Glofitamab Shows Promise in Large B-Cell Lymphoma

The step-up dosing approach with glofitamab in a phase 1 trial enabled researchers to minimize cytokine release syndrome while maximizing outcomes.

In an interview with Pharmacy Times at the American Society of Clinical Oncology (ASCO) 2022 Annual Meeting, Michael Dickinson, MBBS, DMedSci, said the step-up dosing approach with glofitamab in a phase 1 trial enabled researchers to minimize cytokine release syndrome while maximizing outcomes.

What is step-up dosing and why was it investigated for glofitamab?

Michael Dickinson, MBBS, DMedSci: Yeah, so step-up dosing is the idea that within an individual patient, you start at a low dose and then increase on the next step. And a step in this case is separated by a week. And this is something that's actually quite common across all the bispecifics that activate T cells. The main dose-limiting toxicity of T-cell therapy, or CAR T-cell therapy, or bispecific antibodies that activate T cells, is something called cytokine release syndrome, and cytokine release syndrome can make a patient quite unwell. It can be mild, can be as simple as a fever, or it can be more serious. And what we learned during the dose escalation part of the study was that the rate of cytokine release syndrome increases the bigger the first dose that the patient receives. But we also learned that a patient who had cytokine release syndrome on the first cycle was much, much, much less likely to get cytokine release syndrome. Again, it was kind of a first dose effect.

So, we figured let's start with a little dose, get the drug in, and then try to get to our target dose in terms of efficacy—in this case, 30 mg—so that we can deliver to the patient the best chance of responding, but also minimize the risk of high-grade cytokine release syndrome. And so, across all the bispecifics we see this step-up dosing approach. And with glofitamab, fortunately, it's very few steps, you know, 2.5 mg, 10 mg, 30 mg, you're there. And we see very little cytokine release syndrome beyond the first 2 doses and beyond that, beyond that escalation phase. And cytokine release syndrome isn't a practical issue, once you get beyond that step up. And so, it's just, I guess, one of the lessons across all the bispecifics, is that you have to get through that first dose, and then your risk of complications goes down.

How was the study structured and what were the steps in the dosing process?

Michael Dickinson, MBBS, DMedSci: So, the study was initially structured as a first-in-human study and it's gone all the way through to pivotal. So, it's actually got multiple cohorts. And because CD20 is on the surface of B-cell lymphomas, we've explored a range of B-cell histologies. So, we started this study with single patient dosing, where we would start at very, very low doses. And in fact, we started at 5 mg as our starting dose. And we just treated 1 patient at that dose, and then went up a dose level and treated a single patient at the next dose level. And then we switched to cohorts of 3, and tested doses in a rule of 3 type of study. And then once we'd established, you know, where our dose was with this kind of flat dosing, we then moved to this step-up dosing strategy and evaluated that. And then, within those cohorts, we've looked at different histologies. And we've reported some of those different histologies. And the main focus with the most recent cohorts has been to optimize our understanding of high grade and diffuse large B-cell lymphoma and how those patients respond, because we see that as being a very important first question. And then, in the very latest cohort, we're trying to optimize our management of cytokine release syndrome and how to prevent that. And that's turned out very well. So, there's some sort of, you know, ongoing evaluations that that you'll hear more about with time.

What are some considerations for pharmacists when working with glofitamab step-up dosing?

Michael Dickinson, MBBS, DMedSci: Well, you know, I think there are a couple of things. Firstly, there's that first dose of obinutuzumab that has to be given, so patients will have been exposed to that the week before they get their first dose of glofitamab. I can't speak to, you know, how things work in the preparation room. It's not my skill set. But I think understanding what the patient's experience was on the prior dose is always important with the next dose and understanding how the patient's overall situation is. All of these agents are very potent activators of the immune system and so, I think, when you give a dose of any of these drugs, you should always see what happened last time and try to understand that. As I've mentioned, the risks actually decrease with time, but I think it's still really important to do that.

The other thing to say is that once you get past this step-up dosing, we don't use steroid pre-medication as much. So, there's an option to drop the steroid pre-medication. Once you get through that step-up dosing and have 2 doses at the target dose, you can remove that steroid pre-medication. So that's something that a pharmacist might want to check against a physician and say, hey, does this patient need this pre-medication anymore?

And the other thing to say is that we did see some neutropenia in the trial, and that neutropenia doesn't seem to translate to febrile neutropenia. It's very manageable. Some patients respond beautifully to G-CSF. So that's the other thing that a pharmacist might pick up on and talk to the physician about.

I think the only other thing to say is that, for all of these drugs, all drugs that activate T-cells, everyone in the chain of care, from the patient through to the pharmacist and the nursing staff and the doctors, need to understand cytokine release syndrome and how to respond to it. It's very, very manageable. And it's something I think we'll all get used to as these drugs become available. I think the one thing I would say is, it's important to make sure the patient understands what a fever might represent. And I think that's just something that people will get used to and I think in many centers people are used to already from T-cell activating agents and CAR T cells and things like that.

But I can see the potential of glofitamab being used way beyond the sort of treatment centers that use CAR T cells, and that's what's really exciting about the bispecifics. And so, I think there will be a real opportunity for pharmacists and nurses and doctors to realize that these are antibodies, but they're different from the antibodies we've ever used before because they're so good at activating T cells, so just a totally different range of mechanism of action compared to antibodies like rituximab and obinutuzumab.