FRONTIER: FAPi Radioligand OpeN-label, phase 1 study to evaluate safety, Tolerability and dosImetry of [Lu-177]-PNT6555; a dose Escalation study for tReatment of patients with select solid tumors

Introduction: Fibroblast activation protein (FAP), a transmembrane glycoprotein, is a compelling antitumor target present in >90% of epithelial tumors. FAP is expressed within the tumor microenvironment by cancer-associated fibroblasts (CAFs), and by certain cancer cells. PNT6555 is a FAP-targeting compound consisting of a DOTA chelator and a FAP-targeting moiety (Bz-D-Ala-boroPro) connected via an aminomethyl linker. Gallium-68 and lutetium-177 chelates of PNT6555 demonstrated compelling imaging and therapeutic properties in preclinical models.

Methods: FRONTIER (NCT05432193) is a phase I study of PNT6555 in FAP over-expressing pancreatic ductal adenocarcinoma (PDAC), esophageal cancer, colorectal cancer (CRC), melanoma skin cancer, cholangiocarcinoma (CCA), head and neck squamous cell carcinoma, and soft tissue sarcoma (STS). Participants had malignancies that were refractory to prior treatment with alternative therapeutic options being either unavailable, contraindicated, or refused by the patient; had adequate organ function; and were FAP-positive on [Ga-68]-PNT6555 PET/CT scan, defined as ≥50% of lesions with an SUV_max of ≥1.5x the liver SUV_mean.

For imaging, [Ga-68]-PNT6555 was dosed at 120 - 220 MBq, with PET/CT initiated 90 (±30) min later. FAP-positive participants were eligible to receive [Lu-177]-PNT6555 once every 6 weeks for up to 6 cycles. Three [Lu-177]-PNT6555 dose levels were evaluated: 4, 8, and 12 GBq ±10%. The starting dose was 4 GBq ±10% and dose escalation was guided by a modified toxicity probability interval-2 (mTPI-2) design with a targeted toxicity rate of 30%. The dose-limiting toxicity (DLT) evaluation period was 6 weeks following the first treatment.

For dosimetry, whole body quantitative SPECT/CT images were collected at 4 (±2), 24 (±5), and 96 (±5) hours post cycle 1; absorbed doses were estimated in up to five measurable lesions per participant; and cumulative absorbed doses were extrapolated from cycle 1 absorbed doses.

Results: Twenty participants received [Ga-68]-PNT6555 and 18 meet study criteria for FAP-positivity. Ten met all eligibility criteria and received at least one cycle of [Lu-177]-PNT6555, including two with STS, three with CRC, three with PDAC, and one each with CCA and esophageal cancer. Of these ten, two received two cycles, two received three cycles, and no participants received four or more cycles. Four participants received 4 GBq/cycle, three received 8 GBq/cycle, and three received 12 GBq/cycle. Reasons for treatment discontinuation included disease progression (n=6), death (n=2), and withdrawal of consent (n=2).

Cumulative absorbed doses for normal organs after 4 cycles at the highest dose level (12 GBq/cycle) were 6.72, 0.23, 1.04, 0.68, and 0.81 Gy for the kidneys, bone marrow, spleen, heart, and liver, respectively. The mean (range) specific absorbed tumor dose was 0.16 (0.02-0.45) Gy/GBq.

[Lu-177]-PNT6555 was well tolerated at all dose levels evaluated. There were no DLTs and no grade ≥3, or serious, treatment-related adverse events.

Conclusions: Normal organ dosimetry and the safety profile from FRONTIER clearly demonstrate the potential of FAP-targeted radioligand therapy as a precision treatment modality capable of minimal off-target effects. However, the low absorbed tumor doses observed suggest tumor retention time was limited, in sharp contrast to the observations in preclinical models. Improved preclinical approaches may be needed to successfully translate this promising treatment modality to the clinic.