Lutetium (177Lu) vipivotide tetraxetan

Lutetium (177Lu) vipivotide tetraxetan (INN; also known as Lu-PSMA-617; sold under the brand name Pluvicto) is a radiopharmaceutical medication used for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC).[5][7] Lutetium (177Lu) vipivotide tetraxetan is a targeted radioligand therapy.[7][8]

Lu-PSMA-617 is a radioconjugate composed of vipivotide tetraxetan (PSMA-617), a human prostate-specific membrane antigen (PSMA)-targeting ligand, conjugated to the beta-emitting radioisotope lutetium-177, with potential antineoplastic activity against PSMA-expressing tumor cells. Upon intravenous administration of Lu-PSMA-617, it targets and binds to PSMA-expressing tumor cells. Upon binding, PSMA-expressing tumor cells are destroyed by 177Lu through the specific delivery of beta particle radiation. PSMA, a tumor-associated antigen and type II transmembrane protein, is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumor cells.[9]

Lu-PSMA-617 was approved for medical use in the United States in March 2022,[7][10] and in the European Union in December 2022.[6] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[11][12]

Medical uses

Lu-PSMA-617 is indicated for the treatment of adults with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy.[5]

In March 2025, the US Food and Drug Administration expanded the indication for Lu-PSMA-617 to include adults with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer who have been treated with androgen receptor pathway inhibitor therapy and are considered appropriate to delay taxane-based chemotherapy.[13]

The most common adverse reactions include fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation.[7][6]

History

In 2006, scientists from Purdue University designed a targeting ligand that bound with high affinity and specificity to PSMA on prostate cancer cells and patented[14][15] its ability to target attached radionuclides such as 177Lu, 99mTc, 68Ga, etc. to prostate cancers. The patents were licensed to Endocyte in 2007. In 2012, scientists at German Cancer Research Center and University Hospital Heidelberg improved the drug's affinity, patented,[16] and licensed to ABX advanced biomedical compounds, a small German pharmaceutical company, for early clinical development. In 2017, the ABX patent was also acquired by Endocyte[17] and Endocyte together with the above two sets of patents was acquired by Novartis in 2018.[18]

Efficacy and safety was initially investigated as a compassionate access treatment in Germany with high tumor targeting and low doses to normal organs.[19] Physician-scientists from the Peter MacCallum Cancer Centre conducted a phase 2 trial demonstrating high response rates, low toxicity and reduction in pain in men with metastatic castration-resistant cancer who progressed after conventional treatments.[20] The ANZUP co-operative trials conducted the first randomized, multicentre trial comparing lutetium vipivotide tetraxetan to cabazitaxel chemotherapy.[21]

Efficacy was evaluated in VISION,[22] a randomized (2:1), multicenter, open-label trial that evaluated Lu-PSMA-617 plus best standard of care (BSoC) (n=551) or BSoC alone (n=280) in men with progressive, prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer.[7] All participants received a GnRH analog or had prior bilateral orchiectomy.[7] Participants were required to have received at least one androgen receptor pathway inhibitor, and 1 or 2 prior taxane-based chemotherapy regimens.[7] Participants received Lu-PSMA-617 7.4 GBq (200 mCi) every 6 weeks for up to a total of 6 doses plus BSoC or BSoC alone.[7]

Efficacy was evaluated in PSMAfore (NCT04689828), a randomized, multicenter, open-label trial enrolling 468 participants with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer and progression on one androgen receptor pathway inhibitor, who the investigator considered appropriate for delay of taxane-based chemotherapy.[13] Participants were randomized (1:1) to receive Lu-PSMA-617 (7.4 GBq [200 mCi] every six weeks for six doses) or a change in androgen receptor pathway inhibitor.[13] Participants who progressed on the androgen receptor pathway inhibitor arm were allowed to crossover to the experimental therapy.[13]

The US Food and Drug Administration granted the application for Lu-PSMA-617 priority review and breakthrough therapy designations.[7]

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