Glofitamab Leads to Durable Complete Remissions in Relapsed/Refractory LBCL

Cyrus M. Khan, MD

Without continued treatment, most patients with large B-cell lymphoma (LBCL) administered glofitamab (RG6026)who achieved a complete response (CR) at the end of treatment experienced durable responses, according to updated findings from an ongoing phase 1/2 trial.

Glofitamab is a CD20/CD3 T-cell-engaging bispecific monoclonal antibody which redirects T cells to kill normal and malignant B cells. The treatment is off-the-shelf and administered via intravenous infusion for a fixed duration of 12 cycles.

At the American Society of Hematology (ASH) 2022 Annual Meeting, data from the expansion cohorts of this phase 1/2 study (NCT03075696) showed glofitamab to have a manageable safety profile. In patients with relapsed/refractory large B-cell lymphoma, glofitamab also induced frequent and durable complete responses (CRs).

Just 1 of the 44 patients who reached 12 months follow-up after the end of treatment experienced progression, resulting in longer follow-up needed to further confirm the off-treatment durability of glofitamab-induced CRs in this patient population after 12-months.

“As we know, [in the frontline setting,] we are curing about 65% of the patients with diffuse large B-cell lymphoma. That leaves us about 35%-40% of the patients who do relapse. Core standards have been either autologous transplant or CAR T-cell therapy. Either of those mechanisms will about 30%-35% of the patients. That leaves us with a big swath of patients that continue to relapse. We've been waiting for such products where it would help those patients. I think that's where the role will be and I think [an] approval will be there,” stated Cyrus M. Khan, MD, in an interview with Targeted Oncology^TM.

In an interview, Khan, MD, hematologist in the Division of Hematology and Cellular Therapy at West Penn Hospital of Allegheny Health Network, further discussed the background of the phase 1/2 trial and the potential use of glofitamab for patients with LBCL in the future.

Targeted Oncology: Can you discuss glofitamab (RG6026) and its mechanism of action?

Khan: Glofitamab is a CD3/CD20 bispecific T-cell engager. We've had a plethora of agents that target CD19 on the B cells, such as the [chimeric antigen receptor] T-cell therapies and the antibody drug conjugate loncastuximab [Zynlonta]. Then, we have tafasitamab[Monjuvi] the CD19 antibody, but with that sort of CD19 antigen, there are a lot of issues in the relapsed/refractory setting. New versions of quite a few of the bispecific T-cell engagers are coming out that will target CD3 and CD20, and glofitamab is 1 of them. This will be tested in large B-cell lymphomas in the relapsed/refractory setting. We [at AHN] participated in the clinical trial as well.

Would you mind discussing this trial evaluating glofitamab? What were the methods and design of the study?

This was a phase 2 clinical trial, and it took patients with relapsed/refractory large B-cell lymphoma, whether they had transformed lymphomas or hybrid B-cell lymphomas. They took all comers, whether they were post-autologous transplant [or other]. Initially, the idea was to give them 1 dose of obinutuzumab [Gazyva] to minimize the cytokine release syndrome [CRS] because all these products do cause cytokine release syndrome. Then there was a stop dosing involved. It started off at a very small dose and eventually the dose was taken up to the highest dose that was tolerable. The infusion is given every 3 weeks just for 12 cycles. The idea is to get a finite duration of treatment instead of something that would continue indefinitely for those patients. Assessments were done after 3 cycles, and most of the patients will achieve the response at that third cycle.

Who was enrolled in a trial and what were the eligibility criteria?

It was a multicenter clinical trial across many different countries, mostly in Europe, but our center also participated. It was for all comers if they had relapsed/refractory large B-cell lymphoma. There were certain inclusion and exclusion criteria, but it was broad. We could enroll a lot of patients and if you look at the results, there were even patients post-CAR T-cell therapy that were enrolled with refractory disease, primary refractory disease, and so on and so forth. It was a broad-based clinical trial for these difficult to treat patients.

What data from the trial were presented at ASH this year?

A long-term follow-up was presented. We looked at the number of patients who achieved the response. About half of the patients achieved some form of response, about a third of the patients achieved the complete response, and the focus was on those complete responders at this meeting, which was about seven or so patients. The idea was to see what those patients did after completion of those 12 cycles and to see how they're doing or whether they remained in response or progress. About 20% of the patients had responded, a majority had relapsed, but most were still in response. It didn't matter how many treatments they'd had before and didn't matter what kind of disease they had as far as the subtype of large B-cell lymphoma is concerned. It’s certainly interesting to see that it is relatively well-tolerated. Some infections are seen longer term, but most of the patients did well and had lower rates of CRS as well as neurotoxicity.

How do you foresee this research potentially impacting the space in the future?

As we know, [in the frontline setting,] we are curing about 65% of the patients with diffuse large B-cell lymphoma. That leaves us about 35%-40% of the patients who do relapse. Core standards have been either autologous transplant or CAR T-cell therapy. Either of those mechanisms will about 30%-35% of the patients. That leaves us with a big swath of patients that continue to relapse. We've been waiting for such products where it would help those patients. I think that's where the role will be, and I think [an] approval will be there. It's also a benefit that is off-the-shelf, so you don't have to wait for manufacturing and the time it takes for the T-cell collection as sometimes it's very difficult for patients to get CAR T. I think this is going to bridge a lot of those problems and fill up a needed space for patients.

What key takeaways from this study are important for community oncologists to know?

I think this is something that is going to be available to the community oncologists instead of referring them to major tertiary referral centers where CAR T-cell products are available only. This is an infusion that can be done in the community setting. It can be accessed for those patients that perhaps won't be able to go for CAR T to a tertiary center. Perhaps they have already received CAR T and want to stay close to home to receive treatments. I think some training will be required to manage cytokine release syndrome, but I think they're working with other versions of the drug as well. They're working on a subcutaneous version in the future, which might even further minimize the risk for CRS. I think it's going to be a useful tool in the community oncologist toolbox for diffuse large B-cell lymphoma in the relapse setting.

REFERENCE:

Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. Published online December 11, 2022. doi:10.1056/NEJMoa2206913