Impending Therapeutic Agents in Mantle Cell Lymphoma

Kami J. Maddocks, MD

The main goals of treatment for patients with mantle cell lymphoma (MCL) include limiting toxicity and overcoming resistance mechanisms to important therapies like BTK inhibitors. Experts are conducting studies to address these issues, according to Kami J. Maddocks, MD.

“The majority of patients with MCL who progress after initial therapy are going to be treated with an oral covalent BTK inhibitor,” said Maddocks, the director of the Lymphoma Program and a professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center - James Cancer Hospital & Solove Research Institute in Columbus, during a presentation at the 2023 SOHO Annual Meeting.¹

“We know that [most] patients who are treated with a covalent BTK inhibitor are going to respond to therapy. We also know that nearly all patients are going to develop resistance to these therapies and outcomes following progression on covalent BTK inhibitor are poor, with a median overall survival [OS] of approximately 6 to 8 months.”

Maddocks noted that the mechanisms that lead to patients with MCL developing BTK inhibitor resistance are not well understood. She explained that although some patients with MCL develop resistance via mutations in BTK binding sites, like what often occurs in chronic lymphocytic leukemia, these patients are usually in the minority. Instead, Maddocks said that it is hypothesized that patients with MCL develop resistance through a variety of mechanisms, such as the activation of bypass pathways, resistance mutations, and nuances in the tumor microenvironment, making it more difficult to effectively address.

Improving Combinations for MCL

Ibrutinib (Imbruvica), which was granted accelerated approval by the FDA for the treatment of MCL after at least 1 prior therapy recently had its indication voluntarily withdrawn by the agent’s manufacturer in April 2023. The decision was made after data from one of the confirmatory phase 3 trials failed to meet its primary end point and the addition of ibrutinib to chemotherapy was associated with an increase in adverse effects (AEs).²

Despite this, there has still been interest in using ibrutinib for the treatment of patients with MCL as a component in a combination regimen. In findings from the phase 2 AIM trial (NCT02471391), patients with relapsed/refractory MCL who received ibrutinib plus the BCL2 inhibitor venetoclax (Venclexta; n = 23) experienced a median progression-free survival (PFS) of 29 months (95% CI, 13-not estimable [NE]) and a median OS of 32 months (95% CI, 27-NE) at a median follow-up of 37.5 months (range, 1.4-45.3). Notably, the 71% of patients who were treated with combination achieved a complete response (CR).³

Lymphoma | Image Credit: © David A Litman - www.stock.adobe.com

Considering the encouraging findings from AIM, the randomized phase 3 SYMPATICO trial (NCT03112174) was initiated in hopes of producing data showing the benefit of ibrutinib plus venetoclax, which have thus far eluded investigators. Findings from the safety run-in of SYMPATICO have shown promise. At a median follow-up of 31 months (range, 1.5+ to 40.2), patients with relapsed/refractory MCL who receivedibrutinib plus venetoclax with an ibrutinib lead-in (n = 21) achieved an overall response rate (ORR) of 81% (95% CI, 58%-95%), with a CR rate of 62% (95% CI, 38%-82%. The median PFS was 35.0 months (95% CI, 13.7-NE), including an estimated 30-month PFS rate of 60% (95% CI, 31%-80%), and the median OS was 35.0 months (95% CI, 20.7-NE).⁴

“[SYMPATICO] has been fully accrued and it’s anticipated that [data] will read out soon,” Maddocks said. “[Although] I don’t know what the results will be, I think it’s highly possible that it could show that the combination should be a new standard of care. But, given the recent withdrawal of ibrutinib, it remains to be seen if that is a positive trial.”

There is also an exploratory clinical trial underway examining ibrutinib combined with the ROR1-targeted antibody-drug conjugate zilovertamab vedotin. Findings from the phase 1/2 study (NCT03088878), showed that efficacy-evaluable patients with MCL who received the combination (n = 27) achieved an ORR of 85.2%, with a CR rate of 40.7%, and a median PFS of 35.9 months (95% CI, 17.3-NE). There was a phase 3 study underway to further evaluate the combination, but it has since been stopped because of the withdrawal of ibrutinib, Maddocks noted.^1,5

“ROR1 is an oncofetal antigen present during fetal development and absent following birth,” Maddocks explained. “It is expressed on hematologic malignancies, including MCL, and can be targeted [using] different mechanisms including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and CAR T cells.”

Additionally, zilovertamab vedotin monotherapy is being examined as a potential treatment option for patients with MCL. In a first-in-human phase 1 trial (NCT03833180), zilovertamab vedotin was given to patients with hematologic malignancies with a median of 3 prior lines of therapy and displayed evidence of antitumor activity and produced no unexpected toxicities, displaying the clinical proof of concept for targeting ROR1. Initial findings showed that patients with MCL (n = 15) experienced an ORR of 47%, with a CR rate of 13%.⁶

Novel Agents in MCL

According to Maddocks, another agent with a mechanism of action that may help combat treatment resistance in patients with MCL is pirtobrutinib (Jaypirca). The unique noncovalent properties of the agent and high selectivity for BTK will hopefully lead to increased efficacy, less off-target effects, and a more tolerable safety profile for patients, Maddox explained. In January 2023, pirtobrutinib was approved by the FDA for patients with relapsed/refractory MCL following at least 2 lines of systemic therapy, including a BTK inhibitor, based on findings from the phase 1/2 BRUIN (NCT03740529).⁷

Updated findings from BRUIN showed that among patients with MCL who previously received a covalent BTK inhibitor and were treated with pirtobrutinib (n = 90), the ORR was 57.8% (95% CI, 46.9%-68.1%) with a 20.0% CR rate and a median duration of response (DOR) of 21.59 months (95% CI, 7.46-not reached [NR]). Notably, the median OS was NR (95% CI, 14.75-NR) and the median PFS was 7.36 months (95% CI, 5.32-12.45). Efficacy was even more pronounced in patients who were covalent BTK inhibitor naïve (n = 14); the ORR was 85.7% (95% CI, 57.2%-98.2%), with a 35.7% CR rate, and the median DOR, OS, and PFS were all NR.⁸

“Pirtobrutinib was effective in the different populations of patients treated, regardless of prior therapies, prior stem cell transplant, prior CAR T-cell therapy, and high-risk features,” Maddocks said. “The most common toxicities included fatigue, diarrhea, cytopenia, and contusion. A very small number of patients went off treatment due to AEs. [Although] toxicities of interest [for] BTK, including bleeding and atrial fibrillation, did occur with pirtobrutinib, they were in low numbers.”

The phase 3 BRUIN-MCL-321 study (NCT04662255) is currently recruiting patients with MCL who have previously received at least 1 systemic therapy, excluding a BTK inhibitor. The international, open-label trial will look to confirm findings seen in early phase study by randomly assigning a total of approximately 500 patients to receive either pirtobrutinib or a BTK inhibitor of the investigator’s choice. The primary end point is PFS, and secondary end points included ORR, DOR, OS, and event-free survival.⁹

“[In terms of CAR T-cell agents], we have 1 product approved—brexucabtagene autoleucel [Tecartus]— where we’ve seen the [phase 2] ZUMA-2 [NCT02601313] data and real-world outcomes,” Maddocks added in conclusion. “We’ve seen updated data on lisocabtagene maraleucel [Breyanzi], which shows very promising activity and maybe a better safety profile. There are a lot of novel agents being looked at, including bispecific and trispecific [antibodies], CAR, and [allogeneic] CAR. [There are also] bispecific antibodies, CB20 × CD3, approved in relapsed/refractory B-cell malignancies, including large cell lymphoma and follicular lymphoma, with less data in MCL. [Although] [cytokine release syndrome] CRS is the most common toxicity with those, it is [of a] lesser grade than what we see with CAR [T-cell therapies]. There are some novel CD19 × CD3-directed agents that are still very early in development, but also look very promising.”

_References:

_{1. Maddocks KJ. Emerging novel agents in mantle cell lymphoma. Presented at: 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX.}

_{2. Update on Imbruvica (ibrutinib) U.S. accelerated approvals for mantle cell lymphoma and marginal zone lymphoma indications. News release. Abbvie. April 6, 2023. Accessed September 12, 2023. https://news.abbvie.com/news/press-releases/update-on-imbruvica-ibrutinib-us-accelerated-approvals-for-mantle-cell-lymphoma-and-marginal-zone-lymphoma-indications.htm}

_{3. Handunnetti SM, Anderson MA, Burbury K, et al. Three year update of the phase II ABT-199 (Venetoclax) and ibrutinib in mantle cell lymphoma (AIM) study. Blood.2019;134(suppl 1):756. doi:10.1182/blood-2019-126619}

_{4. Wang M, Ramchandren R, Chen R, et al. Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. J Hematol Oncol. 2021;14(1):179. doi:10.1186/s13045-021-01188-x}

_{5. Lee HJ, Choi M, Siddiqi T. et al. Phase 1/2 study of zilovertamab and ibrutinib in mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or marginal zone lymphoma (MZL). Blood. 2022;140(suppl 1):566-568. doi:10.1182/blood-2022-167153}

_{6. Wang ML, Barrientos JC, Furman RR, et al. Zilovertamab vedotin targeting of ROR1 as therapy for lymphoid cancers. NEJM Evid. 2022;1(1). doi:10.1056/EVIDoa2100001}

_{7. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. News release. FDA. January 27, 2023. Accessed September 12, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-relapsed-or-refractory-mantle-cell-lymphoma}

_{8. Wang ML, Jurczak W, Zinzani PL, et al. Pirtobrutinib in covalent Bruton tyrosine kinase inhibitor pretreated mantle-cell lymphoma. J Clin Oncol. 2023;41(24):3988-3997. doi:10.1200/JCO.23.00562}

_{9. Study of BTK inhibitor LOXO-305 versus approved BTK inhibitor drugs in patients with mantle cell lymphoma (MCL) (BRUIN-MCL-321). ClinicalTrials.gov. Updated August 30, 2023. Accessed September 12, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04662255}