Lutetium-177-PSMA-617
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Radiolabeled PSMA-targeting peptide for radioligand therapy; FDA-approved for PSMA-positive metastatic castration-resistant prostate cancer.
Quick Facts
| Property | Value |
|---|---|
| Also Known As | Pluvicto, lutetium Lu 177 vipivotide tetraxetan, 177Lu-PSMA-617, vipivotide tetraxetan |
| Category | Radiolabeled peptide / Radioligand therapy (RLT) |
| Sequence | PSMA-617 peptidomimetic ligand: Glu-urea-Lys motif conjugated to DOTA chelator via naphthylalanine linker, complexed with 177Lu |
| Molecular Weight | ~1216 Da (peptide-chelator complex without isotope) |
| Molecular Formula | C49H67LuN9O16 |
| PubChem CID | Not applicable (radiopharmaceutical) |
| Administration | IV infusion (administered at authorized nuclear medicine facilities only) |
| Typical Dose Range | 7.4 GBq (200 mCi) per cycle; up to 6 cycles |
| Half-Life | 177Lu physical half-life: 6.647 days; effective half-life: ~40 hours (tumor-bound) |
| Storage | Radiopharmaceutical handling; single-use vial; administer within specified calibration window |
| FDA Status | Approved (March 2022) — Pluvicto for PSMA-positive mCRPC after AR pathway inhibitor and taxane chemotherapy |
| WADA Status | Not listed |
Mechanism of Action
Lutetium-177-PSMA-617 is a targeted radioligand therapy that combines a PSMA-binding peptidomimetic ligand (PSMA-617) with the beta-emitting radionuclide lutetium-177, connected via a DOTA chelator. The design exploits the fact that prostate-specific membrane antigen (PSMA/FOLH1/GCPII) is highly overexpressed on the surface of prostate cancer cells (100-1000x higher than normal prostate tissue), making it an ideal target for selective drug delivery.
PSMA-617 binds to the catalytic site of PSMA with high affinity and is rapidly internalized via receptor-mediated endocytosis. Once inside the cell, the 177Lu isotope delivers cytotoxic beta radiation (maximum energy 0.497 MeV, tissue penetration ~2 mm), causing double-strand DNA breaks and tumor cell death. The "crossfire effect" from beta particles also destroys neighboring PSMA-negative tumor cells within the radiation range. Like 177Lu-DOTATATE, the gamma emissions of 177Lu enable post-therapy SPECT/CT imaging for treatment verification and dosimetry.
The VISION trial (PMID 34161051) demonstrated that 177Lu-PSMA-617 plus standard of care significantly improved both overall survival (15.3 vs 11.3 months, HR 0.62) and PFS (8.7 vs 3.4 months, HR 0.40) in patients with PSMA-positive mCRPC. This approach represents the first PSMA-targeted therapy and the first radioligand therapy approved for prostate cancer.
Patient selection requires a 68Ga-PSMA-11 PET/CT scan (Locametz, the companion diagnostic) to confirm PSMA positivity. Approximately 87% of screened mCRPC patients meet PSMA-positivity criteria.
Key Research Areas
- mCRPC (late-line) — VISION trial: OS 15.3 vs 11.3 months (HR 0.62, p < 0.001); PFS 8.7 vs 3.4 months (HR 0.40, p < 0.001) (PMID 34161051)
- Proof-of-concept — LuPSMA Phase 2: 57% PSA response rate, 82% objective response in measurable disease (PMID 29752180)
- FDA regulatory pathway — Traditional approval based on VISION; no REMS required; restricted to authorized facilities (PMID 36469000)
- Earlier-line therapy — PSMAfore trial investigating 177Lu-PSMA-617 before chemotherapy; ongoing studies in hormone-sensitive prostate cancer (UpFrontPSMA)
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | 1 | VISION Phase 3 (pivotal) |
| Human Phase 2 | 1 | LuPSMA proof-of-concept |
| FDA review | 1 | Approval summary |
| Randomized Phase 2 | — | TheraP (vs cabazitaxel; not yet in vault) |
Clinical Applications
- Cancer Adjunct Therapy — FDA-approved for PSMA-positive mCRPC
Protocols Using This Peptide
- No Ageless Peps protocols (FDA-approved radiopharmaceutical, administered only at authorized nuclear medicine facilities)
Ageless Peps Products
- Not sold — Lutetium-177-PSMA-617 (Pluvicto) is an FDA-approved radiopharmaceutical manufactured by Novartis/Advanced Accelerator Applications. It requires specialized nuclear medicine infrastructure and is not available as a research peptide.
Dosing Reference
FDA-Approved Dosing
| Indication | Route | Dose | Frequency | Duration | Source |
|---|---|---|---|---|---|
| PSMA+ mCRPC | IV infusion | 7.4 GBq (200 mCi) | q6 weeks | Up to 6 cycles | FDA label |
Administration Requirements
- Must be administered at authorized nuclear medicine facilities
- 68Ga-PSMA-11 PET/CT required for patient selection (companion diagnostic)
- No amino acid co-infusion required (unlike 177Lu-DOTATATE, which targets kidney-expressed SSTR)
- Post-treatment radiation safety precautions for patient and caregivers
- Blood count monitoring before each cycle; treatment held for cytopenias
Cycling
Not applicable in the traditional sense — treatment consists of up to 6 cycles. Treatment continues until completion of 6 cycles, disease progression, or unacceptable toxicity.
Contraindications & Safety
- Contraindications: Pregnancy; hypersensitivity
- Common side effects: Fatigue (43%), dry mouth (39%, mostly grade 1), nausea (35%), anemia (32%), lymphopenia (grade 3-4 in 8%), thrombocytopenia (grade 3-4 in 8%), leukopenia
- Serious risks: Myelodysplastic syndrome/acute leukemia (~2%); bone marrow failure; renal toxicity (generally mild; salivary gland uptake is the main off-target effect)
- Drug interactions: Prior or concomitant myelosuppressive therapy increases hematologic toxicity risk; AR pathway inhibitors can be continued
- Pregnancy/nursing: Absolutely contraindicated; effective contraception required for 14 weeks after last dose (women partners) and men for duration + 14 weeks
- Special populations: Adequate bone marrow and renal function required; no specific hepatic considerations; elderly patients tolerated treatment similar to younger patients in VISION
Synergistic Combinations
- AR pathway inhibitors (enzalutamide, abiraterone) — Can be continued with 177Lu-PSMA-617 per VISION protocol
- Lutetium-177-DOTATATE — Sister radioligand therapy targeting different receptor (SSTR vs PSMA); same isotope and treatment infrastructure
- PARP inhibitors — Under investigation as potential radiosensitizers in combination
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| 34161051 | VISION: 177Lu-PSMA-617 for mCRPC (pivotal Phase 3) | 2021 | RCT |
| 29752180 | LuPSMA: Phase 2 proof-of-concept trial | 2018 | Phase 2 (single-arm) |
| 36469000 | FDA Approval Summary: Lutetium Lu 177 Vipivotide Tetraxetan | 2023 | FDA Review |
References
- PMID 34161051 — Sartor et al. VISION trial: 177Lu-PSMA-617 for mCRPC (2021)
- PMID 29752180 — Hofman et al. LuPSMA Phase 2 trial (2018)
- PMID 36469000 — Keam. FDA approval summary for Pluvicto (2023)
Related
- Peptide Index
- Condition Index
- Protocol Index
- Cancer Adjunct Therapy
- Lutetium-177-DOTATATE
- Octreotide
FDA Disclaimer: Lutetium-177-PSMA-617 (Pluvicto) is an FDA-approved radiopharmaceutical. The information in this note is for educational and reference purposes only and does not constitute medical advice. Administration must be performed at authorized nuclear medicine facilities by qualified healthcare providers.
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