Emavusertib-Focused Research Is Poised to Expand the PCNSL Treatment Paradigm

Emavusertib (CA-4948)–based combination therapy has generated responses in patients with primary central nervous system lymphoma (PCNSL) who are refractory to BTK inhibitors, according to Grzegorz S. Nowakowski, MD.¹ The ongoing phase 1/2 TakeAim Lymphoma trial (NCT03328078) builds on positive data with emavusertib as monotherapy and in combination with ibrutinib (Imbruvica) in patients with PCNSL. The trial is currently enrolling patients with relapsed/refractory disease to its part B expansion cohort, in which they will receive the combination regimen.²

“Exciting updated data [from this cohort] will hopefully be presented at the [2024] ASH Annual Meeting,” Nowakowski said in an interview with OncLive^®.

In the interview, Nowakowski discussed the unique mechanism of action of emavusertib and where this agent is currently under evaluation in myeloid malignancies. In turn, he highlighted findings from the TakeAim Lymphoma trial that have been seen thus far.

Nowakowski serves as a consultant in the Division of Hematology and the enterprise deputy director of Clinical Research at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.

OncLive: What is the mechanism of action of emavusertib in B-cell malignancies?

Nowakowski: Emavusertib is an interesting novel agent for the management of B-cell and myeloid malignancies. Emavusertib is an IRAK4 inhibitor. It also inhibits FLT3, which led to its ongoing investigation in acute leukemia. However, its mechanism [of interest in] B-cell malignancies is IRAK4 inhibition.

In B-cell malignancies, B-cell receptor signaling is extremely important for the progression of the disease. Downstream from B-cell receptor signaling is BTK signaling, and BTK inhibitors have been a major breakthrough for the management of B-cell malignancies. Parallel to this B-cell receptor signaling, there’s a TLR pathway with myddosome formation, and downstream from that is IRAK4. Both those pathways can modulate NF-κB, which is critical for lymphoma cell survival.

One of the mechanisms of resistance to BTK inhibitors is upregulation of the TLR pathway, and [this is] where inhibition of IRAK4 is extremely important. Number one, it can have its own activity, particularly in MYD88-mutated lymphomas, where this pathway is a primary driver and [perhaps the] BCR pathway is a secondary driver. But number two, there’s a huge opportunity for synergy here with BTK inhibitors and TLR pathway inhibitors, including IRAK4, to inhibit the growth of lymphoma cells. [Emavusertib is] a novel molecule, and we’re excited about its potential effect on B-cell malignancies.

Is emavusertib a clean IRAK4 inhibitor? What does that mean for its safety profile given it is an agent that is continuously administered?

Emavusertib has dual activities [inhibiting] IRAK4, which is important in B-cell malignancies, but also FLT3, [which is important in] acute leukemia. In terms of B-cell malignancies, this inhibition of IRAK4 is quite clean, which has a big significance for its toxicity profile. Findings from the studies of [emavusertib as a] single agent showed it was well tolerated with a favorable safety profile, and that’s the result of its mechanism of action, which has been engineered specifically to impact TLR signaling in IRAK4.

What data with the agent in B-cell malignancies have been previously presented?

We have quite extensive clinical experience now with emavusertib, and as usual in earlier drug development, we have experience with it as a single agent. Emavusertib was tested in a pilot study in [patients with] a broad spectrum of B-cell malignancies. [That trial] had a phase 1 design, and the recommended phase 2 dose was established to be 300 mg twice daily. For the higher dose [of 400 mg twice daily], the dose-limiting toxicity seen was rhabdomyolysis; 300 mg twice daily was shown to be slightly associated with significant myelosuppression and minimal adverse effects.

[Examining] the single agent was important because it showed the proof of principle that this agent has activity. We saw some responses, particularly in MYD88-mutated tumors like Waldenström macroglobulinemia. This has led to subsequent studies where emavusertib was evaluated in combination with BTK inhibitors. Based on the mechanism of action [of emavusertib], we believe the role for this agent is in combination with with BTK inhibitors [to] overcome resistance to and enhance the activity of BTK inhibitors.

One study combined emavusertib with ibrutinib, and responses were seen in patients who were naive to BTK inhibitors, [as well as those who were] refractory to them, which was extremely important. That [combination] is being studied in expansion cohorts.

Please expand on what has been seen thus far from the TakeAim Lymphoma study expansion cohort.

The ongoing TakeAim Lymphoma study expansion cohort, [part B], is [enrolling] patients with PCNSL. Central nervous system [CNS] lymphomas are frequently MYD88 mutated, so there’s a great scientific rationale to do [this study]. There are data to support emavusertib penetration of the CNS, and this study is being done in patients who are refractory to BTK inhibitors, which are used in the second or third line of therapy in patients with relapsed/refractory PCNSL.

[So far, the data from TakeAim Lymphoma have been] encouraging and exciting. We saw responses to the combination of ibrutinib and emavusertib in patients who were refractory to BTK inhibitors. The introduction of emavusertib [in] patients who progressed on BTK inhibitors like ibrutinib resulted in responses including complete responses in heavily pretreated patients.

References

1. Grommes C, Tun HW, de la Fuente Burguera A, et al. Emavusertib (CA-4948) in combination with ibrutinib in patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL). J Clin Oncol. 2024;42(suppl 16):2087. doi:10.1200/JCO.2024.42.16_suppl.2087
2. D’Angelo C. Targeting IRAK4 as novel therapy in primary CNS lymphoma. Curis. August 2024. Accessed September 6, 2024. https://www.curis.com/wp-content/uploads/2024/08/TakeAim-Lymphoma-Clinical-Outcomes-Bermuda-Hematology-2024-Presentation.pdf