Dual-targeted antibody mosunetuzumab elicits durable responses in poor-prognosis non-Hodgkin Lymphoma patients

Prof Stephen Schuster - University of Pennsylvania, Philadelphia, USA

Thanks for that introduction, Dr Shaw [?]. Now that will allow me to be brief. When we approach unmet needs in medicine we solve one and we create another. CAR T-cells have been a major advance in the therapy of patients with refractory B-cell malignancies. We have had approval of two agents in the last two years and, as Dr Shaw said, for a third of patients it has been a success. We presented data earlier this year, we now have 4-5 year follow up, durable remissions following a CD19 directed CAR T-cell therapy.

However, the two-thirds of patients that don’t respond to CAR T-cell therapy are now our new unmet need. So one challenge always leads to another challenge and I suspect this is the way it’s going to be. In any event, mosunetuzumab is a bispecific antibody that binds to CD20 on B-cells and malignant B-cells and CD3 on T-cells. In binding to the T-cells it’s capable of inducing T-cell activation and when engaged with a B-cell it will cause death of the target cell and eliminate those cells.

The trial that I’m going to be showing you data from is really a large international trial that is a schedule finding or schedule optimising and dose finding study of this bispecific antibody, mosunetuzumab, in patients with relapsed refractory B-cell malignancies. We’ve mentioned about the unmet need, in terms of patient eligibility, as Dr Shaw said, one of the problems with the CAR T-cell approach is it can take three weeks to make the cells, it can take two weeks to get insurance approval before you can even do apheresis, a week to schedule apheresis, a month or two months doesn’t sound long but it’s an eternity when you have a patient with a very fast paced disease. So to be able to use the cellular immunotherapeutic approach rapidly in patients that need this approach because traditional immunochemotherapy is no longer working is a real, very important aspect. So an off the shelf product that has alternative B-cell targets to CD19, which the approved CAR T-cell products address, is necessary.

The cohort that our data come from are patients that have a step-up dosing in cycle 1 or an incremental day 1, day 8 low dose followed by what’s the maximum dose for that cohort. There’s a bunch of doses but we see responses from the lowest throughout so I’ll lump that together. There’s a lot of good science behind this at this meeting being presented in the poster sessions. So the data that I’m going to show you come from 270 patients on this arm that got step-up dosing and there were 30 patients that had prior CAR T-cell therapy on this arm. These are the inclusion criteria on the left. This would be a group of patients for whom CAR T-cell therapy would be an appropriate approach, either commercially or on clinical trial. We’ll focus overall on patients that have had other therapies but particularly on those that have had prior CAR T-cell therapy and do a comparison. 30 patients had it, 18 had more than three months of follow-up and we can assess efficacy in that smaller group. Most of these patients had either a large B-cell lymphoma or a large cell transformation of follicular, they’re usually lumped together and they’re both within the label for CAR T-cell therapies. You can see a median of five prior therapies, the slide is self-explanatory.

Two unique toxicities of cellular therapy that we learned during development of CAR T-cell therapy was cytokine release syndrome and what we call immune cell associated neurologic syndrome, or ICANS, neurologic adverse events, manageable now we understand it very well. We see these side effects whether the cellular therapy is a direct CAR T-cell or whether it’s an indirect cellular form of therapy like with a bispecific antibody approach. If you look at the data in the two columns here you can see that the safety with regard to cytokine release and neurologic adverse events are almost identical whether patients have had prior CAR T-cell therapy or not. What’s interesting is that these two adverse events are much more frequent during CAR T-cell therapy so we were concerned that perhaps we would have a higher incidence in these patients but that wasn’t seen.

These show you the changes in tumour diameters for patients with aggressive lymphomas. These are mostly large B-cell lymphomas or transformed follicular to large B-cell. We’ve taken the colours out of the dosing cohorts because we have successes at the lowest doses. At any event you can see that the negative side of the waterfall plot on the left to the right side of the graph there’s an impressive number of responses there. There’s about a 40% response rate, 20% complete response rate by anatomic criteria. On the right you’ll see the indolent lymphomas and, not surprisingly, as always they do twice as good and we see an overall response rate of 60% and a complete response rate of about 40%. What about the patients with prior CAR T-cell therapy? Most of these patients had diffuse large B-cell or transformed and we see the same 40% overall response, 20% complete response, albeit a small number of patients.

What is important is that this is not an ongoing therapy forever. This is a therapy the patients receive until they’re in remission then it’s discontinued. Three-quarters of the patients that are in complete remission in this study remain in complete remission off of… or three-quarters of the remission patients are off therapy and being followed.

This is a case of a patient of mine who had prior CAR T-cell therapy and at about twelve months had progression of disease. We tried to stabilise her with a number of different approaches, nothing was working. She was eligible for this study; the dark material in the lower part of the scan is her tumour. As you can see after the third cycle of mosunetuzumab, and she was in one of the lower dose cohorts, a complete remission. She’s been off therapy for between eight and nine months now and remains in complete remission.

Also patients on the study, four patients, have been retreated. So they’ve been off therapy, actually relapsed and three out of four of them responded to retreatment. One so far is in a complete response, that case is shown on the slide. You can see this patient was initially on a very low dose of the drug in terms of she was part of a dose finding study and had a complete response and then you can see she remained in response off therapy for 16 months, had a recurrence, low tumour volume recurrence at that time, was retreated again at a low dose and you can see that she’s in remission now for 13 months with an ongoing response. This ability to retreat is something that we’ve not been successfully able to do with the CD19 directed CAR T-cell therapies. So that’s another finding that is gratifying.

In any event, this, as a single agent, which is what I’ve showed you, has a really promising efficacy potential and the risks are definitely acceptable vis-à-vis CAR T-cell therapy. We have seen complete responses in those with prior CAR T-cell therapy and in those who have not had CAR T-cell therapy. I should mention here that I’ve actually used this drug as a bridge to CAR T-cell therapy in patients who have a fast-paced disease and I’ll describe some of that in the presentation tomorrow. In any event I’ll stop here and say that there’s lots of studies going on and I think the future for this drug and this approach, this off the shelf approach to exploiting cellular therapy is the direction that we’ll be pursuing in the future.