On March 23, 2022, the FDA accelerated the approval of lutetium Lu 177 vipivotide tetraxetan, formerly known as 177Lu PSMA-617 (Pluvicto; Novartis/Advanced Accelerator Applications) for the treatment of adults with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) after receiving an androgen receptor (AR) inhibitor and taxane-based chemotherapy. The FDA granted this application a priority review and a breakthrough therapy designation.
Lu 177 vipivotide tetraxetan is the first FDA-approved targeted radioligand therapy for patients with mCRPC that combines a targeting compound (ligand) with a therapeutic radioisotope (a radioactive particle).
“The approval of Pluvicto is an important clinical advancement for people with progressing mCRPC, as it can significantly improve survival rates for those who have limited treatment options,” said Oliver Sartor, MD, Medical Director, Tulane Cancer Center, LA. “Pluvicto is a step forward in the evolution of precision medicine for prostate cancer.”
On the same day, the FDA approved gallium Ga 68 gozetotide (Locametz), a radioactive diagnostic agent for PET (positron-emission tomography) of PSMA-positive lesions, including the selection of patients with metastatic prostate cancer for whom lutetium Lu 177 vipivotide tetraxetan PSMA-directed therapy is indicated. This is the first radioactive diagnostic agent approved by the FDA for selecting patients for a radioligand therapeutic agent.
Patients with previously treated mCRPC should be selected for treatment with lutetium Lu 177 vipivotide tetraxetan using gallium Ga 68 gozetotide or another FDA-approved PSMA-11 imaging agent, based on PSMA expression in tumors. PSMA-positive mCRPC was defined as having ≥1 tumor lesions with gallium Ga 68 gozetotide uptake of more than normal liver. Patients were excluded from the study if any lesion exceeding certain size criteria in the short axis had uptake of less than or equal to uptake in normal liver.
The approval of lutetium Lu 177 vipivotide tetraxetan was based on results of the VISION study, a randomized (2:1), multicenter, open-label clinical trial of 831 patients with progressive, PSMA-positive mCRPC. The patients were randomized to lutetium Lu 177 vipivotide tetraxetan plus best standard of care (N = 551) or to best standard of care alone (N = 280). All patients received a gonadotropin-releasing hormone analog or had previous bilateral orchiectomy. Patients had to have received ≥1 AR inhibitors and 1 or 2 previous taxane-based chemotherapy regimens. Patients received lutetium Lu 177 vipivotide tetraxetan 7.4 GBq (200 mCi) every 6 weeks for up to 6 doses plus best standard of care or best standard of care alone.
The primary end points were overall survival (OS) and radiographic progression-free survival (PFS). The OS was significantly better with lutetium Lu 177 vipivotide tetraxetan plus best standard of care (hazard ratio, 0.62; 95% confidence interval [CI], 0.52-0.74; P <.001) compared with best standard of care alone. The median OS was 15.3 months (95% CI, 14.2-16.9) and 11.3 months (95% CI, 9.8-13.5), respectively. The interpretation of the magnitude of the radiographic PFS effect was limited because of a high degree of censoring from early dropout in the control arm.
The most common (≥20%) adverse reactions that had greater incidence in patients in the active group were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients receiving lutetium Lu 177 vipivotide tetraxetan were decreased levels of lymphocytes, hemoglobin, leukocytes, platelets, calcium, and sodium.
Treatment with lutetium Lu 177 vipivotide tetraxetan may be associated with radiation exposure risk, myelosuppression, and renal adverse events. The safety follow-up duration in the VISION study was not sufficient to capture late adverse events associated with radiation.
The recommended dose of lutetium Lu 177 vipivotide tetraxetan is 7.4 GBq (200 mCi) intravenously, every 6 weeks, for up to 6 doses, or until disease progression or unacceptable adverse events.