Tycel J. Phillips, MD, on Mantle Cell Lymphoma: New Findings on Glofitamab Monotherapy
2022 ASH Annual Meeting and Exposition
Tycel J. Phillips, MD, of the City of Hope National Medical Center, discusses data that showed fixed-duration glofitamab monotherapy induced high and durable complete response rates in patients with mantle cell lymphoma (MCL) who received obinutuzumab pretreatment. This is one of the largest data sets and longest follow-ups reported with a CD20/CD3 bispecific monoclonal antibody for patients with relapsed or refractory MCL (Abstract 74).
Disclaimer: This video transcript has not been proofread or edited and may contain errors.
Historically, relapsed refractory mantle cell lymphoma has poor outcomes, especially those who are previously exposed to a BTK inhibitor. We have seen some changes in the landscape with the introduction of brexucabtagene autoleucel, which is sometimes hampered by toxicity and logistical challenges. Glofitamab is a bispecific antibody targeting CD20 and CD3 with two CD20 binding epitopes, which potentially provides a bit more potency compared to some of the other bispecific antibodies on the market.
We previously presented data demonstrating the efficacy of this and acceptable mitigation strategy for CRS with step-up dosing. Additionally, in this study, we evaluated different pre-treatment doses of obinutuzumab, due to the competitive receptor occupancy binding of obinutuzumab and glofitamab, reducing further the risk of CRS, as well as with its rapid clearance not necessarily impacting clinical efficacy.
In this study, we started off with obinutuzumab be either one or two grams on cycle one, day one, followed by glofitamab of cycle one, day eight at 2.5 milligrams; cycle one, day 15 at 10 milligrams; and cycle two, day one at 30 milligrams. Thereafter, glofitamab was given every three weeks at the 30 milligram dose for a total of 12 cycles.
In this study, we enrolled patients with relapse refractory mantle cell lymphoma who received a median of three prior lines of therapy. Majority of the patients on the study were male patients, majority of the patients had advanced stage disease, a third of the patients had high risk MIPI, two thirds of the patients had prior exposure to a BTK inhibitor, and the majority of the patients were refractory to last line of therapy.
In this study, what we saw was still high overall efficacy irrespective of the dose of obinutuzumab given as a pre-treatment, and this also correlated in the BTK refractory or exposed patient population. What we did also see is there was a higher overall response rate in those who received two grams of obinutuzumab and this also correlated into the BTK exposed patient population.
If we look at duration of response, the duration of response on this study is a bit short compared to what we would see with the data with brexucabtagene autoleucel, but with a median follow up of a little less than a year we do see some durability of responses. We see some patients remain in remission even off of therapy, thus indicating that there's potentially for some durability of this treatment.
If we look at patients with a complete remission, we see that 20 of 27 patients who obtained complete remission, still remain in remission on study. If we exclude four patients who came off treatment with CAR-T infections, we have 20 of 23 patients with a median duration of response not reached, indicating that there is substantial durability potential in this treatment response. Also, of note, all the patients who've completed 12 cycles of therapy have not yet have progressed on treatment at this current time.
If we dive into the adverse events, the most common adverse event on treatment is cytokine release syndrome as we see the majority of our patients. The good thing with this treatment is we see the majority of this CRS events are grade one and grade two. We do have a scattered few of grade three and grade four CRS events. Some of the other events of note are neutropenia, tumor flare, elevation of AST and anemia, as well as we have a few neurological events that we will discuss later.
Diving in deeper into the cytokine release syndrome, we see a lower percentage and frequency of CRS events with a two gram of obinutuzumab pre-treatment and there were no grade four CRS events noted with the two gram of obinutuzumab pre-treatment. All TRS events resolved on study treatment and none of these CRS events led to discontinuation irrespective of the amount of obinutuzumab given, whether it was one or two grams.
If we dive into neurological complications, especially ICANS, there were five ICANS events on the study. Four which occurred in the one gram obinutuzumab pre-treatment and the one that occurred in the two gram obinutuzumab pre-treatment group was a great one ICANS event and did resolve on treatment.
The other issues that we discussed are infection because of how this treatment works, we did see upper respiratory infection and some other infections specifically with COVID-19. There, specifically, were four COVID-19 related events and deaths on study treatment. One occurred after the adverse event reporting program, but overall, these necessarily did not lead to any sort of substantial impact or efficacy into what we see in this study treatment.
Moving forward, we see that glofitamab monotherapy with obinutuzumab pre-treatment was effective in this patient population of relapsed refractory mantled cell lymphoma patients. As of today, the plan is to move forward with a randomized phase three study to get a better idea of the sense of efficacy, duration of response, and how this treatment responds in certain patient characteristics, which we will not able to collect on this study versus the standard of care. We will all look forward to seeing how this study plays out and where the glofitamab slots in in the treatment algorithm for patients with relapse refractory mantle cell lymphoma.
Irene Roberts, MD, of Oxford’s Weatherall Institute of Molecular Medicine, discusses children with Down syndrome, who have a more than 100-fold increased risk of developing acute myeloid leukemia before their fourth birthday compared to children without Down syndrome. Their risk of acute lymphoblastic leukemia is also increased by around 30-fold. Dr. Roberts details current knowledge about the biologic and molecular basis of this relationship between leukemia and Down syndrome, the role of trisomy 21 in leukemogenesis, and the clinical implications of these findings.
Eileen M. Boyle, MD, PhD, of the Perlmutter Cancer Center, NYU Langone Health, discusses Fc-mediated antibody effector function, inflammation resolution, and oligoclonality and their role in predicting sustained measurable residual disease negativity in patients with newly diagnosed multiple myeloma who were treated with immunotherapy regimens. For the first time, an analysis of T-cell receptors shows that oligoclonal profiles seen on treatment may influence the fitness of the immune response (Abstract 100).
Jorge E. Cortes, MD, of Georgia Cancer Center at Augusta University, discusses new findings on vodobatinib, which was administered to patients with chronic-phase Philadelphia chromosome–positive chronic myeloid leukemia (CML) and appeared to be efficacious and safe in people who had received therapy with two or three prior tyrosine kinase inhibitors (TKIs). Vodobatinib remains a potential option for these highly refractory patients. A phase II study (NCT02629692) of vodobatinib is ongoing in CML patients whose disease has failed to respond to three or more TKIs, including ponatinib (Abstract 84).
Francesco Maura, MD, of the University of Miami, Sylvester Comprehensive Cancer Center, discusses his team’s findings in which they defined a comprehensive catalogue of genomic determinants of response to DKRd (carfilzomib, lenalidomide, dexamethasone) in newly diagnosed multiple myeloma. The researchers have identified a number of new genomic alterations that explain resistance to the agents currently used in combination regimens (Abstract 470).
Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, discusses phase III findings of the ALPINE study, which showed that zanubrutinib is more efficacious and better tolerated than ibrutinib as a treatment for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). In this first head-to-head comparison of the two BTK inhibitors, the superior progression-free survival of zanubrutinib was observed across all major subgroups, including high-risk patients (Abstract LBA-6).