi) per dose cohort and a maximum dose of 9.25 GBq (250 mCi). The primary objective of phase 1 is to evaluate the safety and tolerability of ¹⁷⁷Lu-FAP-2286 and determine the recommended phase 2 dose (R2PD). Dose-limiting toxicity (DLT) is assessed during cycle 1 (graded per CTCAE v5.0), and organ and tumor dosimetry is evaluated by planar scans at 4, 24, 48, and 168 hours post dose and SPECT/CT scans at 24 and 168 hours post dose. Tumor response is assessed per RECIST v1.1. The R2PD may be further characterized in up to 20 additional patients during the dose expansion phase, and the efficacy of ¹⁷⁷Lu-FAP-2286 will be evaluated in ~120 patients with specific FAP-expressing solid tumors in phase 2.

Results: As of the 2 January 2022 data cutoff, 3 patients with advanced/metastatic solid tumors (2 adenocarcinoma of the colon, 1 appendiceal adenocarcinoma) have been treated in the initial dose cohort and have completed at least 1 cycle. Two patients have received a single dose of 3.7 GBq ¹⁷⁷Lu-FAP-2286, and one has received 3 doses. No DLTs have been reported. All 3 patients have reported at least 1 treatment-emergent adverse event (AE), none of which resulted in discontinuation of study treatment; no grade 3/4 AEs and no clinically meaningful laboratory abnormalities were reported. Overall exposure to organs was low. The mean absorbed doses ranged from 0.66–1.93 Gy (0.18–0.50 Gy/GBq) and 0.16–0.18 Gy (0.04–0.05 Gy/GBq) in the kidneys and red marrow, respectively. Since the data cutoff, 1 patient has been enrolled in the second dose cohort and received a dose of 5.55 GBq (150 mCi).

Conclusions: Initial results from phase 1 of the ongoing LuMIERE study show that no DLTs or grade 3/4 AEs have been reported in the first dose cohort to date. Preliminary dosimetry data is consistent with preclinical data suggesting that renal excretion is the major elimination pathway for ¹⁷⁷Lu‑FAP‑2286. Updated data, including preliminary efficacy and tumor dosimetry results, will be presented at the meeting.