Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other monoclonal antibodies and antibody drug conjugates, ATC code: L01FX28

Mechanism of action

Glofitamab is a bispecific monoclonal antibody that binds bivalently to CD20 expressed on the surface of B cells and monovalently to CD3 in the T-cell receptor complex expressed on the surface of T cells. By simultaneous binding to CD20 on the B cell and CD3 on the T cell, glofitamab mediates the formation of an immunological synapse with subsequent T-cell activation and proliferation, secretion of cytokines and release of cytolytic proteins that results in the lysis of CD20-expressing B cells.

Pharmacodynamics

In Study NP30179, 84% (84/100) patients were already B cell depleted (< 70 cells/µL) before pre- treatment with obinutuzumab. B cell depletion increased to 100% (94/94) after obinutuzumab pre- treatment prior to Columvi treatment initiation and remained low during Columvi treatment.


During Cycle 1 (step-up dosing), transient increases in plasma IL-6 levels were observed at 6 hours post Columvi infusion, which remained elevated at 20 hours post-infusion and returned to baseline prior to the next infusion.

Cardiac electrophysiology
In Study NP30179, 16/145 patients who were exposed to glofitamab experienced a post-baseline QTc value > 450ms. One of these cases was assessed to be of clinical significance by the investigator. No patients discontinued treatment due to QTc prolongation.

Clinical efficacy and safety

Relapsed or refractory DLBCL
An open-label multicenter, multi-cohort trial (NP30179) was conducted to evaluate Columvi in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. In the single-arm monotherapy DLBCL cohort (n=108), patients with relapsed or refractory DLBCL were required to have received at least two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an anthracycline agent. Patients with FL3b and Richter transformation were not eligible. Patients were expected to present CD20-positive DLBCL, but biomarker eligibility was not a requirement for inclusion (see section 4.4).

The study excluded patients with ECOG performance status ≥ 2, significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina), significant active pulmonary disease, impaired renal functions (CrCL < 50 mL/min with elevated serum creatinine level), active autoimmune disease requiring immunosuppressive therapy, active infections (i.e., chronic active EBV, acute or chronic hepatitis C, hepatitis B, HIV), progressive multifocal leukoencephalopathy, current or a history of CNS lymphoma or CNS disease, a history of macrophage activation syndrome / hemophagocytic lymphohistiocytosis, prior allogeneic stem cell transplant, prior organ transplantation, or hepatic transaminases ≥ 3 × ULN.

All patients received pre-treatment with obinutuzumab at Cycle 1 Day 1. Patients received 2.5 mg of Columvi at Cycle 1 Day 8, 10 mg of Columvi at Cycle 1 Day 15, and 30 mg of Columvi at Cycle 2 Day 1 as per the step-up dosing schedule. Patients continued to receive 30 mg of Columvi on Day 1 of Cycles 3 to 12. The duration of each cycle was 21 days. Patients received a median of 5 cycles of Columvi treatment (range: 1 to 13 cycles) with 34.7% receiving 8 or more cycles and 25.7% receiving 12 cycles of Columvi treatment.

The baseline demographic and disease characteristics were: median age 66 years (range: 21 to 90 years) with 53.7% being 65 years or older and 15.7% being 75 years or older; 69.4% males; 74.1% white, 5.6% Asian and 0.9% Black or African American; 5.6% Hispanic or Latino; and ECOG performance status of 0 (46.3%) or 1 (52.8%). Most patients (71.3%) had DLBCL not otherwise specified, 7.4% had DLBCL transformed from follicular lymphoma, 8.3% had high grade B-cell lymphoma (HGBCL) or another histology transformed from follicular lymphoma, 7.4% had HGBCL, and 5.6% had primary mediastinal B-cell lymphoma (PMBCL). The median number of prior lines of therapy was 3 (range: 2 to 7), with 39.8% of patients having received 2 prior lines and 60.2% having received 3 or more prior lines of therapy. All patients had received prior chemotherapy (all patients received alkylator therapy and 98.1% of patients received anthracycline therapy) and all patients had received prior anti-CD20 monoclonal antibody therapy; 35.2% of patients had received prior CAR T-cell therapy, and 16.7% of patients had received autologous stem cell transplant. Most patients (89.8%) had refractory disease, 60.2% of patients had primary refractory disease and 83.3% of patients were refractory to their last prior therapy.

The primary efficacy outcome measure was complete response (CR) rate as assessed by an independent review committee (IRC) using 2014 Lugano criteria. The overall median duration of follow-up was 15 months (range: 0 to 21 months). The secondary efficacy outcome measures included overall response rate (ORR), duration of response (DOR), duration of complete response (DOCR), and time to first complete response (TFCR) as assessed by IRC.

Efficacy results are summarized in Table 6.
Table 6. Summary of efficacy in patients with relapsed or refractory DLBCL 
Efficacy endpoints                                                            Columvi N=108
Complete response
Patients with CR, n (%)                                                    38 (35.2) 95% CI                                                                   [26.24, 44.96] Overall response rate
Patients with CR or PR, n (%)                                              54 (50.0) 95% CI                                                                   [40.22, 59.78] Duration of complete response1
Median DOCR, months [95% CI]                                            NE [18.4, NE] Range, months                                                               02202 12-month DOCR, % [95% CI]3                                            74.6 [59.19, 89.93] Duration of response4
Median duration, months [95% CI]                                         14.4 [8.6, NE] Range, months                                                                02202 Time to first complete response
Median TFCR, days [95% CI]                                                 42 [41, 47] Range, days                                                                 31–308 CI=confidence interval; NE=not estimable; PR=partial response.
Hypothesis testing was conducted on the primary endpoint of IRC-assessed CR rate.
1 DOCR is defined as the date of first complete response until disease progression or death due to any cause.
2 Censored observations.
3 Event-free rates based on Kaplan-Meier estimates.
4 DOR is defined as the date of first response (PR or CR) until disease progression or death due to any cause.


The median follow-up for DOR was 12.8 months (range: 0 to 20 months).

Immunogenicity

Of 418 patients in study NP30179, only two (0.5%) patients were negative for anti-glofitamab antibodies at baseline and became positive following treatment. Due to the limited number of patients with antibodies against glofitamab, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy or safety.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Non-compartmental analyses indicate that glofitamab serum concentration reaches the maximal level (Cmax) at the end of infusion and declines in a bi-exponential fashion. Glofitamab exhibits linear and dose-proportional pharmacokinetics over the dose range studied (0.005 to 30 mg) and is independent of time.

Absorption

Columvi is administered as an intravenous infusion. Peak concentration of glofitamab (Cmax) was reached at the end of the infusion.

Distribution

Following intravenous administration, the central volume of distribution was 3.33 L, which is close to total serum volume. The peripheral volume of distribution was 2.18 L.

Biotransformation

The metabolism of glofitamab has not been studied. Antibodies are cleared principally by catabolism.
Elimination

The glofitamab serum concentration-time data are described by a population pharmacokinetic model with two compartments, and both time-independent clearance and time-varying clearance.

The time-independent clearance pathway was estimated as 0.602 L/day and the initial time-varying clearance pathway as 0.396 L/day, with an exponential decay over time (Kdes ~ 0.445/day). The estimated decay half-life from the initial total clearance value to the time-independent clearance only was estimated as 1.56 days.

The effective half-life in the linear phase (i.e., after the contribution of time-varying clearance has collapsed to a negligible amount) is 6.54 days (95% CI: 3.74, 9.41) based on the population pharmacokinetic analysis.

Special populations

Elderly
No differences in glofitamab exposure were noted in patients 65 years of age and older and those under 65 years based on population pharmacokinetic analysis.

Renal impairment
The population pharmacokinetic analysis of glofitamab showed that creatinine clearance does not affect the pharmacokinetics of glofitamab. The pharmacokinetics of glofitamab in patients with mild or moderate renal impairment (CrCL 30 to < 90 mL/min) were similar to those in patients with normal renal function. Columvi has not been studied in patients with severe renal impairment.

Hepatic impairment
Population pharmacokinetic analyses showed mild hepatic impairment does not affect the pharmacokinetics of glofitamab. The pharmacokinetics of glofitamab in patients with mild hepatic impairment (total bilirubin > ULN to ≤ 1.5  ULN or AST > ULN) were similar to those with normal hepatic functions. Columvi has not been studied in patients with moderate or severe hepatic impairment.

Effects of age, gender and body weight
No clinically significant differences in the pharmacokinetics of glofitamab were observed based on age (21 years to 90 years), gender and body weight (31 kg to 148 kg).