Glofitamab shows ‘curative potential’ in relapsed/refractory diffuse large B-cell lymphoma
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NEW ORLEANS — Patients with large B-cell lymphoma who achieved complete response at the end of glofitamab treatment had durable remissions and rarely experienced off-treatment progression within 1 year of therapy, according to study results.
The findings, presented at ASH Annual Meeting and Exposition, showed an estimated 79% of patients remained in complete response 2 years after stopping treatment.
“These data, while still relatively early in the natural history of [diffuse large B-cell lymphoma], show that patients are unlikely to relapse if they are in a complete remission at the end of treatment, so they can enjoy an indefinite treatment-free period,” Michael J. Dickinson, MB, BS, D.Med.Sc., lead of the aggressive lymphoma disease group within clinical hematology at Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Australia, told Healio.
Methodology
Glofitamab (RG6026, Genentech) — an off-the-shelf, CD20xCD3 bispecific antibody — engages and redirects T cells to eliminate malignant B cells.
“One question that is topical at the moment is whether continuous treatment is required with these bispecific drugs, or whether treatment should be continuous,” Dickinson said. “Glofitamab is a fixed-course treatment. Patients who are on it would want to know how they are going to go, having achieved a complete response.”
Results of a pivotal phase 2 study of the agent, published in The New England Journal of Medicine immediately after the presentation at ASH, showed a complete response rate of 39% (95% CI, 32-48) according to independent review committee among 155 patients with relapsed or refractory large B-cell lymphoma who had at least two previous lines of therapy. Complete responses occurred after a median 42 days and most (78%) lasted 12 months or longer.
Glofitamab appeared well-tolerated at the phase 2 step-up doses of 2.5 mg and 10 mg, followed by 30 mg on day 1 of cycles two through 12. Nine percent of patients discontinued treatment due to adverse events, the most common of which was cytokine release syndrome (63%). Grade 3 or higher adverse events occurred among 62% of patients, but only 4% of patients experienced grade 3 or higher CRS.
Dickinson noted that most of the high-grade adverse events were hematologic and did not result in interruptions or discontinuation of treatment.
“Cytokine release syndrome, while common, is rarely of high grade, especially if dexamethasone is used as a premedication,” he told Healio. “Neurotoxicity attributed to glofitamab is very rare.”
Results
At ASH, Martin Hutchings, MD, PhD, of Rigshospitalet Hospital in Copenhagen reported long-term outcomes of patients who received glofitamab across dose ranges in the phase 1/phase 2 study, starting at 0.6 mg, with a focus on duration of remission among complete responders at end of treatment.
All patients received pretreatment with obinutuzumab (Gazyva, Genentech) to mitigate serious CRS, followed by fixed-duration glofitamab monotherapy for a maximum of 12 cycles, or 8.3 months.
Among 291 patients treated, 52.6% responded to therapy, including 35.4% with a complete response and 17.2% with a partial response. Median time to first complete response was 43 days.
Sixty-one patients (median age, 67 years; 50.8% women) had a complete remission at the end of therapy. Most of them (60.7%) had received three or more prior lines of therapy, 11.5% received prior chimeric antigen receptor T-cell therapy and 36.1% had previously undergone autologous stem cell transplantation.
At 12 months follow-up, 37 of these patients (61%) remained in remission, seven had discontinued the study and 17 remained in follow-up but had yet to reach 12 months.
Two patients who developed progressive disease after the 12-month mark achieved complete response again after retreatment with glofitamab, Hutchings said.
Median PFS and duration of complete response had not been reached at median follow-up of 11.5 months after end of treatment. Hutchings reported a 12-month PFS rate of 92.6% (95% CI, 84.3-100) and estimated 2-year complete response rate of 79.1% (95% CI, 63.3-95).
Conclusions
Having the option of a fixed-course treatment will enable patients to return to a normal quality of life at the end of their treatment, without the disruptions of regular therapy, Dickinson said.
“I think it’s important for the community to understand that fixed-course treatment can deliver this outcome, as several drugs in development in DLBCL are continuous,” he told Healio. “Fixed-course treatment is an important differentiator for glofitamab, to my mind, and I suspect for many patients it will be important knowing that there is a horizon to their treatment plan.”
When asked whether glofitamab may be a curative therapy, Hutchings said: “I think yes. I do not know because I think it’s clear from the presentation that we need more follow-up. ... But I do believe there is a curative potential.”
Bispecific agents could be an excellent option for patients who fail second-line CAR T-cell therapy, Nancy L. Bartlett, MD, Koman professor of medical oncology at Washington University School of Medicine in St. Louis, wrote in an editorial that accompanied the study in The New England Journal of Medicine.
“If longer follow-up confirms that the majority of complete remissions with bispecific agents are durable, on the basis of the advantages of availability (including in the community setting) and more favorable immediate and late toxic-effect profiles, bispecific agents could be considered as the initial choice for second-line (if approved) or third-line therapy,” Bartlett wrote. “CAR T-cell therapy could be held in reserve for patients who do not have a complete response or who have a relapse after a complete response.”
References:
- Dickinson MJ, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2206913.
- Hutchings M, et al. Abstract 441. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
Perspective
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Henry Fung, MD, FACP, FRCPE
Most patients with relapsed/refractory DLBCL will die of the disease shortly after progression if they are not candidates for autologous stem cell transplant and/or CAR T-cell therapy.
Glofitamab, a bispecific antibody, had shown very promising response rates in these patients, including a high rate of complete responses. Some salvage regimens may lead to similar or even better response rates, although brief duration of responses may limit their utility. Here, almost all patients who achieved a complete response with glofitamab remained progression free 12 months after the end of therapy. The durability of responses is significant, as most treatment failures in relapsed/refractory DLBCL occur soon after end of treatment.
For those who remain in complete response longer than 18 to 24 months, a cure may have been achieved. We will soon find this out with longer follow-up.
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Hutchings M, et al. Abstract 441. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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