KORJUNY Concentrate for solution for infusion Ref.[114664] Active ingredients: Catumaxomab

Pharmacotherapeutic group: Antineoplastic agents, other monoclonal antibodies and antibody drug conjugates
ATC code: L01FX03

Mechanism of action

Catumaxomab is a trifunctional rat-mouse hybrid monoclonal antibody that is specifically directed against the epithelial cell adhesion molecule (EpCAM) and the CD3 antigen. The EpCAM antigen is expressed on most cancers especially carcinomas. CD3 is expressed on mature T-cells as a component of the T-cell receptor. A third functional binding site in the Fc-region of catumaxomab enables interaction with accessory immune cells via Fc-gamma receptors. Due to catumaxomab’s binding properties, tumour cells, T-cells and accessory immune cells come in close proximity. Thereby, a concerted immunoreaction against tumour cells is induced which includes different mechanisms of action such as T-cell activation, T-cell mediated killing via the granzyme/perforin system, antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and phagocytosis. This results in destruction of tumour cells in the peritoneal cavity, thereby eliminating a major cause of malignant ascites.

Pharmacodynamic effects

The anti-tumour activity of catumaxomab has been demonstrated in vitro and in vivo. Effective catumaxomab-mediated killing of tumour cells in vitro was observed for target cells with low and high expression of the EpCAM antigen, independent of the primary tumour type. The in vivo anti-tumour activity of catumaxomab was confirmed in an immunologically compromised mouse model of ovarian carcinoma, where tumour development was delayed by an intraperitoneal treatment with catumaxomab and human peripheral blood mononuclear cells.

Clinical efficacy

The efficacy of catumaxomab was evaluated in one phase II/III clinical study. Patients of non-Caucasian origin have not been included in this clinical study.

IP-REM-AC-01

A pivotal, two-arm, randomised, open-label, phase II/III clinical study in 258 patients with symptomatic malignant ascites due to EpCAM-positive carcinomas of whom 170 were randomised to catumaxomab treatment. Presence of EpCAM-positive cells in ascites fluid was determined using an immunohistochemistry (IHC) assay. Patients were eligible for enrolment if ascites fluid contained ≥400 EpCAM-positive cells/10⁶ analysed ascites cells. This study compared paracentesis plus catumaxomab versus paracentesis alone (control).

Catumaxomab was applied in patients where standard therapy was not available or no longer feasible and who had a Karnofsky performance status of at least 60. Catumaxomab was administered as four intraperitoneal infusions with increased doses of 10, 20, 50 and 150 micrograms on day 0, 3, 7 and 10, respectively. On infusion days (Days 0, 3, 7, 10), patients remained hospitalised for at least 24 h (see section 4.2).

Among patients randomised (n=258), 79% of patients were female (100% in the ovarian cancer stratum, 59% in the non-ovarian cancer stratum). Mean age was 58.5 years in the ovarian cancer stratum and 58.8 years in the non-ovarian cancer stratum. Caucasians accounted for 99% of patients overall. The most frequent cancer types in the non-ovarian cancer stratum was gastric cancer (51%), followed by breast cancer (10%); other cancer types (colon, pancreas, lung, endometrium, others) were individually present in < 10% of patients in the non-ovarian cancer stratum.

In this study, the primary efficacy endpoint was puncture-free survival in the randomised, controlled main study period, which was a composite endpoint defined as the time to first need for therapeutic ascites puncture or death, whichever occurred first. The results for puncture-free survival are presented in Table 3. Kaplan Meier estimates for puncture-free survival are given in Figure 1.

Table 3. Efficacy results (puncture-free survival) of study IP-REM-AC-01:

Patients who completed the study at the scheduled study end without therapeutic puncture were censored at the date of the scheduled study end. Patients who discontinued the study after randomisation but before the endpoint of puncture or death were censored at the date of premature discontinuation.

HR: Hazard ratio, PuFS: puncture-free survival

Figure 1. Kaplan-Meier estimates of puncture-free survival in study IP-REM-AC-01:

Ovarian cancer:

Non-ovarian cancer:

Compared with paracentesis alone (control), treatment with paracentesis and catumaxomab in patients with malignant ascites due to EpCAM-positive carcinomas prolonged puncture-free survival from 11 to 48 days in ovarian cancer patients and from 14 to 30 days in non-ovarian cancer patients.

After completion of the main study period, patients were further observed until the end of their lifetime to assess overall survival. Patients receiving paracentesis (control) could cross over to paracentesis and catumaxomab after completion of the main study period; nevertheless, these patients were counted as control patients despite the crossover. There was no worsening in overall survival in patients receiving paracentesis and catumaxomab relative to patients receiving paracentesis (Table 4).

Table 4. Overall survival of study IP-REM-AC-01:

¹ Crossover patients were counted as control patients despite crossing over to paracentesis and catumaxomab treatment; this were 45 of 88 (51%) patients in the control arm.

Immunogenicity

The induction of anti-catumaxomab antibodies is an intrinsic effect of murine monoclonal antibodies. Data on catumaxomab derived from the pivotal study show that <10% of patients were anti-catumaxomab antibodies positive before the 4th infusion. Anti-catumaxomab antibodies were present in 95% of patients one month after the last catumaxomab infusion.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Korjuny in all subsets of the paediatric population in the treatment of malignant ascites (see section 4.2 for information on paediatric use).