REGN2810 alone or in combination with REGN1979 for B-lymphoid malignancies

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Published: 11 Dec 2017
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Dr Max Topp - University of Wurzburg, Wurzburg, Germany

Dr Topp speaks with ecancer at the 2017 ASH annual meeting about safety and preliminary anti-tumour activity of the anti-PD-1 monoclonal antibody REGN2810 alone or in combination with REGN1979 in patients with B-lymphoid malignancies. 

He discusses the construction and current clinical utility of BiTE therapies, detailing the dose escalation studies of a novel anti-CD20 x anti-CD3 bispecific antibody, and notes the tolerability as assessed by MRD status.

Combination REGN2810 with REGN1979 has been well tolerated, and evaluation of the combination with higher REGN1979 doses continues.

ecancer's filming has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

It is altogether the concept of bispecific antibody constructs and a different format of how to do that. The first one that was actually explored is the BiTE construct blinatumomab, a very small compound that was now approved in the States as well as in Europe for the treatment of relapsed refractory ALL. The next level is new development now with the new bispecific antibody constructs using a full length antibody and the target is CD20 which is obviously expressed on lymphoma cells and then, on the other hand, connecting then with CD3 on the T-cells which would then be the effector cells.

Which then leads to the Regeneron, it’s 1979 is the one that doesn’t have the catchier name.

Right, that is a single agent compound and this is a phase I trial that was now presented here, an update. The first data was presented last year at ASH and this is an update now on the progress of the bispecific single agent activity. So we are still in the dose escalation phase, which is good news, because it really shows that this drug so far has been very safe for the patients. No DLT have so far been reported and with the 3 3 design more cohorts have now been treated within this trial.

How’s that in terms of you mentioned the adverse events but combining the BiTE with an anti-PD1.

Maybe we should first focus on now the monotherapy. Here the safety profile is very favourable after some adjustments to the dosing scheme have been done by actually coming in with a low dose for the first week, the second week you do an intermediate dose and then you reach the target dose on week 3. So with that schematic the rate of cytokine release syndrome, the severity has dropped from potentially grade 3s down to grade 1 in the vast majority of patients which is very easily treated.

The second very important point is that this drug doesn’t show any neurotoxicity in these patients which has been described previously for blinatumomab targeting CD19. So it has to be seen if in a bigger cohort this can hold up that there’s no neurotoxicity but, from a safety perspective, those are clearly much more favourable than previously reported with blinatumomab which had 25% grade 3 and grade 4 neurotoxicity.

So we’re talking about efficacy, so we do see after reaching the dose of 5mg for the patients and now dose escalating up to 12mg, the target dose, that in follicular lymphoma patients more than 50% of the patients are showing responses, even complete responses, as single agent. In the aggressive lymphomas which is the second group that has been recruited here we also are starting out to see partial responses in these patients but it’s obviously an open question as we are escalating as these responses will maybe deepen as we now are escalating and perhaps defining then the NTD before we then can have a small expansion cohort to look at the safety profile of the NTD dose and of course the efficacy in these two big cohorts of patients of interest.

So then we can move on to the combination.

The combination, the rationale for that is that in vitro data in animal experiments, as well as in other clinical experiments, there is some upregulation of checkpoint ligands, checkpoint inhibitors. So the question is really here if you add a checkpoint inhibitor would you increase the efficacy of a bispecific in these patients. Regeneron has developed their own anti-PD1 agent and the first question was does this have the same efficacy in Hodgkin’s lymphoma patients and what is the safety of this also in NHL. So in Hodgkin’s lymphoma 60% have an objective response so it basically covers and mirrors what also has been seen with other anti-PD1 therapies which are now being treated for Hodgkin’s lymphoma. There’s some efficacy, definitely less as single agent, with the anti-PD1 in non-Hodgkin’s lymphoma, in FLs as well as in diffuse large cells.

In terms of safety we saw something very new that was if patients were treated with PI3 kinase prior to going on to the clinical trial these patients were at risk of developing severe autoimmune diseases. So we have now amended the protocol that patients with PI3 kinase pre-treatment are excluded from the clinical trial. So after establishing the safety profile now we are taking on the combination but we are in the early stages of that by actually taking on the safety cohorts of the phase I trial with anti-CD3/CD28 antibody construct. So at a very low dose, 2mg at the moment, that was the entry. In terms of safety one major question was are we going to see more severe cytokine release syndrome? Are we going to see more cytokine production? Are we going to see more neurotoxicity? All these three questions can be denied – there’s no more cytokine production, there’s no difference, at least in these cohorts that have been tested, in terms of adverse events, treatment adverse events. So overall the safety profile of applying this drug in combination with already the reported CD3/CD20 construct seems to be OK. Now we are moving into dose levels of the bispecific where we are seeing also clinical efficacy in the phase I trial and it’s now to be seen, once we combine these both, if this also leads then to perhaps a very favourable safety profile, no difference to the single agent but potentially better clinical control for the patients of their disease.

Very encouraging numbers to build on.

Yes, I think so. Obviously it’s early days, it’s just a phase I trial but the plans are as we’re seeing clinical efficacy to go ahead and explore this maybe in more advanced clinical trials.