OTL78 Shows Safety, Feasibility in PSMA+ Prostate Cancer Detection

The investigational prostate-specific membrane antigen (PSMA)–targeted fluorescent tracer OTL78 was well tolerated among patients with prostate cancer and demonstrated potential to improve detection of prostate cancer, according to findings from a phase 2a study published in Lancet Oncology.

"Our data show the safety and feasibility of OTL78 for PSMA-targeted fluorescence-guided surgery in patients with prostate cancer,” according to the study authors.

Within the 18-patient population, there were 3 serious adverse effects (SAEs) in 1 patient who experienced infected lymphocele that drained percutaneously, urosepsis treated with antibiotics and fluid resuscitation, and an intraperitoneal hemorrhage that required percutaneous drainage. Investigators considered all AEs and SAEs to be unrelated to the administration of OTL78 or fluorescence imaging.

The dose-normalized maximum serum concentration of OTL78 was 84.1 ng/mL/mg for the 0.03 mg/kg dose and 79.6 ng/mL/mg for the 0.06 mg/kg dose. Additionally, the half-life was 5.1 hours for the 0.03 mg/kg dose and 4.7 hours for the 0.06 mg/kg dose. For each respective dose level, the volume of distribution was 22.9 L and 19.5 L, and the clearance was 3.1 L/hour and 3.0 L/hour.

Investigators noted that a single intravenous dose of OTL78 at 0.03 mg/kg 24 hours before surgery provided the highest signal-to-background ratio and the best tumor visualization compared with the other dosing levels.

“Our data show the safety and feasibility of OTL78 for PSMA-targeted fluorescence-guided surgery in patients with prostate cancer,” the study authors stated. “OTL78 can intraoperatively enhance visualization of primary prostate tumors, surgical margins, residual prostate cancer in the resection bed, and nodal metastases. These promising results warrant validation in a larger cohort of patients with primary prostate cancer.”

Investigators of the single-arm, phase 2a trial assessed the feasibility of administering OTL78 to patients with PSMA PET–avid prostate cancer scheduled to undergo robot-assisted radical prostatectomy. Based on timing and dose, patients received a single intravenous infusion of OTL78 at 0.06 mg/kg 1 to 2 hours before surgery in cohort 1, 0.03 mg/kg 1 to 2 hours before surgery in cohort 2, or 0.03 mg/kg 24 hours before surgery in cohort 3.

The primary end points were the safety and pharmacokinetics of OTL78. Secondary end points included the sensitivity, specificity, false-negative rate, and false-positive rate for prostate cancer detection as well as the determining the optimal dose and dose interval.

Patients 18 years and older who had prostate cancer with an International Society of Urological Pathology (ISUP) grade group of 2 or more were eligible for inclusion in the study. Additional inclusion criteria included being clinically fit for surgery and willing to comply with study procedures.

Between June 29, 2020 and April 1, 2021, investigators included 18 patients in the study with a median age of 69 years at the time of prostate cancer diagnosis. Overall, 67% of patients had prostate cancer with International Society of Urological Pathology (ISUP) grade group 3 or more. All patients underwent robot-assisted radical prostatectomy, and 89% also underwent extended pelvic lymph node dissection.

Overall, 42% of prostate regions imaged in-vivo had prostate cancer. After dose decreases and interval increases, the mean fluorescence intensity of both tumor and benign background decreased, producing a median in-vivo signal-to-background ratio of 1.0 in cohort 1, 1.3 in cohort 2, and 1.9 in cohort 3.

Ex-vivo imaging revealed prostate cancer in 42% of prostate regions. The sensitivity of OTL78 for prostate cancer detection was higher with ex-vivo compared with in-vivo imaging across all dose cohorts. As with in-vivo imaging, the highest median ex-vivo signal-to-background ratio was observed in cohort 3.

Post hoc analyses indicated that OTL78 allowed visualization of 71% of lesions (n = 272) in microscopic prostate slides during fluorescence microscopy. Imaging sensitivity and signal-to-background ratio at pathology increased with larger tumor volume, dose interval extension, higher ISUP grade, a 0.03 mg/kg dose, and higher immunohistochemical PSMA expression.

In-vivo imaging detected 4 metastatic lymph node clusters that had a median metastasis size of 1.9 mm. When administering OTL78 1 to 2 hours before surgery in cohorts 1 and 2, 22% of lymph node clusters were false-positive in-vivo.

Post hoc gross-macroscopic and microscopic fluorescence imaging detected 9 metastatic lymph nodes and produced respective median signal-to-background ratios of 3.5 and 8.8. Only dose cohorts 1 and 2 had false-positive lymph nodes with gross-macroscopic and microscopic fluorescence imaging.

Reference

Stibbe JA, de Barros HA, Linders DG, et al. First-in-patient study of OTL78 for intraoperative fluorescence imaging of prostate-specific membrane antigen-positive prostate cancer: a single-arm, phase 2a, feasibility trial. Lancet Oncol. Published online April 13, 2023. doi:10.1016/ S1470-2045(23)00102-X