Novel Drug Leads to Responses in Waldenström Macroglobulinemia

Patients with relapsed/refractory Waldenström macroglobulinemia (WM) tended to respond to therapy with NX-5948—a BTK degrader—according to a phase 1a/b trial (NCT05131022).¹

Findings showed that response-evaluable patients (n = 9) achieved an overall response rate (ORR) of 77.8% and a stable disease rate of 22.2%. All 7 patients who experienced a response did so in the first 8 weeks of treatment, and as of the October 10, 2024, data cutoff, 5 patients remained on treatment, including 2 who were ongoing treatment for more than 1 year. Responses were noted irrespective of the presence of baseline MYD88 or CXCR4 mutations.

“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 [CLL],” Paula G. O’Connor, MD, chief medical officer of Nurix Therapeutics, stated 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 inhibitor and patients presenting with Bing-Neel syndrome, 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.”

NX-5948 is an investigational, oral, brain penetrant, small molecule BTK degrader, and the phase 1 trial is currently evaluating the agent in patients with relapsed/refractory B-cell malignancies.

In the phase 1a dose-escalation portion of the study, patients are required to be at least 18 years of age with relapsed/refractory CLL, small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), WM, or primary CNS lymphoma (PCNSL).2 At least 2 prior lines of therapy and the absence of other therapies known to provide clinical benefit are required for patients with malignancies other than PCNSL. Those with PCNSL need to have received at least 1 prior line of therapy.

In the phase 1b cohort-expansion portion of the study, patients need to have CLL, SLL, DLBCL, MCL, follicular lymphoma, 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.

Other key inclusion criteria included 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.

Key exclusion criteria include 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 inhibitor and an additional line of therapy.

Safety is a primary end point in both portions of the study. The incidence of dose-limiting toxicities and determining the maximum tolerated dose/recommended phase 2 dose are also primary end points in phase 1a. ORR is a primary end point 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, which included BTK inhibitors and chemotherapy/chemoimmunotherapy for all patients.1 Notably, 3 patients received prior treatment with pirtobrutinib (Jayprica); 1 patient received prior treatment with a BCL-2 inhibitor. At baseline, 8 patients harbored MYD88 mutations, and 2 patients had CXCR4 mutations.

The safety profile of NX-5948 in patients with WM was consistent with findings from the overall study.

References

1. Nurix Therapeutics presents positive results from the ongoing clinical trial of its BTK degrader NX-5948 in patients with relapsed/refractory Waldenstrom’s macroglobulinemia. News release. Nurix Therapeutics. October 19, 2024. Accessed October 22, 2024. https://ir.nurixtx.com/news-releases/news-release-details/nurix-therapeutics-presents-positive-results-ongoing-clinical-0

2. A study of NX-5948 in adults with relapsed/​refractory B-cell malignancies. ClinicalTrials.gov. Updated July 11, 2024. Accessed October 22, 2024. https://clinicaltrials.gov/study/NCT05131022