Expert Highlights Emergence of Mosunetuzumab in Non-Hodgkin Lymphoma

Stephen J. Schuster, MD

Data for mosunetuzumab presented at the 2019 ASH Annual Meeting by lead investigator Stephen J. Schuster, MD, showed that the novel bispecific antibody induced durable responses in patients with highly refractory non-Hodgkin lymphomas (NHLs) enrolled in the phase I/Ib dose-escalation GO29781 study (NCT02500407).

Of note, complete remissions (CRs) were reached in 22.2% of patients who had previously received CAR T-cell therapy. Across all patients, the overall response rate was 37.1%, including a CR in 19.4% of patients.

In an interview with OncLive, Schuster, who is director of the lymphoma program at Abramson Cancer Center at the University of Pennsylvania, discussed the promising findings and next steps for mosunetuzumab in patients with relapsed/refractory NHL.

OncLive: What is the rationale for evaluating mosunetuzumab in this patient population?

Schuster: There remains an unmet need for new drugs for patients with B-cell lymphomas. That is across the board, including large B-cell lymphomas, aggressive NHLs, and indolent NHLs, despite all the advances we have had in therapies over recent years. That is the rationale for this study.

This agent is a new bispecific T-engaging antibody that binds to CD20 on B cells and CD3 on T cells. It’s a form of indirect cellular therapy, getting the T cells to irradiate the B cells. The study population was comprised of patients with large B-cell lymphomas, mostly diffuse large B-cell lymphoma (DLBCL) but also some patients with follicular lymphoma (FL) or mantle cell lymphoma. These are the aggressive lymphomas, and the other part of the population were the indolent lymphomas, although they were by no means indolent by this stage; these were largely patients with FL.

The study design was a schedule optimizing dose-escalation study in a phase I looking primarily for tolerability, toxicities, maximum tolerated dose, and the usual phase I characteristics. Nowadays, we always look at efficacy regardless of the phase of study, so we are also looking at objective responses.

What did the study findings show?

We found objective responses in both aggressive and indolent lymphomas across the board and across doses tested. What was the most remarkable thing, which I think is the reason this trial has gotten so much attention at this meeting, is patients who had received CAR T-cell therapy but were not responding were able to be rescued in many cases with this drug. We saw similar response rates in patients who had prior CAR T-cell therapy and similar response rates to those with aggressive lymphomas who had not had prior CAR T-cell therapy.

Were you surprised by any of the findings?

The most unexpected finding in this trial was that the patients with prior CAR T-cell therapies fared as well as the patients who hadn’t received CAR T-cell therapy. That was a shocker. The median number of prior therapies in that group was 5, so they were a much worse group in terms of prognosis than the average group.

The other thing is that some of the patients who had prior CAR T-cell therapy had re-expansion of the CAR T cells with the bispecific, so that was another surprise. It was not all [patients] but some.

Do these patients have high-risk features?

These patients had high-risk features because they were relapsed/refractory or resistant to therapy. The median number of prior therapies is 3, and the majority of patients had an anti-CD20 monoclonal antibody and a chemotherapeutic agent within 6 months of enrollment, meaning failing that approach within 6 months to be eligible for this study.

This was a study for patients who didn’t have a lot of good treatment options, and it’s the type of population that we used when we were developing CAR T-cell therapy for B-cell lymphomas, patients who do not have commercially available or standard of care therapeutic options.

What are the next steps?

We have to complete this study because we need more follow-up to see how durable these remissions are going to be. We have a couple of years’ follow-up, but it will take a couple more years to have total confidence in the durability of these responses. However, I see us adding this to our other immunotherapies, to CAR T-cell therapies, to immunomodulatory agents, and to treatment-naïve patients whose immune systems are very much intact and thus much more likely to have a good response to this approach. I would say that among those lymphomas where there is no standard of care, this might be a very attractive agent to test in the first-line because there, they have had no chemotherapy to weaken the response, and this drug relies on eliciting the host immune response against tumor. We might want to try that before other therapies.

Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-Cell (CAR-T) therapies, and is active in treatment through multiple lines. Presented at: American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 6. ash.confex.com/ash/2019/webprogram/Paper123742.html