Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Pharmacotherapeutic group: Diagnostic radiopharmaceuticals, other diagnostic radiopharmaceuticals for tumour detection
ATC code: V09IX14
Gallium (68Ga) gozetotide binds to cells that express PSMA, including malignant prostate cancer cells, which overexpress PSMA. Gallium-68 is a radionuclide with an emission yield that allows PET imaging. Based on the intensity of the signals, PET images obtained with gallium (68Ga) gozetotide indicate the presence of PSMA protein in tissues.
At the chemical concentrations used for diagnostic examinations, gallium (68Ga) gozetotide does not have any pharmacodynamic activity.
The sensitivity and specificity of gallium (68Ga) gozetotide were evaluated in the two following prospective studies:
In van Kalmthout et al, 2020, 103 adult male patients with biopsy-proven prostate cancer and intermediate- and high-risk features indicated for extended pelvic lymph node dissection (ePLND) underwent gallium (68Ga) gozetotide PET/CT imaging. PET/CT scans were read by two independent blinded readers and ePLND was the histopathology reference standard for 96 out of 103 (93%) patients. Patient-based sensitivity, specificity, positive and negative predictive value (PPV and NPV, respectively) of gallium (68Ga) gozetotide PET/CT imaging to detect lymph node metastasis (LNM) are summarised in Table 2.
Table 2. Efficacy results in primary staging in patients with biopsy-proven prostate cancer:
Inter-reader agreement was κ = 0.67 for the 2 independent blinded readers. Of the 67 LNM analysed, 26 were detected by gallium (68Ga) gozetotide PET/CT, resulting in 38.8% node-based sensitivity. Median diameter of the metastatic deposit in these detected LNM was 7 mm (range: 0.3-35). The PET reading missed 41 LNM with a median metastatic deposit of 3.0 mm (range: 0.5 to 35.0).
In Fendler et al, 2019, 635 adult male patients with histopathology-proven and biochemical recurrence (BCR) prostate cancer after prostatectomy (N=262), radiation therapy (N=169) or both (N=204) underwent gallium (68Ga) gozetotide PET/CT or PET/MRI imaging. BCR was defined by serum PSA of ≥0.2 ng/mL more than 6 weeks after prostatectomy or by an increase in serum PSA of at least 2 ng/mL above nadir after definitive radiotherapy. Patients had median PSA level of 2.1 ng/mL above nadir after radiation therapy (range: 0.1-1 154 ng/mL). A composite reference standard, including histopathology, serial serum PSA levels and imaging (CT, MRI, and/or bone scan) findings was available for 223 of 635 (35.1%) patients, while histopathology reference standard alone was available for 93 (14.6%) patients. PET/CT scans were read by 3 independent readers blinded to clinical information other than the type of primary therapy and most recent serum PSA level.
Detection of PSMA-positive lesions occurred in 475 of 635 (75%) patients receiving gallium (68Ga) gozetotide and the detection rate was significantly increased with PSA levels. The detection rate of gallium (68Ga) gozetotide PET positive lesion increased with increasing serum PSA levels (see section 4.4). Sensitivity and positive predictive value (PPV) of gallium (68Ga) gozetotide PET/CT imaging are summarised in Table 3. Inter-reader Fleiss κ for gallium (68Ga) gozetotide PET/CT imaging ranged from 0.65 (95% CI: 0.61, 0.70) to 0.78 (95% CI: 0.73, 0.82) across the assessed regions (prostate bed, pelvic nodes, extrapelvic soft tissues and bones).
Table 3. Efficacy results in patients with histopathology-proven and BCR prostate cancer:
| Composite reference standard N=2231 | Histopathology reference standard N=931 | |
|---|---|---|
| Sensitivity per-patient (95% CI) | NA | 92% (84, 96) |
| Sensitivity per-region (95% CI) | NA | 90% (82, 95) |
| PPV per-patient (95% CI) | 92% (88, 95) | 84% (75, 90) |
| PPV per-region (95% CI) | 92% (88, 95) | 84% (76, 91) |
1 Evaluable population
Gallium (68Ga) gozetotide PET/CT imaging was used to identify adult patients with progressive, PSMA-positive mCRPC cancer for the randomised, multicentre, open-label, phase III study VISION, which tested efficacy of Pluvicto plus best standard of care or best standard of care alone. A total of 1 003 male patients, who had been treated with at least one androgen receptor (AR) pathway inhibitor and 1 or 2 prior taxane-based chemotherapy regimens, were selected based on the PSMA expression of their prostate cancer lesions. Patients underwent a gallium (68Ga) gozetotide PET/CT scan to evaluate PSMA expression in lesions defined by central read criteria. Improved overall survival and radiographic progression-free survival were reported in the PSMA-targeted therapy arm.
The European Medicines Agency has waived the obligation to submit the results of studies with Locametz in all subsets of the paediatric population for visualisation of PSMA in prostate cancer (see section 4.2 for information on paediatric use).
Gallium (68Ga) gozetotide exhibits bi-exponential behaviour in blood, with a biological half-life of 6.5 minutes for the fast component and a terminal half-life of 4.4 hours for the slower component. Based on in vitro data, gozetotide mainly distributes to plasma, with a mean blood-to-plasma ratio of 0.71. Gozetotide is 33% bound to human plasma proteins.
The highest radiation absorbed dose of gallium (68Ga) gozetotide occurred in the kidneys, lacrimal glands, salivary glands, urinary bladder wall and liver.
The estimated radiation absorbed doses to these organs for an administered activity of 259 MBq are 62.1 mGy (kidneys), 28.5 mGy (lacrimal glands), 23.1 mGy (salivary glands), 14.8 mGy (urinary bladder wall) and 13.7 mGy (liver).
Based on in vitro data, gallium (68Ga) gozetotide undergoes negligible hepatic and renal metabolism.
Gallium (68Ga) gozetotide is mainly eliminated via the renal route. Approximately 14% of the gallium (68Ga) gozetotide dose administered is excreted in the urine after 2 hours post-injection.
Based on the gallium (68Ga) gozetotide biological and terminal half-life of 4.4 hours and on the gallium-68 physical half-life of 68 minutes, the resulting gallium (68Ga) gozetotide effective half-life is 54 minutes.
Gozetotide is not a substrate, inhibitor or inducer of cytochrome P450 (CYP450) enzymes. Gallium (68Ga) gozetotide is not expected to have any drug interactions with CYP450 substrates, inhibitors or inducers.
Gozetotide is not a substrate of BCRP, P-gp, MATE1, MATE2-K, OAT1, OAT3 or OCT2. Gozetotide is not an inhibitor of BCRP, BSEP, P-gp, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 or OCT2. Gallium (68Ga) gozetotide is not expected to have any drug interactions with the substrates of these transporters.
In the VISION clinical study, 752 of 1 003 (75%) patients were aged 65 years or older. No overall differences in safety and efficacy were observed between these patients and younger patients.
Gallium (68Ga) gozetotide pharmacokinetics and biodistribution are not expected to be affected by renal/hepatic impairment to any clinically relevant extent.
Gozetotide was evaluated in safety pharmacology and single-dose toxicity studies. Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and single-dose toxicity.
Mutagenicity studies and carcinogenicity studies have not been carried out with gallium (68Ga) gozetotide.
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