Prolonged Responses in DLBCL Spark Talk of a Cure With Bispecific Antibody

NEW ORLEANS — Almost 80% of patients whose relapsed/refractory (R/R) lymphoma had complete responses (CRs) with the bispecific antibody glofitamab remained in that status at 24 months, data from a prospective study showed.

The median duration of CR had yet to be reached, but the median follow-up from first CR was 18.1 months and the median from end of treatment with glofitamab was 11.5 months. Pretreatment with obinutuzumab (Gazyva) minimized the incidence and severity of cytokine release syndrome (CRS).

The findings, though preliminary, suggest that fixed-duration treatment with glofitamab has the potential to cure R/R diffuse large B-cell lymphoma (DLBCL) in a substantial proportion of cases, said Martin Hutchings, MD, PhD, of Rigshospitalet Copenhagen in Denmark, during the 2022 American Society of Hematology annual meeting.

“So the question is whether you can cure patients with glofitamab, and you’re asking whether I think or whether I know,” Hutchings said during the discussion that followed his presentation. “I think yes, I do not know, because I think it’s clear from the presentation that we need more follow-up. The data cut for this presentation was in March of last year, so hopefully we’ll be able to share at least 1 more year of follow-up next year.”

“I do believe that there is curative potential,” he added. “My fellow investigators and I have shared many good stories of patients that we have followed not only 1 or 2 but 3 or even 4 years in CR after the end of treatment. So I think this, as well as the data, support the concept of fixed-duration treatment.”

In response to another question, Hutchings said that loss of CR appeared to result from loss of tumor antigen, not T-cell exhaustion.

The findings came from a subgroup analysis of a pivotal phase II trial of 155 patients with R/R DLBCL. Hutchings’s report focused on patients who achieved CR with glofitamab. Results for the entire study population were published simultaneously in the New England Journal of Medicine.

Glofitamab is a T cell-engaging, bispecific antibody targeting CD20 and CD3. Developed as a fixed-duration therapy, the drug has induced frequent and durable CRs with a manageable safety profile in patients with relapsed/refractory DLBCL and other types of B-cell non-Hodgkin lymphoma.

Of a total of 291 patients with R/R large B-cell lymphomas treated with glofitamab, 153 (52.6%) had partial responses, including CRs in 103 (35.4%). The median time to CR was 43 days.

The pivotal trial included 155 patients with R/R large B-cell lymphomas (three fourths with DLBCL), treated with a single pretreatment dose of obinutuzumab followed by 12 cycles of glofitamab administered over 8 months. Optional retreatment was offered to patients who had progressive disease after an initial response. The results showed an overall response rate of 51.6%, including a CR rate of 39.4% (61 of 155 patients).

Hutchings presented a detailed report on the 61 patients who were in CR at the end of treatment in the pivotal trial. DLBCL accounted for 67.2% of the CRs, followed by transformed follicular lymphoma (29.5%). A majority (60.7%) had received three or more prior lines of therapy.

Of the 61 patients with CR, 48 were in CR after 6 months and 37 after 12 months (end of treatment). Continued follow-up showed that 93% of the patients remained progression free 12 months or longer after the end of treatment.

“Off-treatment progression is uncommon in heavily pretreated, highly refractory patients with large B-cell lymphoma who are in complete remission at the end of treatment with glofitamab,” said Hutchings. “The estimated rate of patients with a complete remission lasting a minimum of 2 years is 79%.”

As reported in the journal article, 63% of patients developed CRS, but it reached grade ≥3 severity in 4% of patients. Grade ≥3 neurologic events occurred in 3%. Overall, 62% of patients had one or more grade ≥3 adverse events, most of which were related to glofitamab.

An unrelated presentation at the ASH meeting provided evidence of glofitamab’s activity in another R/R lymphoma setting. As many as 90% of patients with R/R mantle cell lymphoma (MCL) responded to the same protocol used in the pivotal trial. The study included 37 patients with R/R MCL, 24 of whom had prior exposure to a Bruton’s tyrosine kinase (BTK) inhibitor.

Overall, 83.8% of patients responded, including 90.5% of those who received a higher dose of obinutuzumab. Among patients with prior exposure to a BTK inhibitor, three fourths had objective responses, including complete responses in two thirds.

Grade 3/4 adverse events (AEs) occurred in two thirds of the patients and was related to glofitamab in most cases, although no fatal AEs occurred and no patients discontinued because of AEs, reported Tycel Phillips, MD, of the University of Michigan in Ann Arbor.

“Glofitamab monotherapy with fixed treatment duration of 12 cycles induced high complete response rates in heavily pretreated patients with MCL,” said Phillips. “Complete responses were achieved early and were durable. Glofitamab was well tolerated, and there were no treatment discontinuations due to adverse events. CRS events were manageable and predominantly low grade. A phase III study of glofitamab monotherapy is planned for patients with relapsed/refractory MCL.”