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 large cell lymphoma B heavily pretreated and highly refractory, according to results from a Phase 2 expansion study (NCT03075696) presented at the 2022 Annual Meeting of the American Society for Clinical Oncology (ASCO).
In the single-arm study, 155 patients were refractory to multiple prior treatments, one-third of whom were refractory to prior CAR T-cell therapy. The objective response rate (ORR), which consisted mainly of CR, was 51.6% (95% CI, 43.5% to 59.7%). These responses occurred rapidly, according to lead investigator Michael Dickinson, MBBS, with a mean 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 had not yet been reached and 80.3% were in the process of analysis.
“Glofitamab is a very active drug for a difficult-to-treat disease. We observed complete remissions in 39.4% of patients after treatment with this fixed-duration therapy, regardless of exposure to CAR T cells. These data reflect our routine practice and an area of need in this disease.” said Dickinson, head of the aggressive lymphoma group at the Peter MacCallum Cancer Centre, Royal Melbourne Hospital and University of Melbourne. “Remissions came early and, most importantly, were long-lasting.”
Glofitamab is a bispecific CD20 and CD3 monoclonal antibody in a 2:1 format, with 2 CD20 domains and 1 CD3 domain for T-cell engagement. “Glofitamab is unique because of the potency derived from the 2:1 format, and it’s also unique because it’s given on a fixed dosage schedule,” Dickinson said.
In the study, patients received glofitamab intravenously for up to 12 21-day cycles, with a gradual dosing process during the first cycle to avoid cytokine release syndrome (CRS). On day 1 of the cycle, 1 patient received a single dose of 1000 mg obinutuzumab (Gazyva) as pretreatment followed by glofitamab 2.5 mg on day 8 and 10 mg on day 15. For subsequent 21-day cycles, glofitamab was administered on day 1 at a target dose of 30 mg.
The median age of study patients was 66 years and 64.9% were male. ECOG performance status was divided between 0 (44.8%) and 1 (54.5%). Most patients had Ann Arbor stage 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 in 41.6% of patients, with 11.7% having bulky disease of more than 10 cm.
The median number of prior treatments was 3 (range, 2-7), with 59.7% of patients having 3 or more prior lines of treatment. All patients had previously received a CD20 agent, one-third of patients (33.1%) had received prior CAR T-cell therapy, and 96.8% had received prior anthracycline. Most patients (90.3%) were refractory to any prior therapy and 85.7% were refractory to their last therapy, with 29.9% refractory to CAR T-cell therapy and 58.4% with refractory disease primary. Prior autologous stem cell therapy (ASCT) was received by 18.2% of patients.
The primary efficacy analysis for the primary CR endpoint was performed on the first 108 patients treated with glofitamab. In this analysis, the CR rate was 35.2% according to an independent review, which was statistically significantly better than a historical control group that had a CR rate of 20% (P
Among those who had previously received CAR T-cell therapy (n=52), the CR rate was 35% (95% CI, 22% to 49%). It was 42% (95% CI, 32% to 52%) in those who had not received prior CAR T-cell treatment (n=103). Those who had not received prior ASCT (n=127) had a CR rate of 33% (95% CI, 25% to 42%) or 71% (95% CI, 29% to 96 %) and 67% (95% CI, 43% to 85%) in those who were refractory (n=7) or relapsed (n=21) to ASCT. Patients who were refractory to their last treatment (n=132) had a CR rate of 34% (95% CI, 26% to 43%) and those who relapsed to their last treatment (n=23) had a CR rate with glofitamab of 70% (95% CI, 47% to 87%).
At 10.6 months follow-up, the median duration of ORT was 18.4 months (95% CI 13.7 – not estimable), with 66.3% responding on-going at the data cut-off date. “Sustained remissions have been driven primarily by complete responses, where the median is not reached,” Dickinson said. “The estimated rate of durable complete remission at 12 months is 77.6%. This is striking in this population since these patients stop treatment at 9 months.
To further examine the durability of response to glofitamab, patients from previous cohorts of the study were analyzed, with the median follow-up being 24.8 months. In patients who received the recommended phase 2 dose (n=101), the CR rate was 35%. The median duration of CR in this group was 34.2 months.
“It shows that these full remissions can last after fixed-course therapy,” Dickinson said. “We know that complete remissions over several years in large B-cell lymphoma can translate into a cure. Our 6 most followed patients remain in complete remission for more than 3 years and some have been in complete remission for more than 4 years.
The median progression-free survival (PFS) follow-up 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% to 53.8%) and the 12-month EFS rate was 37.1% (CI to 95%, 28.5% to 45.8%). The median overall survival (OS) was 11.5 months (95% CI, 7.9-15.7) and the OS rate at 12 months was 49.8% (95% CI, 41.1 %-58.5%).
In the study, patients received a median of 5 treatment cycles (range, 1-13) and the median relative dose intensity was 100%. Treatment-related adverse events (ETRA) occurred in 90.9% of patients, of whom 41.6% had grade 3 or 4 ETRA. There were no fatal EMRTs and 29.9% had had a serious EMRT. TRAE led to treatment discontinuation in 3.2% of patients.
Interestingly, 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 during cycle 1 (84.9%), with a median time to onset of CRS at cycle 1, dose 8 of 13.6 hours. Corticosteroids were used by 27.8% of CRS patients and tocilizumab was administered to 32%. Outside cycle 1, 26.8% of CRS cases occurred in cycle 2 followed by 2.9% in subsequent cycles. “This is a first-course phenomenon, becoming much less common once the tapered dosing is complete. Grade 2 CRS is extremely rare after the second dose of treatment,” Dickinson said.
Grade 3 or higher AEs of interest included infection (14.9%), neutropenia (26.6%), febrile neutropenia (2.6%), tumor flare (2.6%), neurological AEs (3.2%) and immune effector cell-associated neurotoxicity syndrome (ICANS; 2.6%), which was not included in the study and was derived after study termination . None of these ICANS-derived cases were linked to glofitamab, Dickinson said.
The results of the extension study, known as NP30179, have been submitted to the European Medicines Agency (EMA). An FDA filing in the United States is expected 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 treatments: pivotal phase II expansion results. J Clin Oncol. 2022;40(supplement 16):7500. doi: 10.1200/JCO.2022.40.16_suppl.7500