On March 23, the U.S. Food and Drug Administration approved lutetium Lu-177 vipivotide tetraxetan (Pluvicto) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. Also on March 23, the FDA approved gallium Ga-68 gozetotide (Locametz), a radioactive diagnostic agent for positron-emission tomography (PET) of PSMA-positive lesions, including selection of patients with metastatic prostate cancer for whom Lu-177 vipivotide tetraxetan PSMA-directed therapy is indicated. Ga-68 gozetotide is the first radioactive diagnostic agent approved for patient selection in the use of a radioligand therapeutic agent.
Patients with previously treated metastatic castration-resistant prostate cancer should be selected for treatment with Lu-177 vipivotide tetraxetan using Ga-68 gozetotide or another approved PSMA-11 imaging agent based on PSMA expression in tumors. PSMA-positive metastatic castration-resistant prostate cancer was defined as having at least one tumor lesion with Ga-68 gozetotide uptake greater than normal liver. Patients were excluded from enrollment if any lesions exceeding certain size criteria in the short axis had uptake less than or equal to uptake in normal liver.
Efficacy was evaluated in VISION (ClinicalTrials.gov identifier NCT03511664), a randomized (2:1), multicenter, open-label trial that evaluated Lu-177 vipivotide tetraxetan plus best standard of care (n = 551) or best standard of care alone (n = 280) in men with progressive, PSMA-positive metastatic castration-resistant prostate cancer. All patients received a GnRH analog or had undergone prior bilateral orchiectomy. Patients were required to have received at least one androgen receptor pathway inhibitor, and one or two prior taxane-based chemotherapy regimens. Patients received Lu-177 vipivotide tetraxetan at 7.4 GBq (200 mCi) every 6 weeks for up to a total of six doses plus best standard of care, or best standard of care alone.
The trial demonstrated a statistically significant improvement in the primary endpoints of overall survival and radiographic progression-free survival. The hazard ratio for overall survival was 0.62 (95% confidence interval [CI] = 0.52–0.74, P < .001) for the comparison of Lu-177 vipivotide tetraxetan plus best standard of care vs best standard of care alone. Median overall survival was 15.3 months (95% CI = 14.2–16.9) in the Lu-177 vipivotide tetraxetan plus best standard of care arm and 11.3 months (95% CI = 9.8–13.5) in the best standard of care alone arm, respectively. Interpretation of the magnitude of the radiographic progression-free survival effect was limited due to a high degree of censoring from early drop-out in the control arm.
The most common adverse reactions (≥ 20%) occurring at a higher incidence in patients receiving Lu-177 vipivotide tetraxetan were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥ 30% of patients receiving Lu-177 vipivotide tetraxetan were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. Treatment with Lu-177 vipivotide tetraxetan may result in risk from radiation exposure, myelosuppression, and renal toxicity. The safety follow-up duration in VISION was not sufficient to capture late radiation-associated toxicities.
The recommended Lu-177 vipivotide tetraxetan dose is 7.4 GBq (200 mCi) intravenously every 6 weeks for up to six doses, or until disease progression or unacceptable toxicity.
This application was granted Priority Review and Breakthrough Therapy designation.