Emavusertib-Based Therapy Produces Responses in BTK Inhibitor–Treated Primary CNS Lymphoma

Updated findings from the phase 1/2 TakeAim Lymphoma trial (NCT03328078) showed clinical responses with emavusertib (CA-4948)–based therapy among patients with relapsed or refractory primary central nervous system lymphoma (PCNSL), including patients whose disease had progressed during previous treatment with a Bruton tyrosine kinase (BTK) inhibitor.¹

As of the July 1, 2026, data cutoff, 10 of 30 evaluable patients who were previously exposed to a BTK inhibitor achieved an objective response, resulting in an overall response rate (ORR) of approximately 33%. Evaluable patients were defined as those who completed at least 1 treatment cycle, or about 1 month, of therapy.¹

When all 39 BTK inhibitor–treated patients were included the ORR was 26%—regardless of whether they completed the first treatment cycle—with 10 patients achieving a response. The findings represent an increase from a previous May 2025 analysis, in which 7 of 26 patients treated with a BTK inhibitor responded (ORR of 27%).¹

The updated results also included 7 patients who had not previously received a BTK inhibitor. Six of these patients achieved an objective response, resulting in an ORR of 86% across the entire BTK inhibitor–naïve group. Among the 5 patients who completed at least 1 treatment cycle and were considered evaluable, all 5 responded.¹

These early findings suggest that emavusertib-based treatment may have activity in both BTK inhibitor–naïve and previously exposed PCNSL. However, the small patient populations, open-label trial design, and absence of randomized comparative results limit the conclusions that can currently be drawn.

TakeAim Lymphoma Evaluates Emavusertib With Ibrutinib

TakeAim Lymphoma is a multicenter, open-label phase 1/2 study evaluating the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral emavusertib alone or in combination with ibrutinib (Imbruvica; Pharmacyclics, Janssen) in adults with relapsed or refractory hematologic malignancies. The PCNSL portion of the trial includes several treatment stages. In part B, investigators are evaluating emavusertib plus ibrutinib in patients with relapsed or refractory PCNSL whose disease progressed directly during BTK inhibitor therapy. Participants receive emavusertib at either 100 mg or 200 mg twice daily in combination with ibrutinib during continuous 28-day treatment cycles.²

Rather than discontinuing BTK inhibition after progression, the study adds emavusertib to ongoing ibrutinib. This strategy is intended to determine whether simultaneous inhibition of BTK-associated signaling and interleukin-1 receptor–associated kinase 4 (IRAK4)–mediated signaling can produce renewed disease control. Part C of the study is evaluating treatment in patients with second-line relapsed or refractory PCNSL who have not previously received a BTK inhibitor. These patients are assigned to emavusertib monotherapy, ibrutinib monotherapy, or the combination of emavusertib and ibrutinib.²

The trial has an estimated enrollment of 152 patients and recruitment is currently ongoing, according to the most recent ClinicalTrials.gov update. The trial’s projected primary completion date is August 2026, with study completion anticipated in October 2026.²

Emavusertib Targets IRAK4 and FLT3

Emavusertib is an investigational oral small-molecule inhibitor of IRAK4 and FLT3. IRAK4 is a signaling protein downstream of toll-like receptors and the interleukin-1 receptor and plays a role in innate immune and inflammatory signaling.^1,3

In B-cell malignancies, IRAK4-mediated signaling may interact with pathways that support malignant-cell survival. The rationale for combining emavusertib with ibrutinib is to inhibit complementary signaling pathways involved in PCNSL growth and treatment resistance.

Preclinical findings have suggested that IRAK4 inhibition may increase sensitivity to therapies targeting B-cell receptor signaling, including BTK inhibitors; however, the current TakeAim findings do not establish the biological mechanism responsible for individual patient responses. Additional translational and clinical analyses will be required to determine whether IRAK4 inhibition can consistently address resistance to BTK-directed therapy.

Emavusertib has also demonstrated blood-brain barrier penetration, an important property for therapies being developed to treat malignancies within the central nervous system.³

Limited Options Remain Following BTK Inhibitor Progression

PCNSL is an aggressive form of non-Hodgkin lymphoma confined primarily to the brain, spinal cord, cerebrospinal fluid, or eyes. Most cases are diffuse large B-cell lymphomas. Because of the disease’s location, treatment must achieve adequate penetration into the central nervous system. High-dose methotrexate–based regimens remain central to initial treatment. However, therapeutic options become more limited when disease relapses or does not respond to treatment.

BTK inhibitors have demonstrated activity in relapsed or refractory PCNSL, but responses may not be durable, and there is no universally established standard regimen for patients whose disease progresses following BTK inhibitor therapy. The response findings among previously exposed patients therefore represent the most clinically consequential portion of the updated TakeAim analysis.

Nevertheless, response rate alone does not establish long-term clinical benefit. Important unanswered questions include the depth and duration of responses, progression-free survival, overall survival, and whether responses vary according to the type or duration of prior BTK inhibitor exposure.

Updated Safety and Durability Data Are Needed

The July 2026 update focused primarily on response rates and did not provide a detailed safety analysis, complete response and partial response breakdown, median duration of response, median follow-up, or survival outcomes.¹ Earlier TakeAim reporting showed grade 3 or higher treatment-related adverse events (AEs) among patients receiving emavusertib plus ibrutinib, including neutropenia, increased amylase or lipase levels, leukopenia, elevated alanine aminotransferase levels, and increased creatine phosphokinase levels.³ These earlier findings may not reflect the final safety profile of the current study population.

For pharmacists, the combination could require monitoring for toxicities associated with both therapies. Ibrutinib is associated with bleeding, atrial arrhythmias, infections, hypertension, and clinically significant drug interactions. The evolving safety profile of emavusertib will also need to be considered when determining whether the combination can be administered safely over extended treatment periods.

Future findings should clarify rates of dose interruption, dose reduction, treatment discontinuation, serious infection, cytopenias, hepatic or pancreatic laboratory abnormalities, and other clinically relevant AEs.

The updated TakeAim Lymphoma findings provide an early efficacy signal in a difficult-to-treat population, particularly among patients previously treated with BTK inhibitors. Larger patient cohorts, longer follow-up, and more complete safety and durability findings will be necessary to determine whether emavusertib-based treatment can meaningfully alter the treatment course of relapsed or refractory PCNSL.

REFERENCES

1. Curis announces positive emavusertib update. Curis, Inc. News release. July 22, 2026. Accessed July 27, 2026. https://www.prnewswire.com/news-releases/curis-announces-positive-emavusertib-update-302831553.html

2. CA-4948-101: open-label, dose escalation and expansion trial of emavusertib in relapsed or refractory primary central nervous system lymphoma. ClinicalTrials identfier: NCT03328078. Updated April 16, 2026. Accessed July 27, 2026. https://clinicaltrials.gov/study/NCT03328078

3. Nowakowski GS, Dabrowska-Iwanicka AP, Grommes C, et al. Preliminary safety and efficacy of emavusertib (CA-4948) in combination with ibrutinib in relapsed/refractory primary central nervous system lymphoma patients with prior exposure to BTK inhibitor. Blood. 2024;144(suppl 1):6020. doi:10.1182/blood-2024-208359