The Importance of Treatment Sequencing in Mantle Cell Lymphoma

As part of our coverage of the 2024 annual meeting of the American Society of Clinical Oncology, we spoke with Tycel Phillips, MD, associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, about his team’s interim analysis of their dose-escalation study of glofitamab, a bispecific T-cell engager (NCT03075696), against relapsed/refractory B-cell non-Hodgkin lymphoma.

In part 1, Phillips addressed the advantages of glofitamab in patients previously refractory to a Bruton tyrosine kinase inhibitor, and here he continues the discussion by explaining the rationale behind pretreating patients with obinutuzumab prior to glofitamab.

This transcript has been lightly edited.

Transcript

Can you discuss the reasons behind pretreatment with obinutuzumab?

Ideally, the biggest issues with T-cell–directed therapy—so, bispecifics, CAR [chimeric antigen receptor] Ts—are cytokine release syndrome, or CRS, or immune effector cell–associated neurological syndromes, which is ICANS. To help mitigate some of these side effects, the bispecifics are given in what we call a step-up dosing fashion, meaning they start at a small dose—in this case, 2.5 mg—and then the following week are escalated to 10 mg and 30 mg. As an extra step to help sort of reduce some of these events, especially cytokine release syndrome, glofitamab is given with a obinutuzumab pretreatment. So this is a competitive sort of situation: The obinutuzumab binds in a very similar region, or the same location, as glofitamab.

Because of that, when these patients are getting the glofitamab, the first initial dose, there is still obinutuzumab there binding to the cancer cell and also the normal B cells. So you get some competitive binding, which reduces the rates and risk of CRS and allows the body to get more acclimated to that drug so that, again, when you get the next dose to 10 mg, you don't really have that competitive binding, but hopefully at that point, the body's already adjusted to the medication. And thus from what we've seen clinically, the rates of CRS are much less from the first dose of 2.5 down to the 10-mg dose, and then even less with the 30-mg dose.

As an aside, especially at least in mantle cell lymphoma [MCL], the good thing is while we get a lot of that competitive binding with a 2.5-mg dose because of how fast the body clears obinutuzumab, it's not much of any around with a 10-mg or 30-mg dose.

What do we know about the preferred sequencing of therapies in MCL?

There's quite a bit of data about bispecifics after CAR T. And then on the flip side, we're starting to get some early data about bispecifics before CAR T. We don't really have that information with patients in mantle cell lymphoma. Presumably because the targets are a little bit different—bispecifics are targeting CD20, CAR T is targeting CD19—we are likely not to have any sort of detrimental impact by using one before the other. So in that situation, I don't think there'll be any harm to the point where if CAR T is a bit limited—because again, patients have to go to CAR T centers, they have to be in those centers for around 14 days, at least, [and] some patients refuse that or they just don't have access to a CAR T center. The fact that glofitamab again does not require a specific center, you don't have to have a specific designation to get glofitamab; the center just has to be able to basically monitor the patients for up to 24 hours and sometimes a little bit longer for these side effects—it does allow for glofitamab to be given, again, in a wider sort of range of clinical settings.

Additionally, glofitamab is an antibody, so it does not require any real manufacturing process. So sometimes the time delay that you have from insurance, or petitioning the insurance, getting insurance approval, getting cell collection, cell manufacturing, cell return, you don't necessarily run into those issues with these bispecific antibodies, because again, it is literally off the shelf. So literally, you get approval, you put in an order, and the drug is being given. So that does allow a little bit more of speed of access.

Reference

A dose escalation study of glofitamab (RO7082859) as a single agent and in combination with obinutuzumab, administered after a fixed, single pre-treatment dose of obinutuzumab in participants with relapsed/refractory B-cell non-Hodgkin's lymphoma. ClinicalTrials.gov. Updated May 14, 2024. Accessed July 15, 2024. https://clinicaltrials.gov/study/NCT03075696