FDA Approves Lutetium Lu 177 Vipivotide Tetraxetan for PSMA-Positive Metastatic Castration-Resistant Prostate Cancer
核心洞察
The FDA granted traditional approval to Pluvicto (lutetium Lu 177 vipivotide tetraxetan) for PSMA (搜索)-positive metastatic castration-resistant prostate cancer (搜索) patients who have received androgen receptor pathway inhibition and taxane-based chemotherapy.
In the pivotal VISION trial, Pluvicto plus best standard of care demonstrated a statistically significant improvement in overall survival (15.3 vs 11.3 months) compared to best standard of care alone, with a hazard ratio of 0.62.
The most common adverse reactions included fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation, with serious adverse reactions occurring in 36% of patients receiving the radioligand therapy.
The U.S. Food and Drug Administration (FDA) has approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as 177Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA (搜索))-positive metastatic castration-resistant prostate cancer (搜索) (mCRPC (搜索)) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy.
The approval, granted on March 23, 2022, was based on results from the VISION trial, a randomized, multicenter, open-label study that demonstrated a significant survival benefit for patients receiving the novel radioligand therapeutic.
Groundbreaking VISION Trial Results
The VISION trial enrolled 831 men with progressive, PSMA (搜索)-positive mCRPC (搜索) who had received at least one androgen receptor pathway inhibitor (ARPI) and one or two prior taxane-based chemotherapy regimens. Patients were randomized in a 2:1 ratio to receive either 177Lu-PSMA-617 plus best standard of care (BSoC) or BSoC alone.
The trial met its co-primary endpoint of overall survival (OS), with patients in the 177Lu-PSMA-617 plus BSoC arm achieving a median OS of 15.3 months compared to 11.3 months in the BSoC alone arm (hazard ratio: 0.62, 95% CI: 0.52, 0.74, p<0.001). This represents a 38% reduction in the risk of death.
The study also demonstrated a significant improvement in radiographic progression-free survival (rPFS), with a median of 8.7 months in the experimental arm versus 3.4 months in the control arm (hazard ratio: 0.40, 95% CI: 0.31, 0.52, p<0.001).
Additionally, objective response rate (ORR) was significantly higher in the 177Lu-PSMA-617 plus BSoC arm at 30% compared to just 2% in the BSoC alone arm.
Mechanism of Action and Administration
177Lu-PSMA-617 represents a novel approach to treating prostate cancer (搜索). The radioligand therapeutic consists of a radionuclide (lutetium-177) linked to a small molecule (PSMA (搜索)-617) that binds with high affinity to PSMA, a protein highly expressed on prostate cancer cells.
Once bound to PSMA (搜索)-expressing cells, the compound delivers targeted radiation via beta emission from lutetium-177, resulting in cell death. This targeted approach allows for the delivery of radiation directly to cancer cells while limiting exposure to surrounding healthy tissues.
The recommended dose of 177Lu-PSMA-617 is 7.4 gigabecquerels (GBq; 200 mCi) administered intravenously every 6 weeks for up to 6 doses, or until disease progression or unacceptable toxicity.
Safety Profile and Considerations
The most common adverse reactions (occurring in ≥20% of patients) with 177Lu-PSMA-617 were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients included decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.
Serious adverse reactions occurred in 36% of patients receiving 177Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients, including sepsis (0.9%), pancytopenia (0.6%), and hepatic failure (0.4%).
Due to the potential for radiation exposure to the kidneys, patients should remain well hydrated and urinate frequently before and after administration of Pluvicto. The FDA has also issued post-marketing requirements to further evaluate long-term safety outcomes, particularly in patients with renal impairment.
Patient Selection
Patients eligible for 177Lu-PSMA-617 treatment must have PSMA (搜索)-positive mCRPC (搜索), which is determined using Locametz (kit for the preparation of gallium Ga 68 gozetotide injection), a radioactive diagnostic agent for PET imaging of PSMA-positive lesions. The FDA approved Locametz on the same day as Pluvicto to facilitate appropriate patient selection.
Addressing an Unmet Need
"The approval of 177Lu-PSMA-617 represents a significant advancement for patients with metastatic castration-resistant prostate cancer (搜索) who have limited treatment options after progressing on both androgen receptor pathway inhibitors and taxane-based chemotherapy," said Dr. Michael Morris, a lead investigator on the VISION trial. "This radioligand therapy offers a novel mechanism of action that can provide meaningful clinical benefit with a manageable safety profile."
Future Directions
The FDA has granted fast track designation to another PSMA (搜索)-targeted radiopharmaceutical therapy, 177Lu-PNT2002, which is currently being evaluated in the phase 3 SPLASH trial for patients with PSMA-expressing mCRPC (搜索) who have progressed following treatment with an androgen receptor inhibitor and are ineligible for chemotherapy.
The SPLASH trial has completed enrollment, with topline data anticipated in the second half of 2023. If successful, this could potentially expand treatment options for patients who are unable to receive chemotherapy.
Clinical Implications
The approval of 177Lu-PSMA-617 adds an important new treatment option for patients with advanced prostate cancer (搜索) who have exhausted standard therapies. Its unique mechanism of action and demonstrated survival benefit make it a valuable addition to the treatment armamentarium for mCRPC (搜索).
Healthcare providers should carefully select appropriate patients based on PSMA (搜索) expression and prior treatment history, while monitoring for potential adverse effects, particularly those related to bone marrow suppression and renal function.
The introduction of this targeted radiopharmaceutical therapy represents a significant step forward in precision medicine for prostate cancer (搜索) and may pave the way for earlier use of radioligand therapies in the disease continuum.