PLUVICTO Solution for injection/infusion Ref.[50608] Active ingredients: Lutetium ¹⁷⁷Lu vipivotide tetraxetan

Pharmacotherapeutic group: Therapeutic radiopharmaceuticals, Other therapeutic radiopharmaceuticals
ATC code: V10XX05

Mechanism of action

The active moiety of Pluvicto is the radionuclide lutetium-177 which is linked to a small-molecule ligand that targets and binds with high affinity to PSMA, a transmembrane protein that is highly expressed in prostate cancer, including mCRPC. Upon the binding of Pluvicto to PSMA-expressing cancer cells, the beta-minus emission from lutetium-177 delivers therapeutic radiation to the targeted cell, as well as to surrounding cells, and induces DNA damage which can lead to cell death.

Pharmacodynamic effects

Unlabelled vipivotide tetraxetan does not have any pharmacodynamic activity.

Clinical efficacy and safety

VISION

The efficacy of Pluvicto in patients with progressive, PSMA-positive mCRPC was evaluated in VISION, a randomised, multicentre, open-label phase III study. Eight hundred and thirty-one (N=831) adult patients were randomised (2:1) to receive either Pluvicto 7 400 MBq every 6 weeks for up to a total of 6 doses plus best standard of care (BSoC) (N=551) or BSoC alone (N=280). Patients who received 4 doses of Pluvicto were reassessed for evidence of response, signs of residual disease, and tolerability and could receive up to 2 additional doses per physician’s discretion.

To maintain castration status, all patients continued to receive a GnRH analogue or had prior bilateral orchiectomy. Eligible patients were required to have progressive, PSMA-positive mCRPC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, at least one metastatic lesion present on computed tomography (CT), magnetic resonance imaging (MRI) or bone scan imaging, and adequate renal, hepatic and haematological function.

Eligible patients were also required to have received at least one AR pathway inhibitor, such as abiraterone acetate or enzalutamide, and 1 or 2 prior taxane-based chemotherapy regimens (with a regimen defined as a minimum exposure of 2 cycles of a taxane). Patients treated with only 1 prior taxane-based chemotherapy regimen were eligible if the patient was unwilling or the physician deemed the patient unsuitable to receive a second regimen. Patients with unstable symptomatic central nervous system metastases or symptomatic or clinically/radiologically impending spinal cord compression were not eligible for the study. Patients underwent a gallium (68Ga) gozetotide positron emission tomography (PET) scan to evaluate PSMA expression in lesions defined by central read criteria. Eligible patients were required to have PSMA-positive mCRPC defined as having at least one tumour lesion with gallium (68Ga) gozetotide uptake greater than in normal liver. Patients were excluded if any lesions exceeding size criteria in short axis (organs ≥1 cm, lymph nodes ≥2.5 cm, bones [soft-tissue component] ≥1 cm) had uptake less than or equal to uptake in normal liver.

BSoC administered at the physician’s discretion included: supportive measures including pain management, hydration, blood transfusions, etc.; ketoconazole; radiation therapy (including seeded form or any external beam radiotherapy [including stereotactic body radiotherapy and palliative external beam]) to localised prostate cancer targets; bone-targeted agents including zoledronic acid, denosumab and any bisphosphonates; androgen-reducing agents including GnRH analogues, any corticosteroid, and 5-alpha reductases; AR pathway inhibitors. BSoC excluded investigational agents, cytotoxic chemotherapy, immunotherapy, other systemic radioisotopes and hemi-body radiotherapy treatment.

Patients continued randomised treatment until evidence of tumour progression (based on investigator assessment per Prostate Cancer Working Group 3 [PCWG3] criteria), unacceptable toxicity, use of prohibited treatment, non-compliance or withdrawal, or lack of clinical benefit.

The primary efficacy endpoints were overall survival (OS) and radiographic progression-free survival (rPFS) as determined by blinded independent central review (BICR) per PCWG3 criteria. Among the secondary efficacy endpoints were overall response rate (ORR) as determined by BICR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and time to first symptomatic skeletal event (SSE) defined as first new symptomatic pathological bone fracture, spinal cord compression, tumour-related orthopaedic surgical intervention, requirement for radiation therapy to relieve bone pain, or death from any cause, whichever occurred first. Radiographic imaging for tumour assessment (CT with contrast/MRI imaging and bone scan) was done every 8 weeks (±4 days) after the first dose for the first 24 weeks (independent of dose delays), then every 12 weeks (±4 days).

Demographic and baseline disease characteristics were balanced between the treatment arms. The median age was 71 years (range: 40 to 94 years); 86.8% White; 6.6% Black or African American; 2.4% Asian; 92.4% had ECOG PS0-1; 7.6% had ECOG PS2. Randomisation was stratified by baseline lactate dehydrogenase (LDH ≤260 IU/L vs. >260 IU/L), presence of liver metastases (yes vs. no), ECOG PS score (0 or 1 vs. 2), and inclusion of an AR pathway inhibitor as part of BSoC at the time of randomisation (yes vs. no). At randomisation, all patients (100.0%) had received at least one prior taxane-based chemotherapy regimen and 41.2% of patients had received two; 97.1% of patients had received docetaxel and 38.0% of patients had received cabazitaxel. At randomisation, 51.3% of patients had received one prior AR pathway inhibitor, 41.0% of patients had received 2, and 7.7% of patients had received 3 or more. During the randomised treatment period, 52.6% of patients in the Pluvicto plus BSoC arm and 67.8% of patients in the BSoC alone arm received at least one AR pathway inhibitor.

Efficacy results for VISION are presented in Table 3 and Figures 1 and 2. The final analyses of OS and rPFS were event-driven and conducted after the occurrence of 530 deaths and 347 events, respectively.

Table 3. Efficacy results in VISION:

BSoC: Best standard of care; CI: Confidence interval; NE: Not evaluable; BICR: Blinded independent central review; PCWG3: Prostate Cancer Working Group 3; RECIST: Response Evaluation Criteria in Solid Tumors.
^a Analysed on an intent-to-treat (ITT) basis in all randomised patients.
^b Based on Kaplan-Meier estimate.
^c Hazard ratio based on the stratified Cox PH model. Hazard ratio <1 favours Pluvicto plus BSoC.
^d Stratified log-rank test one-sided p-value.
^e By BICR per PCWG3 criteria. The primary analysis of rPFS included censoring of patients who had ≥2 consecutive missed tumour assessments immediately prior to progression or death. Results for rPFS with and without censoring for missed assessments were consistent.
^f Analysed on an ITT basis in all patients randomised on or after 05-Mar-2019, when actions were implemented to mitigate early drop-out from BSoC arm.
^g Stratified log-rank test two-sided p-value.
^h By BICR per RECIST v1.1.
ⁱ ORR: CR+PR. Confirmed response for CR and PR.
^j Stratified Wald’s Chi-square test two-sided p-value.
^k Median DOR in the BSoC only arm was not reliable since only 1 of the 2 patients who responded had RECIST v1.1 radiographic progression or death.

Figure 1. Kaplan-Meier plot of OS in VISION:

Stratified log-rank test and stratified Cox model using strata per Interactive Response Technology (IRT) defined by LDH level, presence of liver metastases, ECOG score and inclusion of an AR pathway inhibitor in BSoC at time of randomisation.
n/N: Number of events/number of patients in treatment arm.

Figure 2. Kaplan-Meier plot of BICR-assessed rPFS in VISION:

Stratified log-rank test and stratified Cox model using strata per IRT defined by LDH level, presence of liver metastases, ECOG score and inclusion of an AR pathway inhibitor in BSoC at time of randomisation.
n/N: Number of events/number of patients in treatment arm.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Pluvicto in all subsets of the paediatric population in the treatment of PSMA-expressing prostate cancer (see section 4.2 for information on paediatric use).