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ASH 2021 | Glofitamab step-up dosing in R/R MCL
Tycel Phillips, MD, University of Michigan, Ann Arbor, MI, reports preliminary data from the Phase I/II trial (NP30179; NCT03075696) in patients with relapsed/refractory (R/R) mantle cell lymphoma who received glofitamab with obinutuzumab pretreatment (Gpt) prior to glofitamab monotherapy. Glofitamab set-up dosing as monotherapy after Gpt induced high response rates in patients with R/R MCL irrespective of Bruton’s tyrosine kinase (BTK) inhibitor exposure. Regarding the safety profile, cytokine release syndrome (CRS) rates were observed but primarily low grade and manageable. Immune effector cell-associated neurotoxicity syndrome (ICANS)-like adverse events, one of the concerns with T-cell-directed therapies, were infrequent. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.
Transcript (edited for clarity)
In the study with glofitamab, which is a CD20/CD3 bispecific antibody, we evaluated step-up dosing of glofitamab with pretreatment with obinutuzumab with patients with relapsed/refractory mantle cell lymphoma, specifically being mantle cell lymphoma is a very heterogeneous disease, but patients post-BTK-exposed have very poor outcomes in mantle cell lymphoma. Until recently we had very limited options...
In the study with glofitamab, which is a CD20/CD3 bispecific antibody, we evaluated step-up dosing of glofitamab with pretreatment with obinutuzumab with patients with relapsed/refractory mantle cell lymphoma, specifically being mantle cell lymphoma is a very heterogeneous disease, but patients post-BTK-exposed have very poor outcomes in mantle cell lymphoma. Until recently we had very limited options. As of right now, CAR-T is really the only effective option we have in this patient population, but it does have some adverse events that are concerning and limited to specialized centers that can give CAR-T.
So in this study, we evaluated glofitamab. Again, it is a bispecific that’s a little bit different from some of the other ones on the market. It has a 2:1 binding epitope, so two binding areas for CD20 and one for CD3 to hopefully increase efficacy and targeting of T-cells to the malignant B-cell.
So in this study, it evaluated giving obinutuzumab, which is a CD20 antibody, on Day -7. And initially we did fixed-dosing with glofitamab at 0.6, ten milligrams and thirty milligrams, which is a very small patient population, three patients. And then we proceeded to step up dosing, where with the step up dosing, you proceed with a very small dose of glofitamab and you increase the dose until you get to the final dose of thirty milligrams in an effort to reduce the incidence of the major side effect, which is cytokine release syndrome. Additionally, we continued with the obinutuzumab as a pretreatment at Day -7 to also hopefully decrease some of the receptor occupancy of glofitamab in the early stages where we most likely would see CRS. As mantle cell lymphoma is uniquely situated for a higher clearance of obinutuzumab, it’s not thought that the obinutuzumab would interfere with the efficacy of glofitamab because patients with mantle cell lymphoma clear obinutuzumab very quickly. So once we get to the higher doses, we would expect that glofitamab wouldn’t have any sort of competition with obinutuzumab. So what we saw in this patient population was a very high efficacy. As the majority of our patients were BTK inhibitor-exposed, we did see efficacy rates range from 70% to 80% in this patient population with CR rates from 60% to 70%. Specifically looking at the comparison between BTK inhibitor-exposed and naive, there wasn’t a major difference, meaning that glofitamab was effective in patients with relapsed/refractory mantle cell lymphoma, irrespective of BTK inhibitor exposure. As far as the side effect profile of this treatment, we did see rates of CRS, but most of those were grade 1 to grade 2. They were typically short-lived and alleviated with use of preventative medications, such as tocilizumab and acetaminophen if need be. As far as neurotoxicity, which is another concern of these T-cell directed therapies, there was only one incidence of grade 1 neurotoxicity noted, which alleviated within 24 hours. So in this very small study, it’s very promising data suggesting that glofitamab potentially could be another viable option for patients with relapsed/refractory mantle cell lymphoma, who had been previously exposed to a BTK inhibitor. And because of the off-the-shelf availability of the agent, it does provide for more avenues for patients to get access to this medication, expanding outside of what has been to this point, limited to academic sites within the U.S.