CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 15, 2025
Expiration: October 14, 2025
Covalent vs Noncovalent BTK Inhibitors and Other Therapies
It is known that most patients with MCL will experience relapse or develop treatment-refractory disease. So, the question of the next course of action to take after a patient develops R/R MCL—especially after receiving treatment with a covalent BTK inhibitor—is an important one. As stated earlier, there are 3 available covalent BTK inhibitors: ibrutinib, acalabrutinib, and zanubrutinib. Of the 3, ibrutinib has received EMA approval and the CHMP recently adopted a new indication for acalabrutinib to include the treatment of adult patients with R/R MCL.7-9,24 Recently, pirtobrutinib, a noncovalent BTK inhibitor, received EMA approval as monotherapy for the treatment of adult patients with R/R MCL who have been previously treated with a BTK inhibitor.25 Of note, other noncovalent BTK inhibitors such as nemtabrutinib are in development and being investigated for different B-cell malignancies (NCT06572618, NCT03162536).
Another agent with an indication in this setting is brexucabtagene autoleucel, a CD19-directed CAR T-cell therapy with EMA approval for the treatment of adult patients with R/R MCL after 2 or more lines of systemic therapy including a BTK inhibitor.26 Lastly, emerging agents include glofitamab, a CD20 x CD3 bispecific monoclonal antibody, that is currently being investigated as a single agent or in combination with other agents in several clinical trials for patients with MCL (GLOBRYTE, GOlDiLOX).
Case Study: Patient With R/R MCL in Need of Third-Line Therapy After Relapse on a Covalent BTK Inhibitor
Now, I want to discuss the treatment of a 63-year-old man with R/R MCL with blastoid histology. This patient is frail with severe diabetes and complications, impaired renal function, and cardiac disease including uncontrolled hypertension, history of a stroke, and atrial fibrillation. The patient’s disease harbors TP53 mutations and del(17p) with Ki-67 >30%. He received rituximab monotherapy as first-line therapy without ASCT. After disease progression, he received acalabrutinib plus BR followed by acalabrutinib and rituximab maintenance as second-line therapy. However, within 2 years of completing treatment, his disease progressed.
Based on this patient’s level of frailty, he is ineligible for CAR T-cell therapy as he is unlikely to be able to tolerate CAR T-cell therapy–associated AEs. Therefore, I would recommend pirtobrutinib monotherapy, which is quite tolerable and has demonstrated activity in patients in this setting.
Next, I will discuss the available evidence guiding my treatment choice for this patient with R/R MCL in need of third-line treatment.
BRUIN: Pirtobrutinib in Previously Treated MCL
The EU approval of pirtobrutinib in MCL was based on the results of the single-arm, phase I/II BRUIN trial which investigated pirtobrutinib monotherapy in adult patients with MCL after previous exposure to at least 2 lines of therapy including a covalent BTK inhibitor (NCT03740529). The primary endpoints for the phase I portion of the BRUIN trial were the maximum tolerated dose and the recommended phase II dose, and for the phase II portion, the primary endpoint was ORR. The secondary endpoints included safety, pharmacokinetics, response, and survival.
BRUIN (MCL Population): Responses in R/R MCL
The majority of the patients with R/R MCL achieved tumor regression with pirtobrutinib.15,27,28 The ORR among 19 patients who had previously undergone SCT was approximately 60%, and among 4 patients who had previously received CAR T-cell therapy, the ORR was 50%. Of interest, among 90 efficacy evaluable patients who had previously received a covalent BTK inhibitor, the ORR was 56.7% (CR: 18.9%). Among 21 patients with covalent BTK inhibitor intolerance, the ORR was 81% (CR:42.9%). In the small group of 14 patients without any prior exposure to a covalent BTK inhibitor, the ORR was 85.7% (CR: 42.9%).
BRUIN: Safety of Pirtobrutinib in Patients Previously Intolerant to a Covalent BTK Inhibitor
In patients with prior exposure to a BTK inhibitor, there was no recurrence of cardiac disorders in 75% and no recurrence of atrial fibrillation in 93%.28 Of note, most of the AEs were low grade. Overall, pirtobrutinib was safe and well-tolerated in patients with prior BTK inhibitor intolerance.
ZUMA-2: Brexucabtagene Autoleucel in R/R MCL
Another therapeutic option for patients with R/R MCL who have experienced progression on a covalent BTK inhibitor is CAR T-cell therapy. The EMA approval of brexucabtagene autoleucel in MCL was based on the results of the phase II ZUMA-2 trial.26 Patients (N = 74) with R/R MCL and 1 or more measurable lesion who had received 1 to 5 previous therapies were enrolled on ZUMA-2.29,30 Patients must have previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 monoclonal antibody, and a covalent BTK inhibitor (ibrutinib or acalabrutinib). Following leukapheresis and prior to receiving conditioning therapy, patients with high disease burden received optional bridging therapy with steroids or a covalent BTK inhibitor (ibrutinib or acalabrutinib), followed by conditioning chemotherapy with fludarabine in combination with cyclophosphamide. Thereafter, patients received a single infusion of brexucabtagene autoleucel. The primary endpoint was ORR, and the secondary endpoints included PFS, OS, safety, quality of life, and determination of CAR T-cell levels in blood and cytokines in serum.
ZUMA-2: Efficacy and Safety of Brexucabtagene Autoleucel in R/R MCL
After a median follow-up of 35.6 months, the median OS in all treated patients (n = 68) was 46 months, with a 30-month OS rate of 60.3%. Among 46 patients who achieved a CR, the median OS was not reached with a 30-month OS rate of 76.1%. In the ITT population (n = 74), the median PFS was 24 months compared with 25.8 months among all 68 treated patients. Among 46 patients who achieved a CR, the median PFS was 48 months. The ORR was impressive at 91% among all 68 treated patients and 84% in the ITT population of 74 patients. As demonstrated in ZUMA-2, it is clear that brexucabtagene autoleucel is very effective in patients with R/R MCL.
In terms of safety, the most common grade 3 or higher AEs associated with brexucabtagene autoleucel were cytopenias (94%) and infections (32%). Cytokine release syndrome was reported in 91% of the patients but most were low grade.
Real-world Use of Brexucabtagene Autoleucel for Relapsed/Refractory MCL
A real-world analysis of 168 patients with R/R MCL who received brexucabtagene autoleucel at 16 CAR T-cell centers in the United States demonstrated an ORR of 90%, including 82% who achieved a CR.31 The median PFS after the infusion of brexucabtagene autoleucel was 16.4 months and the 12-month PFS was remarkable at approximately 60%. Of importance, these real-world data support the results of the ZUMA-2 trial.
Of note, CCO has developed an Interactive Decision Support Tool which can be used to access treatment recommendations from 5 EU experts for patients with R/R MCL based on multiple disease characteristics, including the presence or absence of high-risk features and/or comorbidities, age at relapse, and the level of fitness, which can be found here.
Overview of Bispecific Antibodies in Development in MCL
Lastly, T-cell–directed bispecific antibodies, an emerging class of agents, have promising activity in patients with R/R MCL. Mosunetuzumab, glofitamab, and epcoritamab are bispecific antibodies with EMA approval for use in follicular lymphoma and/or diffuse large B-cell lymphoma. However, none of these agents have received approval for use in MCL. All 3 bispecific antibodies bind to CD20 and CD3 on T-cells.32 Glofitamab has a 2:1 tumor T-cell binding configuration whereas mosunetuzumab and epcoritamab have 1:1 binding configuration. Of the 3 bispecific antibodies, glofitamab is furthest along in clinical development for MCL.
Phase I/II Trial of Glofitamab in Heavily Pretreated MCL
In a phase I/II trial, glofitamab elicited encouraging activity in patients with heavily pretreated MCL. In this trial, patients were pretreated with obinutuzumab before receiving treatment with glofitamab.33 Among 31 patients, with previous exposure to a covalent BTK inhibitor, the ORR was 74.2%, including an impressive CR rate of 71%.
Back
