Tycel Phillips, MD, Associate Professor, University of Michigan, Ann Arbor, highlights how glofitamab step-up dosing induces high response rates in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL), most who previously failed prior Bruton’s Tyrosine Kinase Inhibitor (BTKi) therapy. These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Transcript

Hi. My name is Dr. Tycel Phillips. I'm an associate professor at the University of Michigan in Ann Arbor, Michigan.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

With MCL, especially in the post-BTK setting, there are very few useful options for treatment for patients.

Recently, there was a study looking at Tecartus (brexucabtagene autoleucel), which is a CAR-T therapy from Kite, which was directed for patients with mantle cell lymphoma (MCL). It had a very high response rate. Some of the issues with Tecartus was patients were known to have certain special adverse events, such as neurotoxicity and cytokine release syndrome.

Bispecific antibodies function very similarly to CAR-T therapy except, obviously, they don't require manufacturing, so they're more of an off-the-shelf therapy. With recent step-up dosing, we've seen lower incidence of CRS and neurotoxicity.

Based on the efficacy of what we saw with Tecartus and older data that shows allogeneic stem cell transplantation (ASCT) is effective in patients with MCL, we hypothesized at that point that other T-cell-directed therapies would be effective.

We did, after exploring a step-up, escalation dosing’s of this medication in patients with follicular (FL) and diffuse large B-cell lymphoma (DLBCL), there was a separate cohort opened for MCL patients, specifically just to continue to evaluate the safety and efficacy of this agent in this patient population.

OLN: Please briefly describe your study and its findings.

Glofitamab, in this situation, was given in a step-up dosing. We evaluated in this patient population those with MCL. Patients were not required to have exposure to a BTK inhibitor, but as the title indicates, the vast majority of patients did have exposure.

These were patients who had had at least 1 prior line of therapy and have had measurable disease, at least 1.5 cm, that we enrolled into the study. The study was enrolled into a couple different cohorts. There was a few patients that were enrolled with fixed dosing.

Subsequently, patients were enrolled in what we consider the step-up dosing, where patients were given escalating doses of glofitamab until they reached the phase 2 dose in this patient population, which was 30 mg.

Once patients reached the 30-mg dose, the infusion was subsequently then given every 3 weeks thereafter. For the step-up dosing, the doses were given at 2.5 mg, 10 mg, and these were given weekly, up until we reached the 30 mg dose, and then given every 3 weeks.

As an aside, as far as the study, we did evaluate pretreatment with obinutuzumab. Obinutuzumab is a naked CD20 antibody. In this study, it was given more so to help reduce the risk of CRS in this patient population.

The MCL patients, they have a higher clearance of obinutuzumab compared to some of the other non-Hodgkin's lymphoma (NHL) patients. In this situation, we've been able to clean out some of the peripheral and circulating B-cells and including malignant cells.

Because of the high clearance, it did not necessarily interfere with the bonding of glofitamab to the tumor cell, with subsequent cycles of therapy, so that we were able to continue with the efficacy. Again, that was given on Day -7, with an ideal of hopefully blocking some of the receptors on the CD20 receptors on both of the B-cell and the tumor cell.

Thereafter, glofitamab was given, at which point the 2 would compete, at least early on. With the continued weekly dosing of the glofitamab, the obinutuzumab will be clear from the body, and allow the glofitamab to subsequently just bind to the CD20 receptor.

Additionally, glofitamab has a little bit of a unique design compared to other bispecifics. It has 2 CD20-binding epitopes and 1 CD3-binding epitope to help us increase competition with obinutuzumab in this situation and other agents that may interfere with binding of CD20.

OLN: Were any of the outcomes particularly surprising?

We did see in the study that we had a very high overall response rate (ORR), even in those who were refractory to a Bruton tyrosine kinase inhibitor.

I will say that the overall outcome wasn't as surprising as the time to best response. It was probably a little bit quicker than I anticipated in the patients that we enrolled on the study. I will say, that was probably the biggest surprising aspect of the treatment.

OLN: What are the possible real-world applications of these findings in clinical practice?

Moving forward we have smaller numbers, and obviously, these needs to be evaluated in a much larger patient population to truly get a sense of time to best response, and also the complete ORR in this patient population.

OLN: Do you and your co-investigators intend to expand upon this research? If so, what are/will be your next steps?

These are ongoing discussions with the study sponsor, Roche Genentech, to try to figure out what's the next best step. The plans are to further explore this agent. The actual design and concept of it is still something that's in development.

I would hope that, in the next year or so, that we will have a more definitive critical protocol for patients with MCL to get more definitive information on, as I said, time to response, overall response, and the duration of response for this patient population.

OLN: Is there anything else pertaining to your research and findings that you would like to add?

The only other thing I would add to this is that, as I mentioned before, the bispecific was designed and evaluated in this patient population to hopefully reduce some of the side effects we saw with CAR-T, and we did accomplish that goal.

The rates of neurotoxicity and the severity of it were very low, especially compared to what you see with the published data with CAR-T. There were also very low and short durations of what we call cytokine release syndrome.

The 2 main side effects of T-cell-directed therapy, we were able to get a very good control and have very limited and short durations of these adverse events.

It does appear, at least from that aspect, that the bispecific antibody may be a little bit safer in patients with MCL. Again, you need a much larger study to confirm this information.