NX-5948 Demonstrates Promising Activity in Relapsed/Refractory Waldenström Macroglobulinemia
Key Insights
NX-5948, a novel BTK (search) degrader, shows a 77.8% overall response rate in patients with relapsed/refractory Waldenström macroglobulinemia (search) (WM) in a phase 1a/b trial.
Responses to NX-5948 were observed within the first 8 weeks of treatment, irrespective of MYD88 (search) or CXCR4 (search) mutation status, suggesting broad efficacy.
The ongoing phase 1b expansion cohort will further evaluate NX-5948 in WM patients, including those with prior BTK (search) inhibitor treatment and Bing-Neel syndrome (search).
A phase 1a/b trial (NCT05131022) indicates that NX-5948, an investigational BTK (search) degrader, has shown promising activity in patients with relapsed/refractory Waldenström macroglobulinemia (search) (WM). The study demonstrated a 77.8% overall response rate (ORR) among response-evaluable patients, with responses observed regardless of MYD88 (search) or CXCR4 (search) mutation status.
The data, which were cut off on October 10, 2024, showed that of the 9 response-evaluable patients, 7 achieved a response, and 2 achieved stable disease. Impressively, all responders experienced a response within the first 8 weeks of treatment. As of the data cutoff, 5 patients remained on treatment, including 2 who have been on treatment for over a year.
Nurix Therapeutics' Perspective
"We are encouraged by the emerging positive data with NX-5948 in patients with WM, which add to the previously disclosed robust clinical activity observed in patients with chronic lymphocytic leukemia (search) [CLL]," said Paula G. O’Connor, MD, chief medical officer of Nurix Therapeutics, in a news release. "These data support our decision to advance NX-5948 into the ongoing phase 1b expansion cohort in patients who have previously received at least 1 prior line of therapy including a BTK (search) inhibitor and patients presenting with Bing-Neel syndrome (search), a rare form of WM with central nervous system [CNS] involvement where NX-5948’s ability to penetrate the brain may offer a distinct advantage."
About NX-5948
NX-5948 is an investigational, oral, brain-penetrant, small molecule BTK (search) degrader currently being evaluated in a phase 1 trial for patients with relapsed/refractory B-cell malignancies.
The phase 1a dose-escalation portion of the study enrolled patients aged 18 years or older with relapsed/refractory CLL, small lymphocytic lymphoma (search) (SLL), diffuse large B-cell lymphoma (search) (DLBCL), follicular lymphoma (search), mantle cell lymphoma (search) (MCL), marginal zone lymphoma (search) (MZL), WM, or primary CNS lymphoma (search) (PCNSL). Patients with malignancies other than PCNSL were required to have received at least two prior lines of therapy and have no other therapies known to provide clinical benefit. Patients with PCNSL were required to have received at least one prior line of therapy.
The phase 1b cohort-expansion portion of the study includes patients with CLL, SLL, DLBCL, MCL, follicular lymphoma (search), MZL, WM, PCNSL, or secondary central nervous system lymphoma. These patients must meet the criteria for systemic treatment, and prior therapies are required based on indication.
Key inclusion criteria also encompassed measurable disease, an ECOG performance status of 0 or 1 (or 0 to 2 for those with PCNSL and secondary CNS involvement), and adequate organ and bone marrow function.
Exclusion criteria included known or suspected prolymphocytic leukemia or Richter transformation to Hodgkin lymphoma, active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia, bleeding diathesis or another known risk for acute blood loss, and a history of grade 2 or higher hemorrhage within 28 days of first treatment.
In the WM cohort, NX-5948 is being administered to patients who have received prior treatment with a BTK (search) inhibitor and an additional line of therapy.
Trial Endpoints and Patient Characteristics
Safety is a primary endpoint in both portions of the study. In phase 1a, primary endpoints also include the incidence of dose-limiting toxicities and determining the maximum tolerated dose/recommended phase 2 dose. ORR is a primary endpoint in phase 1b.
Among the 13 patients enrolled in the WM cohort, the median age was 74 years, and patients had received a median of 3 prior lines of therapy, including BTK (search) inhibitors and chemotherapy/chemoimmunotherapy. Three patients had prior treatment with pirtobrutinib (Jayprica (search)), and one patient had prior treatment with a BCL-2 inhibitor. At baseline, 8 patients harbored MYD88 (search) mutations, and 2 patients had CXCR4 (search) mutations.
The safety profile of NX-5948 in patients with WM was consistent with findings from the overall study.