Emerging Treatment Strategies in MCL: The Role of CAR T

The Role of CAR T in Early Treatment Setting for MCL

Chimeric antigen receptor (CAR) T-cell therapies that target the CD19 surface protein have emerged as a highly effective treatment among patients with B-cell non-Hodgkin lymphoma and mantle cell lymphoma (MCL) with high efficacy demonstrated among patients with relapsed or refractory (R/R) disease.^1-8 Early investigational studies have largely been focused on assessing CAR T as a therapeutic strategy following failed first and second lines of therapy. However, the need for more effective treatment options in the early disease course, especially those with high-risk disease (eg, blastoid morphology, TP53-mutated disease, high Ki-67, primary refractory disease), has prompted the investigation of CAR T in earlier lines of therapy.^1,9

Studies evaluating CAR T in the second-line treatment setting for B-cell lymphoma have shown higher response rates, progression-free survival (PFS), and overall survival (OS) when compared with standard-of-care treatments.^2,10-12 These findings may suggest a role for CAR T in earlier lines of therapy and highlight the need for future research to determine the use of these agents in this treatment setting^.9

Emerging BTK Inhibitors in MCL

Covalent Bruton tyrosine kinase inhibitors (BTKis) have played a critical role in transforming the treatment and management of MCL. However, treatment-associated resistance or intolerance can lead to treatment failure and the need for additional therapy in some patients.^13,14 C481 mutations that occur in the binding site region of BTK result in decreased drug binding affinity and are the most common cause of covalent BTKi-associated treatment resistance.^15,16 Pirtobrutinib is a noncovalent or reversible BTKi that possesses equivalent potency for both wild-type and C481-mutated BTK variants.¹³ With demonstrated efficacy among patients with MCL and C481-mutant BTK status, pirtobrutinib may offer a potential strategy for overcoming resistance to BTKi therapy.^13,15

BRUIN Trial

The BRUIN trial (NCT03740529) is an open-label, multicenter phase 1/2 study investigating pirtobrutinib in patients with previously treated B-cell malignancies, including MCL.^13,17 In patients who had received prior treatment with a BTKi, ORR was 62% (95% CI, 53%-71%). In patients with BTK C481 mutations, ORR was 75%. The most frequent adverse event (AE) of any grade was fatigue (20%), followed by diarrhea (17%) and contusion (13%). Neutropenia was the most common AE of grade 3 or higher, occurring in 10% (32 of 323 patients), and was not dose dependent. AEs of special interest included bruising, rash, and atrial fibrillation or flutter and were associated with low occurrence rates: grade 1 (15%, 9%, and 0%, respectively) and grade 2 (2%, 2%, and 1%, respectively).

Combination Therapy With Venetoclax in MCL

Although studies evaluating the efficacy of single-agent ibrutinib in MCL have reported ORRs of up to 68%, most treated patients (up to 79%) fail to achieve complete response (CR).¹⁸ Venetoclax is a potent, selective inhibitor of the antiapoptotic protein BCL-2, which is overexpressed in various hematological malignancies, including MCL.9,19 Studies investigating venetoclax in R/R MCL have reported favorable efficacy, with ORRs of 53% to 75% and CRs in 18% to 21% of patients.^20,21

The action elicited by venetoclax appears to complement that of ibrutinib, with preclinical models demonstrating synergistic antitumor effects, including increased apoptosis reported with combination vs single-agent therapy (combination, 23.0%; ibrutinib, 3.8%; venetoclax, 3.0%).^22,23 These findings have prompted further investigation of combination therapy with ibrutinib and venetoclax and may suggest a role for this dual treatment approach in patients with R/R MCL, including those with previous BTKi exposure.²⁴

SYMPATICO Trial

The open-label, randomized, double-blind phase 3 SYMPATICO study (NCT03112174) evaluated the safety and efficacy of ibrutinib in combination with venetoclax in patients with R/R MCL.^22,25 At a median treatment duration of 20.1 months, ORR for all patients was 81% (95% CI, 58%-95%), with a CR in 62% of patients. Median duration of response (DOR), PFS, and OS were 32.3, 35.0, and 35.0 months, respectively. The most common treatment emergent AEs (TEAEs) (any grade) occurring in more than 20% of patients included diarrhea, fatigue, nausea, neutropenia, and thrombocytopenia. The most frequent AEs of at least grade 3 included infection (38%), diarrhea (33%), and neutropenia (33%).

Sequencing Therapies

Intensive induction chemotherapy with a high-dose cytarabine-based regimen followed by autologous stem cell transplant (ASCT) and rituximab maintenance remains the preferred first-line treatment approach in young, fit patients. Preferred approaches in older patients and those not eligible for ASCT or intensive chemotherapy include less-intensive regimens.^24,26

Upon first relapse in the second-line setting, single-agent BTKis using ibrutinib, acalabrutinib, or zanubrutinib have become the standard of care, with selection based on the AE profile of individual agents and other patient factors.²⁴ Most patients eventually relapse following BTKi therapy, as optimal treatment approaches remain unclear. Next-line treatment options in eligible patients often favor CAR T with corticosteroids, lenalidomide, or venetoclax for bridging therapy.

Promising New Therapies in MCL

NVG-111

The bispecific T-cell engager NVG-111 is a small, flexible molecule composed of 2 tandem-linked, antibody-derived single-chain variable fragments: 1 arm binds ROR1, which is a surface antigen expressed by various hematological and solid tumor cancers, whereas the other binds CD3 on the surface of lymphocytes.²⁷ Dual binding of NVG-111 triggers the release of perforins, granzyme B, and cytokines via MHC-independent immune mechanisms, ultimately leading to the targeted destruction of tumor cells.

Phase 1/2 Trial: NVG-111 in MCL

An ongoing, 2-part, open-label phase 1/2 trial (NCT04763083) is investigating the safety and efficacy of NVG-111 in patients with R/R chronic lymphocytic leukemia (CLL) and MCL.^27,28 At the data cutoff of January 2022, 6 patients had been enrolled in the trial (CCL, 5; MCL, 1). All 5 evaluable patients achieved an observed response following 3 cycles of NVG-111. Two patients had undetectable minimal residual disease (MRD) in the blood, with 1 patient also showing negative MRD in the bone marrow.²⁸ The most frequently observed AEs (all grade 1) were lethargy, headaches, nausea, vomiting, and thrombocytopenia. Grade 1 cytokine release syndrome occurred in all 3 patients who received a flat dose of NVG-111 (30 μg/day). Tocilizumab or dose interruptions were only required in 1 patient, who also developed transient grade 3 immune effector cell–associated neurotoxicity syndrome–like symptoms.

Tazemetostat

Tazemetostat inhibits EZH2, which is a subunit of the histone methyltransferase PRC2 that plays a critical role in the epigenetic regulation of genes involved in cell cycle progression, autophagy, and apoptosis.^29,30 Dysregulation of EZH2 can prolong survival and accelerate the proliferation of cells, leading to tumorigenesis and the development of cancer. Mutations resulting in gain-of-function EZH2 enzyme activity have also been identified in hematological malignancies, such as B-cell lymphoma, and are shown to correlate with significantly worse OS in patients with myeloid neoplasms (HR, 2.37; 95% CI, 1.48-3.79; P = .003).^30,31

Tazemetostat With Acalabrutinib in R/R MCL

A 2-part, open-label, multicohort phase 1b/2 study (NCT05205252) is currently recruiting patients with R/R MCL (active comparator arm 3) to receive investigational treatment with tazemetostat in combination with acalabrutinib.^32,33 During phase 1b, all patients will be enrolled in 3 dose-escalation cohorts of tazemetostat (400 mg, 600 mg, 800 mg); the primary end points include recommended phase 2 dosing, TEAEs, DLTs, and AEs. Phase 2 will entail the dose expansion portion of the study; the primary end point is ORR, whereas secondary end points include PFS, OS, and DOR.

Future of MCL: Unmet Needs

Novel therapies, including CAR T, have played a key role in transforming the treatment landscape for MCL.²⁴ However, optimal approaches for treatment sequencing remain unclear, and patients with high-risk, aggressive, or multiple relapse disease continue to experience relatively poor outcomes. High-risk patients often experience suboptimal responses with BTKi therapy following relapse, and the use of CAR T in earlier lines of therapy for this patient population is an important area of future research.^1,9 Demonstrated efficacy of CAR T in high-risk subgroups and a tolerable safety profile may suggest a role for CAR T earlier in the course of treatment for this patient subgroup.

References

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