COLUMVI Concentrate for solution for infusion Ref.[51062] Active ingredients: Glofitamab

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) of patients were already B-cell depleted (<70 cells/μL) before pre-treatment with obinutuzumab. The proportion of patients with B-cell depletion increased to 100% (94/94) after obinutuzumab pre-treatment prior to Columvi treatment initiation, and B-cell counts 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 GO41944 (STARGLO), 63.9% (115/180) of patients were already B-cell depleted (<70 cells/μL) before pre-treatment with obinutuzumab. The proportion of patients with B-cell depletion increased to 79.4% (143/180) after obinutuzumab pre-treatment prior to Columvi treatment initiation, and B-cell counts remained low during Columvi treatment.

Cardiac electrophysiology

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

In study GO41944 (STARGLO), 16/172 patients who were exposed to Columvi experienced a post-baseline QTc value >450 ms. No patients discontinued treatment due to QTc prolongation.

Clinical efficacy and safety

Relapsed or refractory DLBCL

Columvi monotherapy

An open-label multicentre, 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); 34.7% received 8 or more cycles and 25.7% received 12 cycles of Columvi treatment.

The baseline demographic and disease characteristics were: median age 66 years (range: 21 to 90 years) with 53.7% aged 65 years or older and 15.7% aged 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 large B-cell lymphoma (PMBCL). The median number of prior lines of therapy was 3 (range: 2 to 7); 39.8% of patients received 2 prior lines and 60.2% 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 summarised in Table 8.

Table 8. Summary of efficacy in patients with relapsed or refractory DLBCL:

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).

Columvi in combination with gemcitabine and oxaliplatin

The efficacy of Columvi in combination with gemcitabine and oxaliplatin (Columvi+GemOx) was evaluated in study GO41944 (STARGLO), an open-label multicentre, randomised clinical trial in 274 patients with relapsed or refractory DLBCL not otherwise specified (DLBCL NOS).

The study included patients with DLBCL NOS who received only one prior line of therapy who were not candidates for autologous stem cell transplant (ASCT), or who had received ≥2 prior therapies. Patients were required to have ECOG performance status ≤2, CrCL ≥30 mL/min, hepatic transaminases ≤2.5 × ULN, no significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 3 months, unstable arrhythmias, or unstable angina) and no current or prior CNS lymphoma or CNS disease, no active autoimmune disease requiring immunosuppressive therapy, no active infections (i.e., chronic active EBV, active hepatitis B, hepatitis C), and no history of any of the following: HIV, progressive multifocal leukoencephalopathy, hemophagocytic lymphohistiocytosis, prior allogeneic stem cell transplant, or prior organ transplantation. Patients with HGBCL, PMBCL, or history of transformation of indolent disease to DLBCL were excluded.

Patients who received only one prior line of therapy were not considered candidates for transplant if they met at least one of the following criteria: age ≥70 years, ECOG performance status 2, left ventricular ejection fraction ≤40%, insufficient response to salvage therapy prior to ASCT, CrCL ≤45 mL/min, other comorbidities or criteria that preclude use of transplant based on local practice standards or in the investigator’s opinion, or patient refusal of high-dose chemotherapy and/or transplant.

Patients were randomised 2:1 to receive Columvi+GemOx (N=183) or rituximab in combination with gemcitabine plus oxaliplatin (R-GemOx; N=91) for 8 cycles, followed by 4 additional cycles of Columvi monotherapy for patients in the Columvi+GemOx arm. Randomisation was stratified by number of previous lines of systemic therapy for DLBCL (1 vs. ≥2) and outcome of last systemic therapy (relapsed vs. refractory).

In the Columvi+GemOx arm, patients received pre-treatment with obinutuzumab at Cycle 1 Day 1 followed by 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. Gemcitabine (1000 mg/m²) and oxaliplatin (100 mg/m²) were administered intravenously on Day 2 of Cycle 1 and then on Day 1 of subsequent cycles, up to Cycle 8. The duration of each cycle was 21 days in both arms. Patients received a median of 11 cycles of Columvi treatment (range: 1 to 13 cycles); 64.5% received 8 or more cycles and 44.8% received 12 cycles of Columvi treatment.

The baseline demographic and disease characteristics were: median age 68 years (range: 20 to 88 years) with 62.8% aged 65 years or older and 23.7% aged 75 years or older; 57.7% males; 42% white, 50% Asian, and 1.1% Black or African American; 5.8% Hispanic or Latino; and ECOG performance status of 0 (43.3%), 1 (46.6%), or 2 (10.1%). The majority of patients (62.8%) had received 1 prior line of systemic therapy; 37.2% of patients received 2 or more prior lines. All patients had received prior chemotherapy and most (98.5%) had received prior anti-CD20 monoclonal antibody therapy; 7.7% of patients had received prior CAR T-cell therapy, and 4.0% of patients had received autologous stem cell transplant. The majority of patients (66.8%) had refractory disease, 55.8% of patients had primary refractory disease, and 60.6% of patients were refractory to their last prior therapy. The most common reasons why patients were not considered candidates for transplant included age (42.3%), patient refused high-dose chemotherapy and/or transplant (34.7%), and insufficient response to salvage therapy (9.9%).

The primary efficacy outcome measure was overall survival (OS). At the time of the prespecified primary analysis, a statistically significant improvement in OS was observed for patients randomised to the Columvi+GemOx arm compared to patients randomised to R-GemOx (HR 0.59, 95% CI: 0.40, 0.89; p-value=0.011). Median OS in the R-GemOx arm was 9.0 months (95% CI: 7.3, 14.4) and was not reached in the Columvi+GemOx arm (95% CI: 13.8, NE). Statistically significant improvements in progression-free survival (PFS) and CR rate, as assessed by an IRC, were also observed with Columvi+GemOx over R-GemOx. Median PFS was 12.1 months (95% CI: 6.8, 18.3) in the Columvi+GemOx arm versus 3.3 months (95% CI: 2.5, 5.6) in the R-GemOx arm (HR 0.37, 95% CI: 0.25, 0.55; p-value<0.001). The rate of complete response was 50.3% with Columvi+GemOx versus 22.0% with R-GemOx, a difference of 28.3% (p-value<0.001).

Overall survival, PFS, and CR results from an updated analysis conducted after an additional 10.5 months of follow-up continue to demonstrate benefit of Columvi+GemOx over R-GemOx. The key results are summarised in Table 9. Kaplan-Meier plots for OS and PFS from the updated analysis are presented in Figure 1 and Figure 2, respectively. Exploratory subgroup analysis at the time of the updated analysis showed an OS hazard ratio of 1.09 (95% CI: 0.54, 2.18) and PFS hazard ratio of 0.84 (95% CI: 0.44, 1.59) for patients enrolled in Europe.

Table 9. Efficacy in patients with relapsed or refractory DLBCL treated with Columvi in combination with gemcitabine and oxaliplatin (ITT):

CI=confidence interval; HR=hazard ratio; NE=not estimable.

Figure 1. Kaplan-Meier plot of overall survival in study GO41944 (STARGLO, updated analysis; ITT):

Figure 2. Kaplan Meier plot of IRC-assessed progression-free survival in study GO41944 (STARGLO, updated analysis; ITT):

Immunogenicity

Across studies, of 608 patients, only 4 patients (0.7%) 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.

Paediatric population

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).