Phase 2 data indicate promising responses are possible with fixed-duration glofitamab in patients with heavily pretreated, highly refractory large B-cell lymphoma.
Treatment with glofitamab for a fixed duration demonstrated a durable complete remission (CR) rate of 39.4% (95% CI, 31.6-47.5%) for patients with heavily pretreated, highly refractory large B-cell lymphoma, according to findings from a phase 2 expansion study (NCT03075696) presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.
In the single-arm study, 155 patients were enrolled who were refractory to several prior therapies, including a third who were refractory to prior CAR T-cell therapy. The objective response rate (ORR), which primarily consisted of CRs, was 51.6% (95% CI, 43.5%-59.7%). These responses occurred quickly, according to lead investigator Michael Dickinson, MBBS, with the average time to first CR of 42 days, which was the time of the first efficacy assessment (95% CI, 42-44). The median duration of CR was not yet reached and 80.3% were ongoing at the analysis.
“Glofitamab is a highly active drug for a difficult to treat disease. We saw complete remissions in 39.4% of patients following treatment with this fixed-course therapy, irrespective of CAR T-cell exposure. This data reflects our routine practice and an area of need in this disease,” said Dickinson, the lead of the Aggressive Lymphoma disease group at the Peter MacCallum Cancer Centre, Royal Melbourne Hospital and The University of Melbourne. “Remissions came on early and importantly were durable.”
Glofitamab is a CD20 and CD3 bispecific monoclonal antibody with a 2:1 format, with 2 CD20 domains and 1 CD3 domain for T-cell engagement. “Glofitamab is unique due to the potency derived from the 2:1 format, and it is also unique because it is given in a fixed dose schedule,” said Dickinson.
In the study, patients received intravenous glofitamab for a maximum of 12 21-day cycles, with a step-up dosing process in the first cycle to avoid cytokine release syndrome (CRS). On day 1 of cycle, 1 patient received a single dose of 1000-mg obinutuzumab (Gazyva) as pretreatment followed by glofitamab at 2.5 mg on day 8 and 10 mg on day 15. For subsequent 21-day cycles, glofitamab was given on day 1 at a target dose of 30 mg.
The median age of patients in the study was 66 years and 64.9% were male. The ECOG performance status was split between 0 (44.8%) and 1 (54.5%). Most patients had an Ann Arbor stage of IV (55.2%) and the most common subtypes were diffuse large B-cell lymphoma (DLBCL; 71.4%), transformed follicular lymphoma (17.5%), high grade B-cell lymphoma (7.1%), and primary mediastinal large B-cell lymphoma (3.9%). Bulky disease of 6 cm or more was present for 41.6% of patients, with 11.7% having bulky disease of over 10 cm.
The median number of prior therapies was 3 (range, 2-7), with 59.7% of patients having 3 or more prior lines of treatment. All patients had received a prior CD20 agent, a third of patients (33.1%) had received a prior CAR T-cell therapy, and 96.8% had received a prior anthracycline. Most patients (90.3%) were refractory to any prior therapy and 85.7% were refractory to their last therapy, with 29.9% being refractory to CAR T-cell therapy and 58.4% presenting with primary refractory disease. Prior autologous stem cell therapy (ASCT) was received by 18.2% of patients.
The primary efficacy analysis for the primary end point of CR was completed on the first 108 patients treated with glofitamab. In this analysis, the CR rate was 35.2% by independent review, which was statistically significantly better than a historical control group that had a CR rate of 20% (P < .0001). “Responses were consistent across important subgroups, such as age, lymphoma subtype, bulky disease, number of lines of therapy, and indeed whether they were previously exposed to CAR T-cell therapy,” said Dickinson.
In those who received prior CAR T-cell therapy (n = 52), the CR rate was 35% (95% CI, 22%-49%). It was 42% (95% CI, 32%-52%) in those who had not received a prior CAR T-cell therapy (n = 103). Those who had not received a prior ASCT (n = 127) had a CR rate of 33% (95% CI, 25%-42%), which was 71% (95% CI, 29%-96%) and 67% (95% CI, 43%-85%) in those who were refractory (n = 7) or relapsed (n = 21) to ASCT. Patients who were refractory to their last therapy (n = 132) had a CR rate of 34% (95% CI, 26%-43%) and those who relapsed on their last therapy (n = 23) had a CR rate with glofitamab of 70% (95% CI, 47%-87%).
At 10.6 months of follow-up, the median duration of ORR was 18.4 months (95% CI, 13.7-not estimable), with 66.3% of responses ongoing at the data cutoff. “Durable remissions were driven mainly by complete responses, where the median is not reached,” said Dickinson. “The estimated rate of enduring complete remission at 12 months is 77.6%. This is striking in this population since these patients stop therapy at 9 months.”
To further examine the durability of response with glofitamab, patients from earlier cohorts of the study were analyzed, wherein the median follow-up was 24.8 months. In patients who received the recommended phase 2 dose (n = 101), the CR rate was 35%. The median duration of CRs in this group was 34.2 months.
“This shows that these complete remissions can be enduring after fixed-course therapy,” said Dickinson. “We know that multi-year complete remissions in large B-cell lymphoma may translate to cure. Our 6 longest followed patients remain in complete remission for longer than 3 years and some have been in complete remission for longer than 4 years.”
The median follow-up for progression-free survival (PFS) in the study was 12.6 months, and the median PFS was 4.9 months (95% CI, 3.4-8.1). The 6-month event-free survival (EFS) rate was 45.5% (95% CI, 37.2%-53.8%) and the 12-month EFS rate was 37.1% (95% CI, 28.5%-45.8%). The median overall survival (OS) was 11.5 months (95% CI, 7.9-15.7) and the 12-month OS rate was 49.8% (95% CI, 41.1%-58.5%).
In the study, patients received a median of 5 cycles of therapy (range, 1-13) and the median relative dose intensity was 100%. Treatment-related adverse events (TRAEs) occurred in 90.9% of patients, with 41.6% having a grade 3 or 4 TRAE. There were no fatal TRAEs and 29.9% had a serious TRAE. TRAEs led to treatment discontinuation in 3.2% of patients.
Of interest, CRS of any grade occurred in 63% of patients. Grade 1 CRS occurred in 47.4%, grade 2 in 11.7%, grade 3 in 2.6%, and grade 4 in 1.3%. Most CRS occurred in the first cycle (84.9%), with a median time to CRS onset during the day 8 dose of cycle 1 of 13.6 hours. Corticosteroids were utilized by 27.8% of patients with CRS and tocilizumab was administered for 32%. Outside of cycle 1, 26.8% of CRS cases occurred in cycle 2 follow by 2.9% in subsequent cycles. “This is a first course phenomenon, becoming far less frequent once step-up dosing is complete. Grade 2 CRS is extremely rare after the second dose of treatment,” said Dickinson.
Grade 3 or greater AEs of interest included infection (14.9%), neutropenia (26.6%), febrile neutropenia (2.6%), tumor flare event (2.6%), neurologic AEs (3.2%), and immune effector cell-associated neurotoxicity syndrome (ICANS; 2.6%), which was not included in the study and was derived after the study was complete. None of these derived cases of ICANS were related to glofitamab, said Dickinson.
Findings from the expansion study, known as NP30179, have been submitted to the European Medicines Agency (EMA). An application to the FDA in the United States is planned later this year, according to Genentech, the company developing the antibody.
Dickinson M, Carlo-Stella C, Morschhauser F, et al. Glofitamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and ≥ 2 prior therapies: Pivotal phase II expansion results. J Clin Oncol. 2022;40(suppl 16):7500. doi: 10.1200/JCO.2022.40.16_suppl.7500