Emavusertib Plus Ibrutinib Is Under Investigation in the TakeAim Trial in PCNSL

Grzegorz S. Nowakowski, MD

The phase 1/2 TakeAim Lymphoma trial (NCT03328078) is addressing a vital unmet need in patients with primary central nervous system lymphoma (PCNSL), as the combination of emavusertib (CA-4948) and ibrutinib (Imbruvica) represent an important targeted treatment approach for this population, according to Grzegorz S. Nowakowski, MD.

In an interview with OncLive^®, Nowakowski, 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, detailed the potential utility of combining IRAK4 and FLT3 inhibitors to manage this disease, discussed proof-of-principle findings with emavusertib, and highlighted the methods and objectives of the TakeAim Lymphoma part B expansion cohort, which is currently enrolling patients with PCNSL.

Nowakowski talked through data that led to the part B expansion cohort of the TakeAim Lymphoma study, the mechanism of action of emavusertib, and more, in another article.

OncLive: What are the methods and objectives of the ongoing part B portion of the phase 1/2 TakeAim Lymphoma trial?

Nowakowski: The objective of this study is to understand the activity of the combination of ibrutinib and emavusertib in patients with relapsed or refractory PCNSL. Unfortunately, a large proportion of patients with PCNSL will experience relapse after initial chemotherapy, and then there are fairly limited treatment options. A lot of those patients will be older as well, which limits our ability to treat those patients with more intensive chemotherapies, and ongoing therapies require hospitalization, [which is] a huge burden for those patients. [Therefore], there is a need to develop well-tolerated therapies.

This fundamental observation of the synergy between ibrutinib and emavusertib and the dual inhibition of [the BCR and TLR pathways is important]. In this study, patients who have refractory or relapsed disease following chemotherapy and are refractory to BTK inhibitors are eligible. This refractoriness to BTK inhibitors is important because it’s [providing] a proof of principle that the addition of an IRAK4 inhibitor can revert and sensitize the tumors to inhibition of both BTK and IRAK4.

It is an ongoing study, and the early results were presented during the 2023 ASH Annual Meeting. Responses [were seen] in patients with PCNSL who were refractory to BTK inhibitors, including several patients who had a complete response. That’s an extremely important proof of principle that this combination is working in those patients, and the study is ongoing to better understand the efficacy signal in this population.

Do you anticipate any challenges or barriers to trial enrollment?

PCNSL is a relatively rare disease, and there are always challenges in [trial] accrual [in this population]. [Patients sometimes have] a bit of a nihilistic [mindset]; after they relapse following initial chemotherapy, they’re frequently somewhat disengaged to pursue additional therapy because the past therapies were quite toxic and ineffective. This combination puts a new light on what we can do for those patients, and I would encourage all investigators and physicians to refer patients for the trial to the centers that have it open.

The nice thing about [emavusertib] is it’s an oral therapy. It’s well tolerated and can increase the efficacy of BTK inhibitors in this setting. Sometimes we have challenges with accrual to studies because the therapy options are not necessarily exciting. [Emavusertib plus ibrutinib] is an exciting option, and I hope that as we are getting more of a signal of activity, these encouraging results will help us to put more patients on the study, particularly patients being referred to the centers, since it’s a fairly rare disease.

How will positive results from the trial affect the development of emavusertib considering that noncovalent BTK inhibitors are currently in development as well?

Positive results of the study will be extremely important for PCNSL and potentially other clinical [presentations] as well. In terms of PCNSL, to have an agent that can synergize with BTK inhibitors would—in light of the development of BTK inhibitors in this population—open the field for those targeted therapies with future development for PCNSL. I would expect that those agents will be moving up to the front in lines of therapy quickly in those patients if the initial signal of activity that we have seen is maintained.

This trial is addressing patients with PCNSL, [who have] an important unmet need. But we also have to understand that there are thousands of other patients with B-cell malignancies who are refractory to BTK inhibitors. The proof of principle, which we see in PCNSL, that [there is] synergy between IRAK4 inhibitors and BTK inhibitors, is important. It could be applied to other tumors that are refractory to BTK inhibitors. Clinical investigations [of emavusertib] in BTK-refractory mantle cell lymphoma, chronic lymphocytic leukemia, and other common B-cell lymphomas, where we see development of resistance to current BTK inhibitors, will be critical.

What would you like your colleagues who are not involved in this clinical research to take away from this discussion?

There are several takeaway points. One is that this dual inhibition of IRAK4 and BTK could be important in [the management of] B-cell malignancies and is currently under investigation in the PCNSL population. If you have patients who could be eligible for this study, particularly if they are refractory to BTK inhibitors, please consider referring them to the centers that have this exciting study. Or, if you have the study [at your institution], please consider enrolling patients. This dual inhibition could [also] be important in the management of B-cell malignancies beyond PCNSL, so it’s an exciting development. I would like everybody to know that this [study] can help us to better use BTK inhibitors in the future; it could have a huge effect on the field.

Emavusertib appears to be quite safe and is well tolerated, and this opens this opportunity for combinations. BTK inhibitors [are] just 1 possible combination [partner] based on mechanism of action. Particularly regarding the effect of [emavusertib and other agents on] NF-κB, a number of other combinations could be developed in [PCNSL]. Because of the favorable safety profile of emavusertib, I see it as a drug that can be combined with many other drugs in the future.

Reference

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