Glofitamab Leads to Significantly High CR Rate in R/R Hodgkin Lymphoma

Patients with relapsed or refractory non-Hodgkin lymphomas (NHLs) treated with Glofitamab (RG6026) in the phase 1 NP30179 study (NCT03075696, had a significant rate of complete responses.

Results from the study of the T-cell–engaging bispecific antibody presented at the 2020 American Society of Hematology (ASH) Annual Meeting for the first-in-human study also showed that the safety profile for glofitamab was manageable with mostly low-grade cytokine release syndrome (CRS) events reported.

“Thus, step-up dosing of glofitamab is a useful CRS mitigation strategy in addition to obinutuzumab [Gazyva] pretreatment, allowing administration of a high glofitamab target dose of 30 mg, higher than the maximum tolerated dose, when using fixed-dose regimen and with a lower risk of CRS grade 2 or higher,” Martin Hutchings, MD, PhD, explained in his presentation.

Hutchings, a senior consultant in the Department of Hematology and Phase 1 Unit at Rigshospitalet in Copenhagen, Denmark, noted that the antibody has a unique 2:1 molecular configuration, consisting of 2 fragment antigen binding regions for CD20 on B cells and one binding region for CD3 on T cells.

The trial enrolled patients with CD20-positive B-cell relapsed/refractory NHLs who had at least 1 measurable lesion, adequate hematological and liver function, an ECOG performance status of 0 or 1, and had received at least 1 prior line of therapy.

Treatment with step-up dosing consisted of 1000 mg pretreatment with obinutuzumab on day –7 followed by step-up doses of intravenous glofitamab at 2.5 mg on day 1 of cycle 1, 10 mg on day 8 of cycle 1, then either 16 or 30 mg another week later (day 1, cycle 2) in 2 different cohorts. Glofitamab treatment was continued every 3 weeks from cycle 2 and up through 12 cycles.

The study looked to explore the safety, tolerability, pharmacokinetics, and antitumor activity of glofitamab as well as to determine the maximum tolerated dose or optimal biological dose and the recommended phase 2 dose.

A total of 52 patients were treated in the 2 cohorts; these patients had a median age of 68 years (range, 44-85) and 53.8% were male. More than half of the patients (53.8%) had aggressive NHL, including 10 with diffuse large B-cell lymphoma, 6 with transformed follicular lymphoma, 5 with Richter’s transformation, 5 with mantle cell lymphoma, 1 with high-grade B-cell lymphoma, and 1 with grade 3B follicular lymphoma. Twenty-four patients (46.2%) had indolent follicular lymphoma between grade 1 and 3A.

A median of 3 lines of therapy had previously been received by the patients (range, 1-12) consisting of chemotherapy and an anti-CD20 monoclonal antibody in all patients, autologous stem cell transplant in 21.2%, a PI3K inhibitor in 9.6%, chimeric antigen receptor T-cell therapy in 5.8%, and cancer immunotherapy in 1.9%. A majority of the patients were refractory to any therapy (84.6%), to their most recent therapy (76.9%), and to any prior anti-CD20 therapy (73.1%).

When glofitamab was given at ≥10 mg in fixed-dose cohorts, the overall response rate (ORR) in 105 patients was 51.4%, including complete responses (CRs) in 36.2%, according to findings presented earlier this year at the 2020 European Hematology Association Congress.2 In patients with indolent NHL (n = 18), the ORR was 66.7% and the CR rate was 50.0% compared with 49.4% and 34.1%, respectively, in patients with aggressive NHL (n = 85).

In the step-up cohorts, the ORR was 63.5% for all patients with a complete metabolic response (CMR) observed in 53.8% of patients.1 In those with indolent NHL (n = 24), the ORR was 66.7% and the CMR rate was 54.2% versus 60.7% and 53.6%, respectively, in the aggressive NHL group (n = 28).

At the time of data cutoff, 2 patients with aggressive NHL and 6 with indolent NHL had not yet had their response assessment and were considered nonresponders in these data.

CRs were usually achieved early and observed as of the first or second response assessment. A majority of the patients have ongoing responses, including 13 of 15 responders with aggressive NHL and all 13 responders with indolent NHL.

Almost all patients (98.1%) had at least 1 adverse event (AE), and 88.5% had treatment-related events. Serious treatment-related AEs were reported in 53.8% and treatment-related events were grade 3/4 in 34.6%. No fatal AEs were reported in the study and only 2 patients discontinued treatment due to AEs. Discontinuations were due to grade 4 neutropenia in 1 patient and a grade 4 colitis plus grade 3 sepsis in another patient for whom colitis later resolved with ongoing CR observed.

The most common AEs related to treatment with glofitamab were CRS, neutropenia, pyrexia, and thrombocytopenia.

Hutchings noted that the rates of CRS were similar between the fixed (≥10 mg) and step-up dosing cohorts, but grade ≥2 CRS events were reduced in the step-up dosing cohorts (36.3% vs 30.7%). All patients treated with the 25-mg fixed dose had grade CRS, the majority of which was grade 2 or higher in severity, during cycle 1. Comparatively, of the patients who received the 30-mg dose after step-up dosing, only 25.0% had any-grade CRS.

In the overall population from the step-up dosing cohorts, CRS was reported in 63.5% but was only grade 3/4 in severity for 2 patients. These CRS events were only observed in cycles 1 and 2 with a median time to CRS of 14.23 hours after administration of glofitamab and a median duration of 28.7 hours. Tocilizumab was used to manage CRS for 15.4% of patients. Three patients required admission to the intensive care unit, 8 received low-flow oxygen, 3 required single vasopressors, and 1 required mechanical ventilation.

Neutropenia was reported in 38.5% of patients, including grade 3 or higher events in 21.2%, and febrile neutropenia was observed in 3.8%. One patient experienced neutropenic infection.

Across all doses of glofitamab, a transient reduction in peripheral T cells was observed following administration, especially after the first infusion. “This is consistent with the T-cell margination described with other CD3 bispecifics,” Hutchings noted.

Additionally, T-cell activation in terms of granzyme B-positive T cells were observed after each infusion, and especially with the 30-mg step-up dose compared with the 16-mg dose.

_References:

_{1. Hutchings M, Carlo-Stella C, Bachy E, et al. Glofitamab Step-up Dosing Induces High Response Rates in Patients with Hard-to-Treat Refractory or Relapsed Non-Hodgkin Lymphoma. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020. Abstract 403.}

_{2. Dickinson MJ, Morschhauser F, Iacoboni G, et al. CD20-TCB in relapsed or refractory non-Hodgkin lymphoma: durable complete responses and manageable safety observed at clinically relevant doses in phase I dose escalation. Presented at: 2020 EHA Congress; June 11-14, 2020; Virtual. Abstract S241.}