Commentary

Article

Fixed-Duration Glofitamab Yields Responses in R/R Mantle Cell Lymphoma

Author(s):

Tycel Phillips, MD, discusses updated findings from a phase 1/2 trial evaluating glofitamab in relapsed/refractory mantle cell lymphoma.

Tycel Phillips, MD

Tycel Phillips, MD

Treatment with fixed-duration glofitamab-gxbm (Columvi) led to durable responses in patients with relapsed/refractory mantle cell lymphoma (MCL), including those who received prior treatment with a BTK inhibitor, according to updated findings from a phase 1/2 trial (NCT03075696) presented at the 2024 ASCO Annual Meeting.

Findings showed that all evaluable patients (n = 60) achieved an overall response rate (ORR) of 85.0%, including a complete response (CR) rate of 78.3%. In patients who were naive to BTK inhibitors (n = 29), the ORR and CR rate were 96.6% and 86.2%, respectively. In the population of patients who received a prior BTK inhibitor (n = 31), these respective rates were 74.2% and 71.0%.

Furthermore, among all responders, the median duration of response (DOR) and duration of CR were 16.2 months (95% CI, 12.6–not evaluable [NE]) and 15.4 months (95% CI, 12.7-NE), respectively. In those who were previously exposed to a BTK inhibitor, these respective rates were 12.6 months (95% CI, 7.4-NE) and 12.6 months (95% CI, 5.4-NE). The median progression-free survival (PFS) was 16.8 months (95% CI, 8.9-21.6) among all evaluable patients (n = 61) and 8.6 months (95% CI, 3.4-15.6) among evaluable BTK inhibitor–exposed patients (n = 32).

“Because of the data presented at the 2024 ASCO Annual Meeting and what we know [thus far], glofitamab was given breakthrough therapy designation by the FDA. Hopefully, this will be an approved option for our patients [with relapsed/refractory MCL] sooner rather than later as we get more mature data. The phase 3 [GLOBRYTE] trial [NCT06084936] continues to enroll,” Tycel Phillips, MD, said in an interview with OncLive®. Phillips is an associate professor in the Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, at City of Hope in Duarte, California.

In the interview, Phillips detailed on the need for improved later-line treatment options for patients with relapsed/refractory MCL, expanded the updated findings from the phase 1/2 trial, and highlighted the ongoing GLOBRYTE trial further evaluating glofitamab in this patient population.

OncLive: What was the rationale for this phase 1/2 trial investigating glofitamab in patients with relapsed/refractory MCL?

Phillips: This study was built off the original phase 1 safety-finding study with glofitamab in [patients with] various subtypes of relapsed/refractory non-Hodgkin lymphoma. Once safety was identified, the study was expanded out into several different cohorts, looking at some varying relapsed/refractory patient populations. One specifically was relapsed/refractory MCL.

MCL, especially in the relapsed/refractory setting, is of interest because of some limitations in [treatment] options [in later lines of therapy], especially effective options after patients [experience disease] progression on BTK inhibitors.

What did prior findings from this study show?

From the original presentation, we presented safety data that suggested the safety profile of this treatment in MCL was similar to what we saw another B-cell lymphoma subtypes, and overall, it demonstrated safety. Specifically, we did notice there was higher incidence of cytokine release syndrome in [patients with] MCL than what we saw in patients with diffuse large B-cell lymphoma. Therefore, there was an exploration of different doses of obinutuzumab [Gazyva] pretreatment prior to glofitamab in step-up dosing.

In the protocol, we explored 1000 mg or 2000 mg of obinutuzumab on cycle 1, day 1, and glofitamab was subsequently given the following week on cycle 1, day 8 at 2.5 mg, and then on cycle 1, day 15 at 10 mg. At cycle 2, day 1, [glofitamab] was given at 30 mg. Thereafter, the 30-mg dose was continued [once every 21 days] for a total of 12 cycles.

The key point is that in the beginning part, the obinutuzumab dosing was varied because we do know that between these 2 drugs—obinutuzumab and glofitamab—there was some competitive binding, which did lead to receptor occupancy between the 2 drugs and reduced some of the binding of glofitamab among these patients, helping induce some tolerance. Due to the high clearance of obinutuzumab in patients with MCL, this competitive binding was only [observed] at cycle 1, day 8, and it did not necessarily affect the efficacy of the drug. The body would clear [obinutuzumab] very quickly when we proceeded with the cycle 1, day 15 dose and the cycle 2, day 1 dose, which was a full, effective dose [of glofitamab].

What were the key highlights from the updated data presented at the 2024 ASCO Annual Meeting?

In the updated efficacy [analysis], we did reconfirm of the ORR and CR rate in more patients. There were 60 evaluable patients, and from this, we still saw consistent efficacy, irrespective of prior BTK exposure; albeit, there was a higher ORR and CR rate in BTK inhibitor–naive patients.

When we shifted to looking at DOR and PFS, we had more mature data [at a median] follow-up of [19.6 months (95% CI, 11.9-26.1)]. We did notice a median PFS of 16.8 months in the overall patient population. There was a slight PFS difference between BTK inhibitor–naive and –exposed patients. A lot of this was accounted for by some non-progression events, meaning [these events] weren’t related to disease progression; rather, they were other PFS events that happened in the [BTK inhibitor–exposed] patient population. Therefore, the [PFS] numbers do look a bit different [between these 2 populations]. Again, it's comforting to know that [the difference in PFS] wasn't related to disease progression in these events, and this would hopefully be something we can mitigate moving forward.

Were there any noteworthy safety data in the updated findings?

We did not notice any new safety signals; however, we did have several incidents of COVID-19 fatalities, which, unfortunately, were prevalent during the time of the pandemic because of the integration of new drugs and the evolution of COVID-19 during that period of time, with the more virulent Omicron variant coming on during late 2021 and dominating most of 2022.

Moving forward, as we [continue] explore this combination in the phase 3 trial that's ongoing, [we have] language and strategies in place to help mitigate COVID-19; however, the current strains do not appear to be as virulent as what we saw with Omicron. [These mitigation strategies] are in place to help investigators.

How will GLOBRYTE continue to evaluate glofitamab in patients with relapsed/refractory MCL?

GLOBRYTE will look at patients [with relapsed/refractory MCL] who are BTK inhibitor–exposed because we have very limited options in this patient population. As of today, we have 2 CAR T-cell therapies, which come with the limitation of access to CAR T-cell therapy. There are areas around the country where certain patients cannot necessarily access CAR T-cell therapy because of the lack of a caregiver or the inability to get to a CAR T center.

Other than CAR T-cell therapy, we have an oral medication, pirtobrutinib [Jaypirca], which is a noncovalent BTK inhibitor. To date, if we look at efficacy [from non–head-to-head trials], the CAR T-cell therapies have a longer PFS and DOR vs pirtobrutinib. Thus, we do need more drugs available to increase the access for patients.

In GLOBRYTE, glofitamab will be compared to standard-of-care options. I’m sure some people would rather compare it with CAR T-cell therapy, but unfortunately that wasn't the case. Because of how it was mandated, [the control arm] will be standard-of-care with bendamustine plus rituximab [Rituxan] or lenalidomide [Revlimid] plus rituximab. The randomized 1:1, phase 3 trial will enroll 182 patients.

The good thing for GLOBRYTE is that it does allow patients to cross over to glofitamab at time of progression in the standard-of-care arm. For the most part, [the study protocol] will allow the majority of patients [enrolled] to get access to glofitamab, which is an important step given the [treatment] limitations in this patient population. The hope is that this trial will continue to enroll robustly. There have been some delays with activation in the United States, but hopefully once that gets going, we'll have this information very quickly, and then hopefully, we'll have another FDA-approved agent for these patients with relapsed/refractory MCL.

Reference

Phillips TJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab monotherapy in patients with heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL): Updated analysis from a phase I/II study. J Clin Oncol. 2024;42(suppl 16):7008. doi:10.1200/JCO.2024.42.16_suppl.7008

Related Videos
Sumanta Kumar Pal, MD, FASCO, chair, Kidney and Bladder Cancer Disease Team; co-director, Kidney Cancer Program; professor, vice chair, Academic Affairs, Department of Medical Oncology & Therapeutics Research, City of Hope
Amrita Krishnan, MD, City of Hope
Alexey Danilov, MD, PhD
Tycel Phillips, MD
Tycel Phillips, MD
Manali Kamdar, MD
Tycel Phillips, MD
Alexey Danilov, MD, PhD
Ibrahim T. Aldoss, MD; and Elias Jabbour, MD
Ibrahim T. Aldoss, MD; and Elias Jabbour, MD