Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Pharmacotherapeutic group: Antineoplastic agents, other monoclonal antibodies and antibody drug conjugates
ATC code: L01FX28
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.
In Study NP30179, 84% (84/100) patients were already B cell depleted (<70 cells/µL) before pretreatment with obinutuzumab. B cell depletion increased to 100% (94/94) after obinutuzumab pretreatment 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.
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.
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 5.
Table 5. 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).
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.
The European Medicines Agency has deferred the obligation to submit the results of studies with Columvi in one or more subsets of the paediatric population in treatment of mature B-cell neoplasms. (see section 4.2 for information on paediatric use).
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.
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.
Columvi is administered as an intravenous infusion. Peak concentration of glofitamab (Cmax) was reached at the end of the infusion.
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.
The metabolism of glofitamab has not been studied. Antibodies are cleared principally by catabolism.
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.
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.
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.
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.
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).
No studies have been conducted to establish the carcinogenic potential and mutagenic potential of glofitamab.
No fertility assessments in animals have been performed to evaluate the effect of glofitamab.
No reproductive and developmental toxicity studies in animals have been performed to evaluate the effect of glofitamab. Based on low placental transfer of antibodies during the first trimester, the mechanism of action of glofitamab (B cell depletion, target-dependent T cell activation, and cytokine release), the available safety data with glofitamab and data on other anti-CD20 antibodies, the risk for teratogenicity is low. Prolonged B cell depletion can lead to increased risk of opportunistic infection, which may cause foetal loss. Transient CRS associated with Columvi administration may also be harmful to the foetus (see section 4.6).
In a study in cynomolgus monkeys, animals experiencing severe CRS after a single intravenous dose of glofitamab (0.1 mg/kg) without obinutuzumab pre-treatment had erosions in the gastrointestinal tract and inflammatory cell infiltrates in spleen and sinusoids of the liver and sporadically in some other organs. These inflammatory cell infiltrates were likely secondary to cytokine-induced immune cell activation. Pre-treatment with obinutuzumab resulted in the attenuation of glofitamab-induced cytokine release and related adverse effects by depleting B cells in peripheral blood and lymphoid tissue. This allowed at least 10 times higher doses of glofitamab (1 mg/kg) in cynomolgus monkeys resulting in a Cmax of up to 3.74 times the human Cmax at the recommended 30 mg dose.
All findings with glofitamab were considered pharmacologically mediated effects and reversible. Studies longer than 4 weeks were not performed, as glofitamab was highly immunogenic in cynomolgus monkeys and led to loss of exposure and loss of the pharmacologic effect.
As all relapsed or refractory DLBCL patients to be treated have been exposed to anti-CD20 treatment before, the majority will likely have low circulating B cell levels due to residual effects of prior antiCD20 therapy, before treatment with obinutuzumab. Therefore, the animal model without prior rituximab (or other anti-CD20) treatment may not fully reflect the clinical context.
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