Safety and efficacy of escalating doses of Hu5F9-G4 with rituximab in patients with R/R DLBCL and indolent lymphoma

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Published: 20 Jun 2019
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Dr Mark Roschewski - National Cancer Institute, Bethesda, USA

Dr Mark Roschewski speaks to ecancer at the 2019 European Hematology Association (EHA) Annual Meeting on the phase IB/2 results of a study evaluating the safety and efficacy of escalating doses of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab in patients with R/R DLBCL and indolent lymphoma.

He explains that the study enrolled patients who were ineligible for CAR T therapy as they would be considered as having very limited treatment options.

Dr Roschewski reports that the escalating of doses means that anaemia is less of a problem and it causes the patient's haemoglobin to rise over time.

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

Today I’m presenting data from an ongoing clinical trial that’s testing in phase II the safety and efficacy of two agents. One of them is novel, it’s known as Hu5F9, it’s a monoclonal antibody that targets something called CD47. It’s paired with rituximab which is a standard therapy for lymphoma. So the patients on this study have relapsed or refractory diffuse large B-cell lymphoma, which is aggressive, as well as follicular lymphoma and other indolent lymphomas. 

The results of this phase I have already been published in The New England Journal of Medicine and that study was able to show that this was both safe and the maximal tolerated dose was 45mg/kg. So this is an expansion of that. The expansion in both diffuse large B-cell lymphoma as well as follicular lymphoma with the main question being the remissions that were seen in the phase I, do they last? Are they durable and is there additional toxicity when you continue to dose these two agents?

What we’ll be presenting today shows us that patients that get a good response or a remission early, it seems to be quite durable. So we now have patients that are out past two years and with continuous dosing they remain in remission. Those are the longest patients out. This is about a hundred patients and it shows us that the overall response rate is right at 50%. It’s a little bit higher in follicular lymphoma or indolent lymphomas than diffuse large B-cell lymphoma but one important difference was in the phase II part.

So what we’re presenting here the patient population was a little bit different. Because the patients that have the worst prognosis and have the fewest treatment options are those that are ineligible for CAR T therapy then all of these diffuse large B-cell lymphoma patients on this study were considered ineligible for CAR T, either because their disease was too aggressive or risk of toxicity or access. So this is the group of patients that really don’t have good treatment options. Once you become refractory if you can’t get something like CAR T then effective treatment options are quite limited.

What about the toxicity and safety profile of these drugs?

One of the things that you would know would happen if you gave an agent like this is you would see some anaemia. What we have seen on this study is that that happens early, it happens in the first month; so patients get a drop in their haemoglobin after the first few doses. The way that we get around that is we first give a priming dose, we give a very low dose of the medicine on the first day and then a week later we give a higher dose, a maintenance dose. When you do that and you load the receptor you don’t see a lot of clinically relevant anaemia that requires transfusion. But, more importantly, when you keep giving the treatment with continuous dosing that haemoglobin actually rises over time. So it’s not a toxicity that is dose dependent, it just happens right away and then when you keep going that becomes less of a problem over time.

Are these agents suitable for all patients?

Yes, one of the benefits here is that virtually any patient can get this, so of any age. It doesn’t have a lot of side effects and so patients with other comorbidities would be eligible. It’s not a procedure that requires timing, it can be gotten off the shelf. So that is probably one of the biggest strengths of this type of approach is that it basically applies to almost all patients. The one group of patients that can’t get this is those that have a haemolytic anaemia. So if you’re already chewing up your red cells then it’s not safe for those patients but other than that there’s very few reasons to not think about this.

What are the next steps?

One of the things that I see is that we need to have a better understanding of who benefits the most so those patients can be targeted. There is a regulatory pathway in diffuse large B-cell lymphoma for those patients that are ineligible for CAR T because that’s such an unmet need. So the company is focussing on that. In indolent lymphoma it’s a little bit less clear, that’s being discussed, about how to get this doublet out. It would be nice to have a better understanding of which patients respond.

But because the safety profile is quite modest, what we’ll probably see with this agent, and maybe others like it, are additional combinations. So now a lot of people are thinking about what could be a third agent or other to be added to this because the safety profile allows for that.

Can this model be applied to other types of cancer?

Yes. We focussed on lymphoma in this study but the concept here of enabling the macrophages to eat the cancer is not specific to lymphoma. In fact, the preclinical data suggests that this is broadly applicable across a bunch of different cancers and potentially even not just cancer. It could be effective in viral driven processes and these kinds of things, anything where the cell is evading the immune system or evading phagocytosis, this strategy could potentially be effective to then induce phagocytosis of that cell.