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ORLANDO -- Half of patients with relapsed, difficult-to-treat non-Hodgkin lymphoma (NHL) responded to an investigational bispecific antibody, including patients resistant or refractory to CAR T-cell therapy, data from a large phase I study showed.

Mosunetuzumab induced objective responses in 46 of 124 evaluable patients with aggressive NHL and in 42 of 67 patients with indolent lymphomas. In a subgroup of patients with prior CAR T-cell therapy, seven of 18 responded to the antibody, which targets CD3 and CD20.

The two most prominent toxicities of CAR T-cell therapy -- cytokine release syndrome (CRS) and neurologic adverse events (AEs) -- occurred in 28.9% and 43.7% of patients, respectively, and were mostly grade 1/2 in severity. Neither AE occurred more often in patients with prior exposure to CAR T-cell therapy, reported Stephen J. Schuster, MD, of the University of Pennsylvania Abramson Cancer Center in Philadelphia, at the American Society of Hematology (ASH) annual meeting.

"What I think is important is that this is not an ongoing therapy forever; this is a therapy patients receive until they are in remission and then it is discontinued," Schuster said during an ASH press briefing. "Three quarters of patients in complete remission remain in complete remission, off therapy, and continue to be followed."

"Four patients have been retreated," he added. "They were off therapy and relapsed, and three out of four responded to retreatment, including one complete response. Retreatment is something we have not been able to do with CD19-directed CAR T-cell therapy."

Mosunetuzumab production involves an "off-the shelf" process (no ex vivo T-cell manipulation), as opposed to the time-consuming, patient-specific production process required for CAR T-cell therapy, said Schuster.

An off-the-shelf product has considerable appeal as compared with CAR T-cell therapy, said press briefing moderator Gary Schiller, MD, of UCLA Health in Los Angeles. At the same time, he said he wondered whether a strategy such as the bispecific antibody for patients with relapse after CAR T-cell therapy might be salvaging some of the CAR T-cell response.

"An off-the-shelf product is always an attractive thing; it all depends on durability [of response]," said Schiller. "It might be more desirable, [because of] ease of preparation, and speed. As a simple clinician -- and I'm often a simple clinician who needs to take care of patients with desperate diseases -- tolerability is secondary to access and feasibility. Whatever product -- whether cellular or bifunctional -- that we have access to tomorrow will be better and easier for us to deal with.

"The second question, in the next phase [of investigation], will be, What's the durability? If it is only an issue that we can retreat and also get good response, I think clinicians will tolerate it and accept it and patients will accept that, too. Access is very important."

The bispecific antibody, along with multiple other next-generation strategies for difficult hematologic malignancies, had its genesis in an ongoing cycle of meeting one unmet need in medicine and creating another, said Schuster. CAR T-cell therapy represented a major advance in the treatment of relapsed/refractory B-cell malignancies, despite achieving success in about a third of patients.

"The two-thirds of patients who don't respond to CAR T-cell therapy are our new unmet need," he said.

With mosunetuzumab, the CD3 component redirects T cells to engage and destroy B cells whereas the CD20 component directly targets B cells. To date, an international team of investigators has treated 270 patients with relapsed/refractory NHL, including 30 patients with prior CAR T-cell therapy.

The trial called for eight cycles (21 days each), followed by an initial response evaluation. Patients who attained a complete response discontinued treatment. Those who had a partial response, or stable disease, continued for as many as 17 cycles of therapy. Retreatment was allowed for patients who relapsed after initial treatment.

Aggressive NHL -- primarily diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma, and mantle cell lymphoma -- accounted for two-thirds of the study population, and follicular and other indolent lymphomas made up the rest of the cohort. Schuster said 72% of the patients were refractory to their last prior therapy, and 86% were refractory to prior anti-CD therapy.

CRS occurred in 28.9% of patients, but reached grade 3 severity in only three patients. Neurologic AEs occurred in 43.7% of patients and were grade 1/2 in all but 10 patients. CRS and neurologic events occurred in a similar proportion of the subgroup with prior CAR T-cell therapy.

The treatment led to objective responses in 37.1% of 124 patients with aggressive NHL, including complete responses in 19.4%. Response rates were similar among patients with three or more prior lines of therapy, including those who were refractory to prior anti-CD20 therapy and those with prior autologous stem-cell transplant.

In the subgroup with indolent lymphomas, the overall response rate was 62.8%, including complete responses in 43.3%.

Schuster said studies are ongoing with single-agent mosunetuzumab and combinations. The studies include patients with untreated DLBCL.

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