A new step-up dosing schedule with glofitamab, an investigational T-cell engaging bispecific antibody, has demonstrated strong clinical activity, with high complete response rates in patients with hard-to-treat relapsed or refractory non-Hodgkin lymphoma (NHL), according to data presented at the ASH 2020 annual meeting.
The results of the first-in-human clinical trial of glofitamab showed more than 50% complete response rates. The study included pretreatment with obinutuzumab (Gazyva), which was intended to reduce cytokine release syndrome (CRS) and to enable an increasing dosing schedule. The majority of patients were still receiving treatment with glofitamab at the data cutoff.
“Step-up dosing of glofitamab combined with obinutuzumab pretreatment is a useful CRS-mitigation strategy. The new dosing strategy allowed administration of a high glofitamab target dose of 30 mg, which is higher than the maximum tolerated dose when using a fixed-dose regimen, and with a lower risk of CRS grade 2 or higher,” said lead study investigator Martin Hutchings, MD, PhD, of Rigshospitalet, Copenhagen, Denmark.
For this clinical trial, patients received 1000 mg obinutuzumab 7 days before the first administration of glofitamab. Glofitamab was given intravenously every 3 weeks for up to 12 cycles, with step-up doses starting at 2.5 mg, then 10 mg, and then 16 mg or 30 mg. Inclusion criteria included a diagnosis of relapsed or refractory CD20-positive B-cell NHL, in adults who received at least 1 previous line of therapy, measurable disease, adequate organ function, and good performance status (grade 0 or 1).
A total of 52 patients were enrolled in the study (median age, 68 years). The patients were heavily pretreated, with a median of 3 previous lines of therapy, and the majority of patients had disease refractory to the most recent line of therapy and to an anti–CD20-containing therapy regimen.
More than 50% of the patients had aggressive lymphomas, and all patients with indolent lymphomas had follicular lymphoma, grade I to IIIA.
“Compared with fixed-dose cohorts, the high response rates in follicular lymphoma are maintained, while the complete response rates in aggressive lymphomas appear higher in the step-up cohorts,” said Dr Hutchings, who noted that the vast majority of both aggressive and indolent lymphomas had clear tumor regressions.
“Complete response rates in both groups were higher than 50%,” Dr Hutchings added.
At the time of the data cutoff, the majority of patients were in remission and were still receiving treatment. In patients with aggressive lymphoma, 13 of the 15 complete remissions are ongoing, whereas in patients with follicular lymphoma, all 13 complete remissions are ongoing.
Almost all patients had ≥1 adverse events. Serious treatment-related adverse events were observed in approximately 50% of the patients, and no fatal adverse events were reported, said Dr Hutchings. Only 2 adverse events led to treatment discontinuation.
Of note, the CRS-mitigation strategy was successful.
“Although overall rates of CRS were similar between the fixed-dosing and step-up dosing cohorts, step-up dosing reduced the frequency of grade 2 or higher CRS,” said Dr Hutchings. Furthermore, 36% of patients who received fixed dosing of ≥10 mg had more serious CRS compared with 31% of patients in the step-up dosing cohorts.
All patients who received the 25-mg fixed dose had CRS after the first administration, and the majority of cases were grade ≥2. By contrast, only 25% of patients in the step-up dosing cohort had CRS after their first treatment with the target dose of 30 mg glofitamab.
Of the 52 patients enrolled on study, 64% had CRS, but only 2 patients had CRS higher than grade 2. CRS events were also confined to cycles 1 and 2, said Dr Hutchings. The median time to CRS from the first glofitamab dose was 14 hours, with a median duration of 29 hours.
Tocilizumab (Actemra) was used to manage CRS in 8 patients. In all, 3 patients were admitted to an intensive care unit; 8 patients received low-flow oxygen; 3 patients received single vasopressors; and 1 patient required mechanical ventilation.
Overall, the safety profile of glofitamab after the step-up dosing was manageable, Dr Hutchings concluded.
