Exploring the Efficacy of BTK Inhibitor Glofitamab Among Patients With R/R MCL

Tycel Phillips, MD, City of Hope National Medical Center, Duarte, California, reports updated findings from a phase 1/2 trial examining the efficacy and safety of glofitamab, a Bruton’s tyrosine kinase (BTK) inhibitor, among patients with heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL). 

Transcript: 

Hello, my name is Dr. Tycel Phillips. I am an associate professor of medicine at City of Hope National Medical Center in Duarte, California. Today, we will briefly overview the study of glofitamab in patients with relapsed/refractory mantle cell lymphoma.

In general, relapsed/refractory mantle cell lymphoma is a disease with few curative options, mainly only being allogeneic stem cell transplantation. The advent of BTK inhibitors has improved outcomes quite a bit, but it is not a curative therapy. Outcomes for those patients have been quite dismal once they field that line of therapy.

More recently, we've seen some benefits with other drugs, such as CAR T [-cell therapy], which is chimeric antigen receptor therapy treatment. There's one FDA-approved treatment for patients with mantle cell lymphoma, but due to limitations to access, and some high adverse event rates with CAR-T and mantle cell lymphoma, other treatments are needed. So in this study, we looked at glofitamab, which is a bispecific antibody. It has a 2-to-1 binding epitope for CD20, 2 binding receptors there, and 1 for CD3, which will help direct T-cells to the malignant and also normal B-cells to induce a treatment response.

We looked to evaluate the safety and efficacy of glofitamab in this patient population. At our initial presentation, we evaluated 37 patients in total. In this patient population, we looked at glofitamab, which was given in a step-up dosing fashion. What I mean by that is glofitamab was given in doses of 2.5 mg on cycle 1, day 1; 10 mg on cycle 1, day 8; and then 30 mg on cycle 1, day 15. Every 3 weeks thereafter, again, it was given at 30 mg for a total of 12 cycles, which is approximately 8.3 months.

As part of this, patients did receive a pre-treatment with obinutuzumab, which is a CD20 monoclonal antibody. The study looked at 2 treatment regimens for the obinutuzumab pre-treatment, one that used 1,000 mg and the other one that used 2,000 mg, all given on what we consider day -7, prior to the initiation of glofitamab.

The purpose of obinutuzumab in this study was to provide some receptor occupancy competition with glofitamab and help reduce the incidents of cytokine release syndrome, which is one of the main side effects we see with bispecific therapies in patients who are treated with lymphomas.
Because of the high clearance rate of obinutuzumab in patients with mantle cell lymphoma, the competitive binding competition was only really noted during the first initial infusion with glofitamab. Thereafter, glofitamab was able to bind to the malignant tumor without any competition from obinutuzumab, thus not impairing any kind of clinical activity and response with the pre-treatment.

What we notice in this study, specifically if we looked at response rates, is for all patients we had an overall response rate of 83.8% with a complete metabolic response rate of 73%. If we look at the 21 patients who received the 2 grams of obinutuzumab pre-treatment, we noted an overall response rate of 90.5% and a complete response rate of 81%.

Specifically, as I mentioned, patients with prior BTK inhibitor exposure had poor outcomes once [they came] off those drugs. We did notice in those patients—24 of the 37 patients—that we had an overall response rate of 75% and a complete metabolic response rate of 66.7%. In the 13 patients who got 2 grams of pre-treatment obinutuzumab, we did have a higher overall response rate noted at 84.6% and a complete metabolic response of 77%.

At the early follow-up, we only had 8 months of median follow-up, but we did notice that there was some durability of responses, especially in those who had a complete remission. The median duration of complete response in the study was 10 months. At the data cutoff, 74.1%, or 20 of 27 patients, remained in complete remission at the time of data cutoff.

Those patients who are in complete remission that came off the study had events related to COVID-19 and not disease progression. If we take away those patients, we had a median of 87% of those patients remaining in remission, and that was 20 of 23 patients at the time of data cutoff.

Specifically, the most common adverse events with this treatment were cytokine release syndrome, as I mentioned before; neutropenia, which was a low neutrophil count; anemia, and fatigue. Specifically with CRS, or cytokine release syndrome, we noted that there was an incidence of 75.7% of all patients enrolled in the study. Neutropenia was noted at 45.9%.

The vast majority of patients enrolled in the study were noted to have grade 1 or grade 2 cytokine release syndrome. If we look at all patients, 29.7% of those patients had grade 1, 29.7% of those patients had grade 2, and 16.2% of the patients had grade 3 or above.

We noticed a decrease in the severity of cytokine release syndrome with the 2-gram obinutuzumab pre-treatment dose with those patients. So, 21 patients. We had 33% of those patients had grade 1 CRS. 23.8% had grade 2, and only 9.5% of those patients had grade 3. No patients had grade 4 CRS.

The median time to CRS onset was 9.31 hours, and patients were treated with a combination of tocilizumab and corticosteroids for resolution of CRS. Other adverse events of interest included infections, where we did notice 32.4% of patients had grade 3 or 4 above infections. 

Neutropenia was 27% grade 3 or 4. More importantly, we noted that 5 patients had immune effector cell neurological syndrome, of which most of these were grade 1 to grade 2. In those who received the 2-gram pre-treatment dose of obinutuzumab, there was only 1-grade [immune effector cell-associated neurotoxicity syndrome] (ICANS) event, which resolved without any major intervention required.

In summary, in this early study, we see that glofitamab appears to be relatively effective in patients with relapsed/refractory mantle cell lymphoma, including those with prior BTK inhibitor exposure. The treatment also produced expected adverse events, including high rates of cytokine release syndrome. More importantly, we noted very few episodes of immune effector cell-associated neurotoxicity syndrome, which is an important distinction from what we see with CAR-T.

Moving forward, this treatment will be further studied in a phase 3 trial in patients with relapsed/refractory mantle cell lymphoma. That'll more than likely happen in the first quarter of 2024. With that, I'll conclude my presentation. Thank you.

Source: 

Phillips T, Dickinson M, Morschhauser F, et al. MCL-467 Glofitamab monotherapy induces high complete response rates in patients with heavily pretreated relapsed or refractory mantle cell lymphoma. Clinical Lymph Myel and Leuk. Published online: September 2023. doi: 10.1016/S2152-2650(23)01378-2