TakeAim Lymphoma Tests Proof of Concept for Dual IRAK4/FLT3 Blockade in B-Cell Malignancy Treatment

Grzegorz S. Nowakowski, MD

Combining the IRAK4 and FLT3 inhibitor emavusertib (CA-4948) with a BTK inhibitor has the potential to create a new successful approach for treating patients with primary central nervous system lymphoma (PCNSL) based on data showing improved activity with dual blockade of B-cell receptor and Toll-like receptor (TLR) pathways.¹

There are currently no approved treatments for patients with the rare and aggressive form of lymphoma in the relapsed or refractory setting. Targeting IRAK4, which is highly expressed in the PCNSL tumor microenvironment, with the first-in-class oral inhibitor emavusertib could prove to be a viable treatment option and one that offers needed blood-brain barrier penetration.²

“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. The clinical investigations in BTK-refractory mantle cell lymphoma [MCL], chronic lymphocytic leukemia, and other common B-cell lymphomas, where we see development of resistance to BTK inhibitors of our time, will be very critical,” Grzegorz S. Nowakowski, MD, said in an interview with OncologyLive.

Following encouraging data seen with emavusertib as monotherapy and in combination with ibrutinib (Imbruvica), the phase 1/2 TakeAim Lymphoma trial (NCT03328078) is currently enrolling patients with PCNSL to the part B expansion cohort of the trial to receive the combination.^1,3

“[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,” Nowakowski said. “Based on the mechanism of action, we do believe that the role for this agent is for it to be combined with BTK inhibitors [to] overcome resistance to BTK inhibitors but also to enhance the activity of BTK inhibitors.”

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

Data Leading up to the TakeAim Lymphoma Expansion Cohorts

Preliminary efficacy from the dose escalation portion of the trial (part A2) with emavusertib plus ibrutinib showed that 5 of the 16 evaluable patients experienced a complete response (CR) to treatment with the combination; 2 of the patients had MCL, both of whom had not received prior therapy with a BTK inhibitor, and 3 had PCNSL. All patients with PCNSL who experienced a CR had received prior therapy with a BTK inhibitor.²

“The nice thing about [emavusertib] is it’s an oral therapy. It’s very well tolerated and can increase the efficacy of BTK inhibitors in this setting,” Nowakowski said. “In the studies of the single agent, it was well tolerated with a very favorable safety profile, and that’s the result of its mechanism of action, which has been engineered specifically to impact TLR signaling [through] IRAK4.”

Regarding safety findings from part A2 of TakeAim Lymphoma, grade 3 treatment-related adverse effects occurred in 74% of patients in the safety population (n = 19), which included those treated at the 100 mg (n = 2), 200 mg (n = 10), and 300 mg (n = 7) twice daily doses of emavusertib plus ibrutinib. The grade 3 toxicities observed were decreased platelet count (16%), increased alanine aminotransferase levels (11%), increased aspartate aminotransferase levels (11%), fatigue (11%), hyponatremia (11%), and increased lipase levels (11%). Data also showed that the median treatment duration was 96 days (range, 21-613).

Two Is Better Than One: Blocking the BCR and TLR Pathways

“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,” Nowakowski said. “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.”

Research has shown that IRAK4 forms a myddosome complex with MYD88 adaptor protein which drives overactivation of NF-κB, thus causing inflammation and tumor growth. The rare and aggressive PCNSL tumors are a form of extranodal non-Hodgkin lymphoma in the CNS or vitreoretinal space. PCNSLs represent approximately 4% of newly diagnosed brain tumors, and approximately 70% of patients with PCNSL tumors have MYD88 mutations.²

“The currently ongoing TakeAim Lymphoma study expansion cohort, [part B], is in patients with PCNSL. CNS lymphomas are frequently MYD88-mutated, so there’s a great scientific rationale to do [this study],” Nowakowski explained. “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.”

Nowakowski added that because emavusertib is an IRAK4 and FLT3 inhibitor, the FLT3 aspect of the agent has led to its investigation in ongoing studies for patients with acute leukemia, but the IRAK4 mechanism of the agent is of interest for patients with B-cell malignancies.

“Emavusertib has dual activities [inhibiting] IRAK4, which is important in B-cell malignancies, but also FLT3 [which is important for] acute leukemia,” he noted. “It’s a novel molecule, and we’re very excited about its potential impact on B-cell malignancies.”

Magnifying TakeAim Lymphoma Enrollment Criteria: Filling an Unmet Need

Part A1, the emavusertib monotherapy dose escalation portion, and part A2, the emavusertib plus ibrutinib evaluation portion, of TakeAim Lymphoma have been completed, paving the way for the currently enrolling part B which is comprised of 2 cohorts.³

“Unfortunately, a large proportion of patients with PCNSL will relapse after initial chemotherapy, and then there are fairly limited treatment options,” Nowakowski said. “A lot of those patients will be elderly as well, which limits our ability to treat those patients with more intensive chemotherapies, and ongoing therapies do require hospitalization [which is] a huge burden for those patients. [Therefore], there is a need to develop well tolerated therapies.”

The non-randomized, global, open-label TakeAim Lymphoma study is enrolling patients at approximately 30 locations spanning the US, Israel, Czechia, France, Italy, Poland, and Spain. Adult patients with a life expectancy of at least 3 months, an ECOG performance status of 2 or less, and histopathologically confirmed PCNSL will be enrolled.

The Part B PCNSL expansion cohorts will not include patients with intraocular PCNSL without brain lesion or cerebrospinal fluid involvement or T-cell lymphoma or systemic presence of lymphoma. Additionally, patients who have non-CNS lymphoma metastatic to the CNS, a prior history of non-lymphoma malignancies, or an active malignancy requiring systemic therapy aside from PCNSL, will not be eligible for enrollment.

“In this study, patients who have refractory or relapsed disease following chemotherapy and are refractory to BTK inhibitors are eligible,” Nowakowski noted. “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.”

Patients in the first part B cohort will receive emavusertib 100 mg twice daily in combination with ibrutinib 560 mg once daily in a 28-day cycle. Approximately 6 to 9 patients will be enrolled in this cohort, whereas at least 9 patients will be enrolled in cohort 2 of Part B. The second cohort will administer emavusertib 200 mg twice daily plus the same dose of ibrutinib.

The primary end point of part B is safety, and a secondary end point is to estimate the blood-brain barrier penetration. Secondary end points of the study as a whole are overall survival, progression-free survival, disease control rate, duration of response, overall response rate, and pharmacokinetics.

More to Come With Emavusertib in Hematologic Malignancies

“To have an agent that can synergize with BTK inhibitors would—in light of the development of BTK inhibitors in this space—open the field for those targeted therapies with future development for PCNSL. I would expect that those agents will be moving up front in lines of therapy very quickly in those patients if this initial signal of activity which we have seen is maintained.”

Furthermore, the first-in-class, small molecule inhibitor also received orphan drug designation from the FDA in 2021 for the treatment of patients with acute myeloid leukemia and myelodysplastic syndromes.4 The agent was evaluated as monotherapy in the phase 1/2 TakeAim Leukemia trial (NCT04278768).

“Emavusertib appears to be quite safe and is well tolerated, and this opens this opportunity for combinations. BTK inhibitors [are] just 1 possible combination [option] based on mechanism of action. Particularly on the impact of NF-κB, you can imagine a number of other combinations which could be developed in this space [of PCNSL],” Nowakowski said. “Because of the favorable safety profile of emavusertib, I see it as a drug which can be combined with many other drugs in the future.”

References

1. D’Angelo C. Targeting IRAK4 as novel therapy in primary CNS lymphoma. Curis. August 2024. Accessed September 6, 2024. bit.ly/3AO1x7m
2. 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
3. A study of CA-4948 in patients with relapsed or refractory primary central nervous system lymphoma. ClinicalTrials.gov. Updated July 15, 2024. Accessed September 6, 2024. https://clinicaltrials.gov/study/NCT03328078
4. Curis receives FDA orphan drug designation for CA-4948 for the treatment of AML and MDS. News release. April 19, 2021. Accessed September 6, 2024. bit.ly/47f6PVy