Acalabrutinib Continues to Showcase Impressive Activity in Relapsed/Refractory MCL

Michael Wang, MD

Acalabrutinib (Calquence) continued to showcase robust activity and durable responses in patients with relapsed/refractory mantle cell lymphoma (MCL) at 38.1 months of follow-up, which confirms that the agent is highly active in this population, according to Michael Wang, MD.

Updated results from the phase 2 ACE-LY-004 trial (NCT02213926) showed that the agent elicited an overall response rate (ORR), with a complete response rate of 48%.¹ Notably, the ORR was not found to be significantly different for patients who received 1, 2, or 3 or more prior lines of therapy, at 83.1%, 86.5%, and 71.4%, respectively.

The median overall survival achieved with acalabrutinib was 59.2 months (95% CI, 36.5–not evaluable), and was consistent across subgroups. Moreover, the median duration of response (DOR) and the median progression-free survival (PFS) were 29 months and 22 months, respectively. The median overall survival was 59.2 months overall. In those who received 2 or more prior therapies, the median OS was 55.9 months; it had not yet been reached in those who received 1 prior therapy.

“For a single agent, after 2 prior lines of therapy, these are remarkable data,” Wang said.

In an interview with OncLive® during the 2021 Pan Pacific Lymphoma Conference, Wang, a professor of lymphoma and melanoma at The University of Texas MD Anderson Cancer Center, discussed the impact of acalabrutinib in patients with MCL, the implications of the phase 2 ACE-LY-004 trial, and the challenges faced with treating those who harbor TP53 mutations.

OncLive®: What were the updated data reported with acalabrutinib in the ACE-LY-004 trial?

Wang: I had the privilege to present the long-term [data] on single-agent acalabrutinib in [patients with] relapsed MCL. The original study was published in Lancet Oncology in 2017. This clinical trial with single-agent acalabrutinib in patients with relapsed MCL after 2 prior lines of therapy was paved the way to the FDA approval of the drug in 2017.

The 38-month follow-up on this clinical trial showed that the response rates are still very high, at 81%. The CR rate is much higher than before, at 48%. Most importantly, the DOR was [approximately] 29 months, and [the median] PFS was 22.0 months. Remarkably, these patients have survived [a median of about] 59 months. These data indicated that acalabrutinib is a good therapy [for use] as a monotherapy in relapsed MCL.

Shifting over to caring for those who harbor TP53 mutations, what should be known about this subset? What approaches are under exploration to address the challenges faced in this population?

It is important to clarify that although data [in chronic lymphocytic leukemia show that 17p deletion (del[17p])] is a very negative prognostic factor, in MCL, there is [debate] about this. Del(17p) has not been uniformly reported to be associated with negative prognoses in MCL, and therefore, it is not [thought to be] as important as [it is] in CLL.

TP53 needs to form a tetramer to be functional. If even 1 of the monomers in the tetramer contains a mutation, it will render the monomer nonfunctional. Therefore, the whole tetramer will not be functional. If the TP53 is not functioning, [it will result in] resistant and aggressive MCL. [The data show that patients with] TP53 mutations are prognostically [worse] than those with del(17p). This is the other issue that we hope to overcome.

CAR T-cell therapies and multiple combination therapies of about 3 agents [are under examination]. Thus far, single agents and doublet [approaches], have not been reported to overcome TP53 mutations in MCL.

Reference

1. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma: final results from a phase 2 study. Presented at: 2021 Pan Pacific Lymphoma Conference; August 9-13, 2021; Big Island, HI. https://bit.ly/3jZ3VfB