ZYNYZ Concentrate for solution for infusion Ref.[110050] Active ingredients: Retifanlimab

Pharmacotherapeutic group: Antineoplastic agents, PD-1/PD-L1 (Programmed cell death protein 1/death ligand 1) inhibitors
ATC code: L01FF10

Mechanism of action

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.

Pharmacodynamic effects

Immunogenicity

Anti-drug antibodies (ADA) were uncommonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.

Clinical efficacy and safety

Squamous cell carcinoma of the anal canal (SCAC)

The efficacy and safety of retifanlimab in combination with carboplatin and paclitaxel was studied in the POD1UM-303/InterAACT-2 study, a randomised, multicenter, double-blind phase III study that enrolled patients with chemotherapy-naïve metastatic or inoperable locally recurrent SCAC. 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, Eastern Cooperative Oncology Group (ECOG) performance score (PS) ≥2, or evidence of interstitial lung disease or active noninfectious pneumonitis were ineligible. Patients who had not received prior systemic therapy other than a radiosensitising agent or neoadjuvant or adjuvant therapy completed >6 months prior to study entry were eligible as were patients who were HIV-positive if they had an undetectable viral load, a CD4+ count ≥200 cells/microliter and were receiving antiretroviral therapy. The study did not enroll patients who received prior treatment with PD-(L)1 directed therapies. Randomisation was stratified by PD-L1 expression (<1% versus ≥1%), region, and extent of disease (locally recurrent versus metastatic). Patients were randomised (1:1) to receive either:

• Retifanlimab 500 mg intravenously every 4 weeks on Day 1, carboplatin AUC of 5 mg/mL on Day 1, and paclitaxel 80 mg/m² on Days 1, 8, and 15 for 6 cycles followed by retifanlimab 500 mg intravenously every 4 weeks.
• Placebo intravenously every 4 weeks on Day 1, carboplatin AUC 5 mg/mL on Day 1, and paclitaxel 80 mg/m² on Days 1, 8, and 15 for 6 cycles followed by placebo 500 mg intravenously every 4 weeks.

Treatment with retifanlimab continued until disease progression, unacceptable toxicity, death, or withdrawal of consent, for up to 12 months. Tumour response assessments were performed every 8 weeks throughout the treatment period. Patients who received placebo in combination with carboplatin and paclitaxel and who experienced documented disease progression (verified by blinded independent central review (BICR)), had the option of receiving retifanlimab 500 mg monotherapy in a crossover treatment period.

Among the 308 patients enrolled, the median age was 62 years (range, 29–86 years) with 31 (10.1%) age 75 or older; 27.9% of patients were male, 87.3% of patients were Caucasian and the ECOG performance status was 0 (54.5%) or 1 (45.1%). Seventy-one percent of patients were reported to have had prior radiotherapy and 34.7% had prior surgery. Four percent of patients were HIV-positive. Eighty-three percent of patients had metastatic disease at baseline. PD-L1 expression of ≥1% was present in 91% of tumours.

The primary efficacy endpoint was progression-free survival (PFS) as assessed by a BICR according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and the key secondary endpoint was overall survival (OS). Additional secondary efficacy endpoints included objective response rate (ORR) and duration of response (DOR).

Efficacy results are summarised in Table 3, Figure 1, and Figure 2.

Table 3. Efficacy results in POD1UM-303/InterAACT-2 for patients with metastatic or inoperable locally recurrent SCAC:

CI = confidence interval.
^a Based on primary analysis.
^b Median duration of follow-up for PFS: ZYNYZ in combination with carboplatin and paclitaxel = 7.6 months (range, 0 – 33.9 months); placebo in combination with carboplatin and paclitaxel = 7.1 months (range, 0 – 27.4 months).
^c Two-sided p-value based on the stratified log-rank test.
^d Based on final analysis; OS did not reach the prespecified threshold for statistical significance.

Figure 1. Kaplan-Meier curve for PFS in POD1UM-303/InterAACT-2 (Final Analysis):

Figure 2. Kaplan-Meier curve for OS in POD1UM-303/InterAACT-2 (Final Analysis):

Merkel cell carcinoma (MCC)

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 4. The median duration of treatment was 10.3 months (range, 1 day – 24.8 months).

Table 4. Efficacy results in POD1UM-201 study for patients with metastatic or recurrent locally advanced MCC:

CI = confidence interval; NE = not estimable; + denotes ongoing response. Median duration of follow-up: 17.6 months (range, 1.1 – 38.7 months).

Efficacy and PD-L1/MCPyV status

Clinical activity was observed regardless of PD-L1 or MCPyV status. Table 5 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 5. Objective response rates by tumour PD-L1 expression and MCPyV status:

MCPyV = Merkel cell polyomavirus.
^a PD-L1 expression was determined by IHC using Combined Positive Score (CPS) interpretation.

Elderly population

Squamous cell carcinoma of the anal canal (SCAC)

Of the 154 patients treated with retifanlimab in combination with carboplatin and paclitaxel in the efficacy population in POD1UM-303/InterAACT-2, 37.7% (58/154) were 65 years or older, and 9.1% (14/154) were 75 years or older. No overall differences in efficacy were observed between elderly patients and younger patients treated with retifanlimab in combination with carboplatin and paclitaxel.

Merkel cell carcinoma (MCC)

Of the 101 patients treated with retifanlimab in the efficacy population in POD1UM-201, 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.

Paediatric population

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 and SCAC. See 4.2 for information on paediatric use.