Novel Treatment Approaches in Relapsed/Refractory Mantle Cell Lymphoma

Mantle cell lymphoma MCL) is a non-Hodgkin lymphoma (NHL) subtype with relapse expected in almost all patients at some point. Thus management of relapsed or refractory (R/R) disease is a highly relevant topic for patients and the clinicians who treat them. The treatment landscape for relapsed MCL has changed rapidly over the past decade, with the development and approval of Bruton tyrosine kinase (BTK) inhibitors at the forefront of the changing treatment paradigm.

“Novel Treatment Approaches in Relapsed/ Refractory Mantle Cell Lymphoma,” presented by Kami Maddocks, MD, at the Society of Hematologic Oncology 2021 Annual Meeting, provided an overview of recent developments in the treatment of R/R MCL with updates outlined by class of therapies. With the approval of chimeric antigen receptor (CAR) T-cell therapy for R/R MCL, referral to an authorized CAR T-cell treatment center is critical when considering options for patients seen in clinical practice. Despite the plethora of emerging treatment options, clinical trial participation should be strongly encouraged for patients with R/R MCL. Results of a number of ongoing clinical trials are expected to lead to new approvals and changes in clinical practice in the near future.

Covalent Irreversible Bruton Tyrosine Kinase (BTK) Inhibitors

Three covalent irreversible BTK inhibitors are approved by the FDA for the treatment of R/R MCL, including first-in-class ibrutinib (Imbruvica) and the more selective acalabrutinib (Calquence) and zanubrutinib (Brukinsa). All 3 drugs are approved as single-agent therapy with overall response rates of 67% to 84% and median progression-free survival (PFS) of 13 to 22 months.^1-3 Improved duration of response to BTK inhibitors is seen when they are used in second line versus in later lines of therapy. Although ibrutinib, acalabrutinib, and zanubrutinib are efficacious and typically well-tolerated options for relapsed MCL, almost all patients eventually will progress on these therapies. Historically, outcomes following progression with prior classes of approved MCL therapies have been poor.4 There is reason for further optimism, however, with multiple emerging novel therapeutic approaches demonstrating promising activity in ongoing and recently completed studies.

Combination Therapy

Although a growing assortment of combinations incorporating BTK inhibitors are under investigation in phase 1 and 2 studies for patients with relapsed MCL, the one farthest along in development is the combination of ibrutinib with BCL-2 inhibitor venetoclax (Venclexta). The randomized phase 3 SYMPATICO trial (NCT03112174) comparing ibrutinib and venetoclax with ibrutinib alone in R/R MCL has completed accrual, and mature data are awaited to determine whether this combination results in superior efficacy compared with single-agent treatment. Additional triplet combinations incorporating anti-CD20 monoclonal antibodies also are under investigation. When evaluating these combination strategies, differences in treatment toxicity and cost will need to be weighed against possible improvements in efficacy.

Noncovalent BTK Inhibitors

Noncovalent reversible BTK inhibitors represent an emerging therapeutic option for patients with B-cell malignancies, offering improved selectivity mitigating off-target toxicities as well as the potential to overcome resistance to irreversible BTK inhibitors. The selective noncovalent reversible BTK inhibitors pirtobrutinib (formerly LOXO- 305) was studied in the recently published phase 1/2 BRUIN study (NCT03740529) and demonstrated impressive clinical efficacy, including in patients with prior BTK inhibitor treatment.5 Of the 56 evaluable patients with R/R MCL enrolled on BRUIN, 52 (93%) had been previously treated with covalent BTK inhibitors, with a median of 3 prior lines of therapy. More than half of patients with MCL achieved an objective response (ORR), with an ORR of 52% among all evaluable patients. Discontinuation due to adverse events (AEs) was infrequent (1.5%), with dose interruptions required in 8% of patients. The majority of AEs were grade 1 or 2. Thus, pirtobrutinib represents a promising potential option for patients with relapsed MCL with progression on irreversible BTK inhibitors or intolerance. A randomized phase 3 study (BRUIN-MCL-321; NCT04662255) is planned to assess for superiority of pirtobrutinib to the currently approved ibrutinib, acalabrutinib, or zanubrutinib in patients with R/R MCL.

Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) allow for targeted delivery of chemotherapy drug payload to tumor cells by linking to a monoclonal antibody targeted to a tumor antigen. Although multiple ADCs are approved for other NHL subtypes, there are no currently approved ADCs for the treatment of relapsed MCL. The ADC at the forefront of development is VLS-101, a tyrosine kinase–like orphan receptor 1 antibody conjugated to the monomethyl auristatin E (MMAE) chemotherapy payload. In a phase 1 study, 15 patients with MCL treated across various dose levels had an ORR of 47% including 13% complete response (CR), with 6 of 7 responses ongoing with duration of treatment ranging from 35 to 58 weeks.⁶ Similar to other MMAE-containing ADCs, VLS-101 was associated with neuropathy (grade 3 in 9% of patients).

PI3 Kinase Inhibitors

Although multiple PI3 kinase inhibitors have shown clinical activity in previously treated MCL, the FDA has not approved any for this indication. Parsaclisib is an investigational selective PI3 kinase δ inhibitor that has been studied in patients with relapsed MCL in recently presented phase 2 studies of patients who are BTK inhibitor–naïve and patients previously treated with a BTK inhibitor. Among 53 patients with R/R MCL previously treated with a BTK inhibitor, the ORR was 25% (2% CR) with a median PFS of 4 months, whereas the ORR was 70% (15% CR) with median PFS of 11 months among 108 patients with MCL enrolled in the BTK inhibitor–naïve study.^7,8

One frequently observed adverse effect was diarrhea, which occurred in 31% of BTK inhibitor–naïve patients and 23% of previously BTK inhibitor–treated patients.

Bispecific Antibodies

Bispecific antibodies allowing for engagement of T cells and other immune subsets with tumor cells are a class of treatment under investigation in multiple NHL subtypes, including R/R MCL. Preliminary data demonstrate clinical activity for this class of treatment in MCL and further data are eagerly anticipated. Preliminary results were recently presented at the 2021 American Society of Clinical Oncology Annual Meeting from the NP30179 study (NCT03075696), a phase I dose expansion study of the CD20/CD3 bispecific antibody glofitamab. Five patients with R/R MCL were enrolled on this study, and notably 4 of 5 patients achieved CR.⁹

Chimeric Antigen Receptor T-Cells

Brexucabtagene autoleucel (Tecartus) is a CD19-directed CAR T-cell therapy that is FDA-approved for the treatment of R/R MCL. The approval was based upon results of the pivotal phase 2 ZUMA-2 study (NCT02601313) in which 74 patients with R/R MCL, all previously treated with BTK inhibitors, were enrolled and 68 patients successfully received CAR T-cell infusion following lymphodepletion.¹⁰ In addition to prior BTK inhibitor treatment, the study population had other high-risk features, including high Ki67 index of 30% or greater in 40 patients and blastoid morphology in 31% of patients. The ORR among the 60 infused patients was 93% with 67% achieving a CR. Even when assessing the entire study population, including patients who did not receive CAR T-cell infusion, the ORR remained 85% with 59% CR. The 1-year estimated PFS among evaluable patients was 61%, with similar response rates and PFS seen among patients with high-risk features, including TP53 mutation or blastoid morphology. Cytokine release syndrome (CRS) and neurotoxicity of any grade were frequently observed (91% and 63% of patients, respectively), with grade 3 or higher neurotoxicity occurring in 31% of patients. The anti-CD19 CAR T-cell therapy lisocabtagene maraleucel (Breyanzi) also is under investigation for treatment of MCL in the TRANSCEND NHL-001 study (NCT02631044).¹¹ The observed ORR was 84% with 59% CR, with follow-up not yet mature for PFS estimate. CRS of any grade occurred in 59% of patients, whereas neurotoxicity of any grade was observed in 34%, rates that are lower in comparison than those observed with brexucabtagene autoleucel. It also is notable that patients with central nervous system involvement by MCL were eligible for TRANSCEND NHL- 001. Final results will provide further data regarding the efficacy of CAR T-cell therapy in this difficult-to-treat scenario.

Bright Future

The future today is brighter for patients with previously treated MCL, with the approval of both BTK inhibitor and CAR T-cell therapies providing 2 highly effective classes of treatment for patients with R/R disease. Randomized studies are looking at combination treatment options as well as comparing noncovalent reversible BTK inhibitors with the currently approved covalent BTK inhibitors in patients with R/R disease. Despite this progress, further treatment options are needed, but multiple new therapies are on the horizon, including noncovalent BTK inhibitors as well as ADCs.

_REFERENCES:

_{1. Rule S, Dreyling M, Goy A, et al. Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies. Br J Haematol. 2017;179(3):430-438. doi:10.1111/bjh.14870}

_{2. Song Y, Zhou K, Zou D, et al. Treatment of patients with relapsed or refractory mantle-cell lymphoma with zanubrutinib, a selective inhibitor of Bruton’s tyrosine kinase. Clin Cancer Res. 2020;26(16):4216-4224. doi:10.1158/1078-0432.CCR-19-3703}

_{3. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667. doi:10.1016/S0140- 6736(17)33108-2}

_{4. Martin P, Maddocks K, Leonard JP, et al. Post-ibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127(12):1559-1563. doi:10.1182/blood-2015-10-673145}

_{5. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5}

_{6. Wang ML, Barrientos JC, Furman RR, et al. VLS-101, a ROR1-targeting antibody-drug conjugate, demonstrates a predictable safety profile and clinical efficacy in patients with heavily pretreated mantle cell lymphoma and diffuse large B-cell lymphoma. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; virtual. Accessed 8/20, 2021. https://ash. confex.com/ash/2020/webprogram/Paper136373.html}

_{7. Mehta A, Trněný M, Walewski J, et al. Phase 2 study evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory MCL not previously treated with a BTK Inhibitor. Blood. 2020;136(suppl 1):22-23. doi:10.1182/blood-2020-134872}

_{8. Zinzani PL, Delwail V, Paneesha S, et al. Phase 2 study evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory mantle cell lymphoma previously treated with ibrutinib (CITADEL-205). Blood. 2020;136(suppl 1):43-44. doi:10.1182/blood-2020-134609}

_{9. Carlo-Stella C, Hutchings M, Offner FC, et al. Glofitamab step-up dosing (SUD): complete response rates in updated efficacy data in heavily pretreated relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) patients (pts). J Clin Oncol. 2021;39(suppl 15):7519. doi:10.1200/ JCO.2021.39.15_suppl.7519}

_{10. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331- 1342. doi:10.1056/NEJMoa1914347}

_{11. Palomba ML, Gordon LI, Siddiqi T, et al. Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in Transcend NHL 001. Blood. 2020;136(suppl 1):10-11. doi:10.1182/blood-2020-136158}