ORDSPONO Concentrate for solution for infusion Ref.[113373] Active ingredients: Odronextamab

Pharmacotherapeutic group: Antineoplastic agents; other monoclonal antibodies and antibody drug conjugates
ATC code: not yet assigned

Mechanism of action

Odronextamab is a human IgG4-based bispecific antibody that binds to CD20, a B-cell surface antigen present on normal and malignant B cells and CD3, a T-cell antigen associated with the T-cell receptor complex. Simultaneous engagement of both arms of odronextamab results in formation of a synapse between the T cell and the CD20-expressing cell, resulting in T-cell activation and generation of polyclonal cytotoxic T-cell response, which result in redirected lysis of the targeted cells, including malignant B cells.

Pharmacodynamic effects

Circulating B-cell count

Following administration of the recommended doses of odronextamab, median circulating B cells decreased to undetectable levels (<1 cells/microliter) by Week 4 (Cycle 2, Day 1, after the first 80-mg 19 dose for r/r FL or 160-mg dose for r/r DLBCL) administered in patients who had detectable B cells at baseline. The B-cell depletion was sustained while patients remained on treatment.

Cytokine concentration

Concentrations of cytokines (IL-2, IL-6, IL-10, TNF-α, and IFN-γ) in serum were measured. Transient elevation of circulating cytokines was observed at dose levels of 0.2 mg and above. After administration of the recommended step-up dosing regimen of odronextamab, the highest elevation of systemic cytokine concentrations was observed within 24 hours after each intravenous infusion in Cycle 1, typically observed in the first two weeks. The elevated cytokine concentrations generally returned to baseline prior to the next infusion during the step-up dosing period (Cycle 1). Limited cytokine release was observed following subsequent doses.

Immunogenicity

During treatment in Study 1625 and Study 1333, anti-odronextamab antibodies (ADA) were detected in 1.5% (6/400) of patients. No neutralizing antibodies were observed. No evidence of ADA impact on pharmacokinetics or safety was observed, however, data are still limited.

Clinical efficacy and safety

Relapsed or refractory follicular lymphoma (r/r FL)

The efficacy of Ordspono was evaluated in 128 patients with r/r FL (based on WHO Classification 2017) in an open-label, multi-centre, non-randomized, multi-cohort study: Study 1625. The trial included adult patients with histologically confirmed grade 1-3a follicular lymphoma whose disease relapsed or became refractory after at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent. This study included patients with adequate bone marrow and organ function. The study excluded patients with central nervous system (CNS) involvement or prior allogeneic stem cell transplantation.

Following step-up dosing in Cycle 1, patients were treated with Ordspono 80 mg weekly until the end of Cycle 4 followed by 160 mg every 2 weeks until disease progression or unacceptable toxicity. Patients who maintained complete response (CR) for 9 months switched from maintenance dosing of 160 mg every 2 weeks to 160 mg every 4 weeks.

Among the 128 patients with r/r FL in Study 1625, the median age was 61 years (range: 22 to 84), 38% were age 65 or older, 53% were male, 62% were White, 27% were Asian, 51% with Eastern Cooperative Oncology Group performance status (ECOG PS) 0, and 48% with ECOG PS 1. The median number of prior therapies was 3 (range 2 to 13), 72% of patients had disease that was refractory to the last line of therapy, 74% were refractory to an anti-CD20 antibody in an earlier line of therapy, and 42% were double refractory (to anti-CD20 antibody and alkylating agents) in any line of therapy. Fourteen percent of patients had received a prior PI3K inhibitor, 13% had received prior lenalidomide in combination with rituximab, 26% had a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 (intermediate) and 58% had a FLIPI score of 3 to 5 (high), 14% had bulky disease, 49% had progression of disease within 24 months (POD24), and 30% had prior hematopoietic stem cell transplant (HSCT).

Efficacy was established based on the primary efficacy endpoint of objective response rate (ORR) and the secondary endpoint of duration of response (DOR) as assessed by an independent central review committee (IRC) using 2014 Lugano criteria (see Table 8).

Table 8. Efficacy results in patients with r/r FL in Study 1625:

CI=confidence interval; K-M=Kaplan-Meier; NE=Not estimable.
^a DOR is defined as the time from the initial occurrence of a documented PR or CR until the patient experiences an event (documented disease progression or death due to any cause, whichever occurs first).
^b DOCR is defined as the time from the initial occurrence of a documented CR until the patient experiences an event (documented disease progression or death due to any cause, whichever occurs first).

The median follow-up for DOR was 17.6 months (95% CI: 14.8, 29 months).

Relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL)

The efficacy of Ordspono was evaluated in 187 patients with r/r DLBCL (based on WHO Classification 2017) in two open-label, multi-centre, non-randomized, multi-cohort studies: Study 1625 (n=127) and Study 1333 (n=60). Both trials included adult patients with r/r DLBCL after at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent. Study 1333 included patients who progressed after CAR-T therapy. Both studies included patients with adequate bone marrow and organ function. Both studies excluded patients with central nervous system (CNS) involvement or prior allogeneic stem cell transplantation.

Following step-up dosing in Cycle 1, patients were treated with Ordspono 160 mg weekly until the end of Cycle 4 followed by 320 mg every 2 weeks until disease progression or unacceptable toxicity. Patients who maintained CR for 9 months switched from 320 mg every 2 weeks to 320 mg every 4 weeks.

Study 1625: r/r DLBCL CAR-T therapy naïve

Among the 127 patients with r/r DLBCL in Study 1625, the median age was 67 years (range: 24 to 88), 57% were age 65 or older, 60% were male, 48% were White, 42% were Asian, 32% with ECOG PS 0, and 68% with ECOG PS 1. The median number of prior therapies was 2 (range: 2 to 8). The diagnosis was de novo DLBCL in 76%, DLBCL transformed from indolent lymphoma in 19%, and Richter’s transformation in 6%. Of these patients, 87% had disease refractory to last line of therapy, 55% had primary refractory disease, 91% had DLBCL NOS, 9% had high-grade B-cell lymphoma with double-hit or triple-hit gene rearrangements (MYC with BCL2 and/or BCL6 rearrangements), 56% had an International Prognostic Index (IPI) of 3 (high-intermediate) to 5 (high), 44% had activated B-cell-like (ABC) DLBCL/non-germinal centre B-cell-like (non-GCB) DLBCL, 78% were refractory to an anti-CD20 antibody in an earlier line of therapy, 65% were double refractory (to anti-CD20 antibody and alkylating agents) in any line of therapy, and 17% had prior HSCT.

Efficacy was established on the basis of the primary efficacy endpoint of objective response rate (ORR) and secondary endpoint of duration of response (DOR) as assessed by an independent central review committee (IRC) using 2014 Lugano criteria (see Table 9).

Table 9. Efficacy results in patients with r/r DLBCL in Study 1625:

CI=confidence interval; K-M=Kaplan-Meier; NE=Not estimable.
^a DOR is defined as the time from the initial occurrence of a documented PR or CR until the patient experiences an event (documented disease progression or death due to any cause, whichever occurs first).
^b DOCR is defined as the time from the initial occurrence of a documented CR until the patient experiences an event (documented disease progression or death due to any cause, whichever occurs first).

The first response assessment occurred at 12 weeks. The median time to first response was 2.6 months (range: 0.8 to 6.4 months) and the median time to first complete response was 2.6 months (range: 1.4 to 8.1 months).

The median follow-up for DOR was 30 months (95% CI :14.7, 32.2 months).

Study 1333: r/r DLBCL after CAR-T therapy

In Study 1333, of the 60 r/r DLBCL patients who relapsed or were refractory to CAR-T therapy, the median age was 63 years (range: 27 to 82), 45% were age 65 or older, 65% were male, 77% were White, 3.3% were Black, 8% were Asian, 23% with ECOG PS 0, and 77% with ECOG PS 1. The median number of systemic prior therapies was 3 (range: 2 to 9), and 72% were refractory to CAR-T for any line of therapy.

Efficacy was established based on the primary efficacy endpoint of objective response rate (ORR) and the secondary endpoint of duration of response (DOR) as assessed by an independent central review committee (IRC) using 2014 Lugano criteria (see Table 10).

Table 10. Efficacy results in patients with r/r DLBCL in Study 1333:

CI=confidence interval; K-M=Kaplan-Meier; NE=Not estimable.
^a DOR is defined as the time from the initial occurrence of a documented PR or CR until the patient experiences an event (documented disease progression or death due to any cause, whichever occurs first).

The median duration of follow-up for DOR was 15 months (95% CI: 4.3, 16.3 months).

Paediatric population

The European Medicines Agency has deferred the obligation to submit results of studies with Ordspono in one or more subsets of the paediatric population in the Treatment of mature B cell malignancies (see section 4.2 for information on paediatric use).

Conditional approval

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.