ASH 2024 | A Phase I study of glofitamab plus a novel CD19 x CD28 costimulatory agonist in R/R B-NHL

So this particular clinical trial is a combination trial that includes glofitamab, a known drug, plus a novel drug. Glofitamab is a CD20 x CD3 bispecific antibody that’s been approved for the treatment of relapsed and refractory diffuse large B-cell lymphoma after two prior lines of treatment. What’s interesting about glofitamab is that it works through binding of CD3 and direct activation of T-cells. Now we know from the experience of CAR T-cell therapy that having a second signal might be important in augmenting T-cell function. And so the purpose of this particular clinical trial was to establish whether a co-stimulatory signal might increase or change the effects of glofitamab. This new drug is a drug that targets CD19 and CD28, the co-stimulatory CD28. And essentially in this clinical trial, we evaluated the addition of that new agent to glofitamab from a mechanistic point of view with some really detailed translational work that was presented by Koorosh Korfi in one of the oral presentations here but also had a look at clinical activity. We evaluated two schedules of the addition of this novel agent which I’ll call the CD28 x CD19 bispecific and essentially we allowed glofitamab step-up dosing. One schedule introduced the CD28 bispecific after dose escalation of glofitamab and the other one introduced the CD28 bispecific during the dose escalation of glofitamab. Our goal with the addition of this second agent was to increase the complete remission rate of lymphoma to the combination but also have a look at this translational research and see whether this second co-stimulatory signal provided immunological proof of concept. For the data that we’ve presented so far we had just over 50 patients the majority had aggressive lymphomas but 19 patients had follicular lymphoma and we saw a complete remission rate from the combination that was pretty similar to glofitamab monotherapy in the case of aggressive lymphoma but remarkably high in the case of follicular lymphoma where virtually all patients responded and retained their response during the observation period of the clinical trial which was just over 12 months. So in that indolent lymphoma population quite an interesting clinical signal and in the aggressive lymphoma population a signal that this agent could be delivered without any additional toxicity. We saw no increased CRS, we saw no neurotoxicity, but a complete remission rate that was probably pretty similar in reality to glofitamab monotherapy. The peripheral blood analyses and the translational research which, as I’ve mentioned was presented in detail in an oral presentation, really reaffirmed that the provision of this second signal changes the immunological reaction that glofitamab induces. And so I think this sort of combination with a second co-stimulatory signal needs further exploration. There’s another clinical trial that’s also looked at a different way of providing a second signal to glofitamab, and that’s using a 4-1BBL bispecific that’s being presented by Martin Hutchings at this conference, and that has shown a very interesting clinical signal of an increased complete response rate compared to glofitamab monotherapy on a naive comparison of fairly similar patient population. So we’ve got two agents here that are providing a second signal. This idea of providing a second signal to bispecific antibodies is one which may enable the creation of a chemo-free or a chemo-light treatment regimen for patients with relapsed aggressive lymphoma or even perhaps be used to develop new regimens that reduce our dependency on cytotoxic chemotherapy, and that’s really the goal that we have, and so it’s been a pleasure to present this preliminary data at ASH.

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