Updates on REG1979 in R/R B-cell non-Hodgkins lymphoma
Dr Rajat Bannerji - Rutgers Cancer Institute of New Jersey, New Brunswick, USA
I’ll be presenting an update on our first in human phase I study of this bispecific antibody REGN1979. It’s a bispecific antibody that binds CD20 on B-cell lymphomas and CD3 on T-cells. We have presented data on this study before at ASH but the update this year is that we’ve completed our dose escalation of the study and we have not seen any dose limiting toxicities. So we have actually taken the study to the highest planned dose in our protocol. In addition, we’ll be presenting some data on a few patients who have then moved into our expansion cohorts which are part of the study as well.
In the study we dosed patients with a step-up dosing strategy so that an individual patient is dosed over the course of four weeks at incrementally higher doses reaching their full assigned dose at the end of the four week period. Using this strategy we’ve minimised a lot of the toxicity that potentially we may have seen. We were focussed on cytokine release syndrome as a potential toxicity and we do see that, primarily grade 1 and 2 toxicity, a few grade 3s. All of that toxicity when it does occur is in the first few weeks of treatment, paradoxically at lower doses of drug and the toxicity occurs early and we’re able to then take the patient to a higher final dose of drug. Using this strategy, as I said, we’ve gotten to the highest dose that we had planned to look at without any dose limiting toxicities.
We’ve also seen, importantly, some neurotoxicity but again all of that has been grade 1 and 2 for the most part, a few cases of grade 3 neurotoxicity and no grade 4 or above neurotoxicity. So we have a drug that’s looked safe in our dose escalation study.
Looking at the activity of the drug we’re looking at very heavily pre-treated patients with various B-cell non-Hodgkins lymphomas. In this study about two-thirds are large cell lymphoma, about one-third are follicular lymphoma and then we have a smattering of some other diagnoses including mantle cell lymphoma, marginal zone lymphoma and even less frequent ones.
In the follicular lymphoma patients we have, again, a very heavily pre-treated group. We’ve seen very promising activity. We have close to 100% response rate in this analysis, about 96%, and a very high complete remission rate as well in that group. In the diffuse large B-cell lymphoma patients we looked at patients who had received prior CAR T therapy and also patients who had not received prior CAR T therapy. In both groups of patients at our higher dose levels we have very promising activity, again high rates of overall response rates and also very high rates of complete remission in the non-CAR T population and very promising CR rates in the CAR T population. So we’re seeing activity in patients who have really become very chemotherapy refractory and in some cases refractory to other immune strategies in the setting of the CAR T.
Finally, tomorrow we’ll be presenting some data which is an important part of these types of studies. We’ve had paired biopsies and we’ve also asked for biopsies at the time of disease progression. So with these serial biopsies we’ve looked at some biomarkers and on Monday I’ll be presenting data that may suggest some possible mechanisms of resistance to bispecific antibodies that we see on the basis of these paired biopsies. So one obvious mechanism is loss of antigens, you lose the target antigen, and the patients become resistant to this type of therapy. Another less obvious type of resistance are in patients who continue to maintain the target antigen but they become resistant to treatment. In those patients we see clear activation of a checkpoint pathway with upregulation of PD-L1 and PD-1. So we’ll be sharing some of that data as well.
What needs to be done to bring this drug to approval?
That’s a question for everyone, certainly for the sponsor but for us academics as well. With this drug the level of activity that we’re seeing would support monotherapy in these multiply relapsed patients and we know there are a number of agents out there now that are approved second line and beyond, for example, the PI3 kinase inhibitors in follicular lymphoma. So in that setting, as a monotherapy, we have a very active drug that could be used well there.
In the setting of CAR T failure, a very refractory population, we have activity including complete remissions that are durable. So that would be another setting where this drug could be used as monotherapy. Then there are really a host of potential combinations where it could be combined with other drugs and used in earlier lines of therapy. One combination that our data that we’ll be presenting suggests is combining with checkpoint inhibitors. Since we see upregulation of PD1/PD-L1 in patients treated with this drug combining with a checkpoint inhibitor makes sense as an obvious next step.
Is there anything you would like to add?
I would just say that our study continues in expansion cohorts and we will be looking at ways to optimise outcome based on treatment sequence in the phase I expansion cohorts. The sponsor has already opened a phase II study, choosing doses from the study that we’ve just completed that are going forward in follicular lymphoma, large cell lymphoma and other lymphoma subtypes.