Novel bispecific antibody exudes promise for relapsed/refractory DLBCL

In a phase I/II study, the novel T-cell-engaging bispecific antibody glofitamab bares its potential for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL).

“[At a median follow up of 12.6 months,] glofitamab therapy led to a complete response (CR) in 39 percent of patients with poor prognosis DLBCL, in which treatment is often ineffective,” said the researchers. The effect was also seen in patients who had prior CAR T-cell therapy* (35 percent).

The primary endpoint of CR was assessed by an independent review committee. The responses were seen early, usually at the first scheduled assessment (at around 1.4 months). At data cutoff, 80 percent of CRs was ongoing, translating to durable responses.

The CR rate compare well with those seen with other** approved novel therapies for R/R DLBCL, the researchers noted. “[However,] glofitamab is unique owing to its fixed treatment duration and the relatively low number of [treatment visits] required over time.”

A total of 155 R/R DLBCL*** patients (median age 66 years, 65 percent male) who had received at least two prior^# lines of therapy were enrolled. They were pretreated with IV obinutuzumab 1,000 mg to mitigate cytokine release syndrome (CRS), followed by fixed-duration IV glofitamab monotherapy (step-up doses of 2.5 and 10 mg, followed by 30 mg on day 1 of cycles 2 through 12). [N Engl J Med 2022;387:2220-31]

Survival, safety

The estimated 12-month overall survival was 50 percent. “[This] was meaningful given the poor prognosis with conventional chemotherapy (CT) in this disease,” the researchers noted.

The most common adverse event (AE) was CRS (63 percent), which was mostly associated with the initial glofitamab doses. However, most were low grade, perhaps due to the strategies implemented to mitigate CRS incidence and severity. “[Also, CRS] is a common AE with T-cell-engaging immunotherapies,” they said.

Treatment cessation owing to AEs were uncommon (n=14), and only five patients stopped treatment due to glofitamab-related AEs. About two-thirds had grade ≥3 AEs, the most common being neutropenia (27 percent). Nonetheless, this did not lead to treatment withdrawal in most cases.

New active therapy?

Up to 40 percent of DLBCL patients relapse or have disease that is refractory to R-CHOP^##, the standard first-line treatment for DLBCL. [Blood 2015;125:22-32] For patients who are eligible for ASCT^###, more than half relapse shortly thereafter or do not proceed after receiving salvage CT. [Blood 2017;130:1800-1808; N Engl J Med 2022;386:640-654; J Clin Oncol 2010;28:4184-4190]

Of the approved treatment regimens for R/R DLBCL, CAR T-cell therapies appear to be the most effective. However, logistic, geographic, or resourcing constraints could be outpaced by disease progression and death, the researchers pointed out.

The CR rate in the study rivals that seen with CAR T-cell therapy, commented Dr Nancy Bartlett from the Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri, US, in a separate editorial. [N Engl J Med 2022;387:2285-2286] Although promising, “it is still too early to estimate the curative potential of glofitamab,” she said.

“[Nonetheless,] the efficacy, novel mechanism of action, and unique 2:1 structure [of glofitamab therapy] provide a strong rationale for combinations with other treatments … [A] fixed course of glofitamab therapy [could be] a new active therapy for patients with this disease,” said the researchers.

Bartlett further emphasized that even with a fixed treatment course, the CRs were maintained after treatment completion.