Dr Nowakowski on the Use of Emavusertib in Relapsed/Refractory Hematologic Malignancies

Grzegorz S. Nowakowski, MD, consultant, professor, vice chair, Oncology and Medicine, Division of Hematology, deputy director, Mayo Clinic Comprehensive Cancer Center for Clinical Research, discusses findings from the ongoing phase 1/2 TakeAim Lymphoma trial (NCT03328078) of emavusertib (previously CA-4948) in combination with ibrutinib (imbruvica) in patients with relapsed/refractory hematologic malignancies.

The multicenter, open-label, dose-escalation and -expansion trial is evaluating the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the orally administered, novel IRAK4 inhibitor emavusertib in combination with ibrutinib. Findings from this trial were presented at the 2023 ASH Annual Meeting.

In the initial phase of the study, the recommended phase 2 dose of emavusertib monotherapy was identified as 300 mg twice daily and was tolerated well, Nowakowski says. The combination involving the BTK inhibitor ibrutinib evaluated emavusertib at 2 dose levels: 100 mg twice daily and 200 mg twice daily, alongside the standard 560-mg daily dosage of ibrutinib, with a 28-day cycle duration, he explains. Notably, the study focused on patients previously exposed to BTK inhibitors, Nowakowski notes.

The primary efficacy results yielded promising outcomes, with 19 evaluable patients undergoing response evaluation. Among these patients, 5 complete responses (CRs) were observed, 2 occurring in patients with mantle cell lymphoma and 3 occurring in patients with primary central nervous system lymphoma (PCNSL), he expands. Notably, all patients with PCNSL had prior exposure to BTK inhibitors, providing evidence that the preclinically observed synergy of emavusertib plus a BTK inhibitor is translating into clinical success, he emphasizes.

Nowakowski goes on to say that the aspect of these data generating the highest level of excitement revolves around the challenging-to-treat PCNSL patient population, especially cases resistant to chemotherapy, which have limited treatment options. The combination of the oral agents emavusertib and ibrutinib, which has produced CRs, is a notable advancement, he states. Although ibrutinib has been known to drive responses in PCNSL, these responses were transient and accompanied by eventual resistance, Nowakowski says. The addition of emavusertib to ibrutinib in this patient population led to CRs, validating the preclinical hypothesis that the simultaneous inhibition of BTK and IRAK4 is critical for suppressing B-cell proliferation and survival, he concludes.