Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Incyte Biosciences Distribution B.V., Paasheuvelweg 25, 1105 BP Amsterdam, Netherlands
Pharmacotherapeutic group: Antineoplastic agents, PD-1/PD-L1 (Programmed cell death protein 1/death ligand 1) inhibitors
ATC code: L01FF10
Retifanlimab is an immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed death receptor-1 (PD-1) and blocks its interaction with its ligands PD-L1 and PD-L2. Engagement of PD-1 with its ligands PD-L1 and PD-L2, which are expressed by antigen presenting cells and may be expressed by tumour cells and/or other cells in the tumour microenvironment, results in inhibition of T-cell function such as proliferation, cytokine secretion and cytotoxic activity. Retifanlimab binds to the PD-1 receptor, blocks interaction with its ligands PD-L1 and PD-L2, and potentiates T-cell activity.
Anti-drug antibodies (ADA) were uncommonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.
The efficacy and safety of retifanlimab was studied in the POD1UM-201 study, an open-label, single-arm, multiregional study that enrolled patients with metastatic or recurrent locally advanced MCC who had not received prior systemic therapy for their advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression, severe hepatic or renal impairment, clinically significant cardiac disease, history of organ transplant, or Eastern Cooperative Oncology Group (ECOG) performance score (PS) ≥2 were ineligible. Patients who were HIV-positive, with an undetectable viral load, a CD4+ count ≥300 cells/microliter and receiving antiretroviral therapy were eligible.
Patients received retifanlimab 500 mg every 4 weeks until disease progression or unacceptable toxicity for a maximum of 2 years. Assessment of efficacy was performed every 8 weeks for the first year of therapy and 12 weeks thereafter. The major efficacy outcome measure of confirmed objective response rate, and duration of response were assessed by an independent central review committee according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. All ongoing responses were followed for a minimum of 12 months.
A total of 101 patients were analysed for efficacy. The median age of enrolled patients was 71.1 years (range, 38 – 90 years) with 39 (39%) age 75 or older; 67.3% of patients were male, all but one patient were Caucasian and the Eastern Cooperative Oncology Group performance status was 0 (73.3%) or 1 (26.7%). Thirty-seven percent of patients were reported to have had prior radiotherapy and 68.3% had prior surgery. Ninety percent of patients had metastatic disease. One patient was HIV-positive. The majority of tumour samples tested (72.3%) were positive for Merkel cell polyomavirus (MCPyV).
Efficacy results are summarized in Table 3. The median duration of treatment was 10.3 months (range, 1 day – 24.8 months).
Table 3. Efficacy results in POD1UM-201 study for patients with metastatic or recurrent locally advanced MCC:
| Endpoint | ZYNYZ (N=101) |
|---|---|
| Objective response rate | |
| Objective response rate (95% CI) | 53.5% (43.3, 63.5) |
| Complete response | 16.8% |
| Partial response | 36.6% |
| Duration of response | |
| Median in months (95% CI) | 25.3 (14.2, NE) |
| Minimum, maximum (months) | 1.1, 38.7+ |
CI = confidence interval; NE = not estimable; + denotes ongoing response.
Median duration of follow-up: 17.6 months (range, 1.1 – 38.7 months).
Clinical activity was observed regardless of PD-L1 or MCPyV status. Table 4 summarises the objective response rates by tumour PD-L1 expression and MCPyV status of chemotherapy-naïve MCC patients with central biomarker results in the POD1UM-201 study.
Table 4. Objective response rates by tumour PD-L1 expression and MCPyV status:
| ZYNYZ Objective response rates (95% CI) N=101 | |
|---|---|
| PD-L1 expressiona at cut-off of ≥1% | |
| Positive (n=83) | 57.8% (46.5, 68.6) |
| Negative or missing (n=18) | 33.3% (13.3, 59.0) |
| MCPyV status | |
| Positive (n=73) | 52.1% (40, 63.9) |
| Negative, equivocal, or missing (n=28) | 57.1% (37.2, 75.5) |
MCPyV = Merkel cell polyomavirus.
a PD-L1 expression was determined by IHC using Combined Positive Score (CPS) interpretation.
Of the 101 patients treated with retifanlimab in the efficacy population, 76.2% (77/101) were 65 years or older, and 38.6% (39/101) were 75 years or older. Objective response rates in these age groups were 55.8% (95% CI: 44.1, 67.2) and 48.7% (95% CI: 32.4, 65.2), respectively.
The European Medicines Agency has waived the obligation to submit the results of studies with ZYNYZ in all subsets of the paediatric population for the treatment of MCC. See 4.2 for information on paediatric use.
The pharmacokinetics (PK) of retifanlimab were characterised using a population pharmacokinetics analysis with concentration data collected from 634 patients with various cancers who received retifanlimab doses of 1, 3, 10 mg/kg every 2 weeks, 375 mg every 3 weeks, or 3 mg/kg, 10 mg/kg, 500 mg and 750 mg every 4 weeks. The AUC was dose proportional in the studied dose range. The geometric mean (CV%) of Cmax and AUC at steady state for the recommended 500 mg every 4 weeks dose were 193 mg/L (24.1%) and 2190 day*mg/L (32.4%).
The geometric mean value (CV%) for volume of distribution at steady state is 6.1 L (20.2%).
The metabolic route of retifanlimab has not been characterised. Retifanlimab is expected to be catabolised through protein degradation processes.
A geometric mean (CV%) clearance of 0.314 L/day (36%), without accounting for the time-varying part of the clearance, with a half-life of 14.6 days (31.5%) and 18.7 days (28.7%), after first-dose and at steady-state, respectively, were estimated in the population pharmacokinetic analyses.
The following factors are not expected to have clinically important effects on the pharmacokinetics of retifanlimab: age (range: 18 to 94 years), weight (35 to 133 kg), sex, race, or tumour burden.
The effect of renal impairment on the clearance of retifanlimab was evaluated by population pharmacokinetic analyses in patients with mild (n=277) or moderate (n=142) renal impairment (eGFR between 89 and 30 mL/min/1.73m²; n=419) compared to patients with normal renal function (eGFR ≥90 mL/min/1.73m²; n=200). No clinically important differences were found in the clearance of retifanlimab. There are limited data in patients with severe renal impairment (n=4, lowest eGFR 26.0 mL/min/1.73m²). Retifanlimab has not been studied in patients with end-stage renal disease.
The effect of hepatic impairment on the clearance of retifanlimab was evaluated by population pharmacokinetic analyses in patients with mild (n=78; TB > ULN to 1.5 ULN or AST > ULN) hepatic impairment compared to patients with normal (n=555; TB and AST ≤ ULN) hepatic function. No clinically important differences were found in the clearance of retifanlimab. There are limited data in patients with moderate (n=1; TB between 1.5 and 3.0 times ULN and any AST) hepatic impairment. Retifanlimab has not been studied in patients with severe (TB between 3.0 and 10 times ULN and any AST) hepatic impairment.
No findings of toxicological significance were observed in monkeys in studies of up to 13 weeks duration at exposures sufficiently in excess compared to the clinical exposure at the recommended dose of 500 mg retifanlimab every 4 weeks.
No studies have been performed to assess the potential of retifanlimab for carcinogenicity or genotoxicity.
Animal reproduction and development toxicity studies have not been conducted with retifanlimab. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the foetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the foetus and to result in an increase in foetal loss; therefore, potential risks of administering retifanlimab during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, foetal exposure to retifanlimab may increase the risk of developing immune-mediated disorders or altering the normal immune response.
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