Preliminary Efficacy of Glofitamab Signals Hope for Relapsed/Refractory MCL Treatment

Tycel Jovelle Phillips, MD

One challenge associated with treating patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) is that options remain limited for those who fail Bruton tyrosine kinase (BTK) inhibitors. Research presented at the 2021 American Society of Hematology Annual Meeting and Exposition found that glofitamab may be an option for these patients.

Glofitamab is a CD20xCD3 bispecific antibody. A phase 1 step-up dosing trial (NCT03075696) was conducted in order to determine the efficacy of this agent in the R/R MCL population along with other tumor types. The trial has an estimated enrollment of 860 participants.

At the time of data cutoff, 29 patients were included in an analysis of the R/R MCL cohort. The agent was found to be safe and well tolerated in this patient population, with limited neurotoxicity.

Tycel Jovelle Phillips, MD, a clinical associate professor at the University of Michigan Health, discussed the use of glofitamab in patients with R/R MCL who have failed BTK inhibitors in an interview with Targeted Oncology^TM.

TARGETED ONCOLOGY: Can you give an overview of glofitamab step-up dosing for patients with r/r MCL most of whom dad failed prior BTK inhibitor therapy?

PHILLIPS: In this clinical study, we basically were evaluating the efficacy of glofitamab, which is a bispecific antibody that binds CD20, and CD3. Glofitamab has a bit of a unique design compared to some of the other bispecifics on the market, as a 2:1 binding for CD20 compared to CD3. So, in this situation, based on some data that we've seen preliminarily with other bispecifics, it would appear that MCL is quite sensitive to T cell directed therapies. And so, we embarked upon this clinical trial.

What is glofitamab's mechanism of action? What is it designed to do in this patient population?

Glofitamab, being a bispecific antibody, in essence has two binding epitopes. It'll bind to CD20, which is on the malignant B cell and also bind to CD3, which is on the patient's T cell. And in that aspect, it brings it into close proximity with the hope of activating the T cell and causing a clonal T-cell expansion or to allow the patient's own immune system their T cells in this instance, to attack and kill off the tumor cells. Again, in this way, it's almost like an off the shelf CAR T product without the need for manufacturing. So, by using the patient's immune system, ideally, we can avoid some of the toxicities we see with some other mechanisms or treatments that we typically use for this patient population.

Can you go into the design of the trial?

So, this was part of a much larger study where they evaluated a couple of different dosing mechanisms. They also evaluated the ability of obinutuzumab (Gazyva) given as a pretreatment to prevent some of the side effects we see with bispecific antibodies.

The main side effects of these treatments are cytokine release syndrome and neurotoxicity. For cytokine release syndrome (CRS) specifically, we did evaluate the use of obinutuzumab as a pretreatment to clear out some of the malignant B cells that may be in circulation and some of the nonmalignant B cells that the patient has in circulation to allow improved targeting of Glofitamab to the tumor.

We evaluated the efficacy of this in this patient population and the safety of this agent. Because of some of the safety concerns, obviously, this was given in a step of dosing fashion. So, we gave a very low dose in the beginning, a little bit higher dose the following week, and then the full dose was subsequently given on the third week. Thereafter, the infusion was given once every 3 weeks. Those first 3 weeks, the patients were monitored very closely. And these patients were hospitalized for observation, to observe for any incidence of CRS or neurotoxicity. After we reached the full dose, thereafter, the patients did not have any complications. They were subsequently treated as an outpatient every 3 weeks without any further need for hospitalization. Again, most of the safety concerns we would expect to occur early on, especially with CRS and neurotoxicity. Patients were still evaluated for safety, but we shifted to focus more on the efficacy of this agent in this patient population.

What are the results of this study?

As of right now, it's still very small numbers. But even with the very small numbers, we had a very impressive efficacy for this patient population. We wanted to evaluate the ability of glofitamab in a BTK refractory patient population. All the patients on the study were not refractory to BTK inhibitors. But we had a large number of patients who were. What we've seen clinically, in clinical practice and has been published in several reports is that patients who are refractory to BTK inhibitors and MCL generally have very poor outcomes. We wanted to evaluate the efficacy in this situation.

So, what we were able to establish and demonstrate in this study is a very high efficacy in those patients who were naive to BTK inhibitors and those who were exposed and refractory to BTK inhibitors. So, it proves that this agent could potentially be another option for those who failed BTK inhibitors. As of right now the only effective agent we typically have that we can offer these patients is utilization of the CAR T treatment, which has its own limitations based on non-select sites that can do CAR T and some of the complications that may prevent some of the older patients being eligible. So, I think one of the key points in addition to the efficacy is safety of this treatment, we have very low incidence of CRS. We only reported one episode of neurotoxicity, which was also a grade 1 neurotoxicity it resolved very quickly in this treatment modality. So, in that regards, based on the off the shelf applicability of this agent and the ability as of right now to be to be very safe. This is something that potentially could be used in sort of wider array of treatment facilities, not necessarily select academic centers that are accredited to give CAR T. So, in some situations, you can see this given in some private practice facilities, that they've become more accustomed with this agent, which, in essence will allow more patients to be treated with these treatments, compared to what we can sort of see right now with some of these more limited treatments such as CAR T.

What is the future of this research?

I think that is still under discussion. It's my understanding that the company is interested in exploring this in a larger patient population, but none of that has been finalized as of yet. Also, the role in how they'll use obinutuzumab as a pretreatment is also still to be determined. So, whether it'll be given on day -7 as 1000 mg or 2000 mg, which we both explored in this study is still yet to be determined.

What unmet needs still exist in this space?

As of right now, the only real agent we have that has shown any demonstrable efficacy in this R/R MCL population post BTK inhibitors has been a CAR T product. As for agents that we've explored venetoclax, lenalidomide, the PI3kinase inhibitors, all have shown to be very ineffective in this patient population. There is a retrospective study that is demonstrated that bendamustine and cytarabine appears to be effective, but a lot of these patients will have already seen bendamustine. And a lot of them will already seem cytarabine, by the time they fail the BTK inhibitor. So, again, based on the limited availability of CAR T products to most patients, because even in our state, there are only select centers within a state that can administer this treatment. And they're all for the most part saturated in the southeast corner of Michigan. There's a whole swath of our state that's not necessarily within close proximity to a CAR T center. So again, CAR T is still at this point limited for most patients because of selectivity to where they live in relation to a CAR T center. So again, a lot of these patients don't have access to sort of a readily accessible treatment option post BTK inhibitors. A lot of these patients, they can't get to a CAR T center, or they don't want to necessarily separate from their families, they don't have a lot of great options and will succumb to the disease. So, the post BTK R/R MCL patient is still a patient as it has a very high need for new and novel treatments and even more treatment that can actually be given in the community and don't necessarily require being treated at a select center.

_REFERENCE:

_{Phillips T, Dickinson M, Morschhauser F, et al. Glofitamab step-up dosing induces high response rates in patients (pts) with relapsed or refractory (R/R) mantle cell lymphoma (MCL), most of whom had failed prior Bruton's tyrosine kinase inhibitor (BTKi) Therapy. Blood. 2021; 138 (1): 130. doi.org/10.1182/blood-2021-148949}