BGB-16673 Shows Tolerability, Activity in Waldenström Macroglobulinemia

No cases of atrial fibrillation, major hemorrhage, febrile neutropenia, or pancreatitis were observed in the study.

BGB-16673, a BTK degrader, demonstrated safety and tolerability among patients with relapsed/refractory Waldenström Macroglobulinemia, according to findings from a subgroup analysis of the phase 1 CaDAnCe-101 trial (NCT05006716) presented at the 2025 European Hematology Association Congress.

Efficacy results from the trial revealed that among 36 patients treated with the investigational therapy, antitumor activity was exhibited, with particular benefit observed among patients with BTK inhibitor-resistant mutations, TP53 and CXCR4 mutations, and those with previous exposure to chemoimmunotherapy, as well as covalent BTK (cBTK) and noncovalent BTK (ncBTK) inhibition. The overall response rate (ORR) was 84.4% (n = 27/32) across the overall population, with a very good partial response (VGPR) rate of 31.3% (n = 10/32).

Additional results showed a major response rate, which includes VGPRs and PRs, of 75.0%, with a median time to first response of 1.0 month (range, 0.9-3.7). Additionally, the ORR by mutational status was 100% for patients with BTK mutations, 89.3% for MYD88-mutant disease, 94.1% for CXCR4-mutant disease, and 100% for TP53-mutant disease.

“[In] the phase 1 CaDAnCe-101trial, the BTK degrader, BGB-16673, was well tolerated, even in heavily pretreated patients with relapsed/refractory Waldenström Macroglobulinemia,” Anna Maria Frustaci, MD, professor in the Department of Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda in Milano, Italy, stated in the presentation. “Only 2 patients discontinued treatment due to treatment-emergent adverse [effects]. We saw promising antitumor activity in all patients.”

Patients with Waldenström Macroglobulinemia who had 2 or more prior therapies, an ECOG performance score of 0 to 2, and adequate organ function received oral BGB-16673 daily for 28-day cycles. A part 1a dose-escalation study assessed 50 mg, 100 mg, 200 mg, 350 mg, 500 mg, and 600 mg of the investigational therapy, and a part 1b safety expansion followed, with an additional safety expansion added for these patients.

The median patient age across the study population was 72.0 years (range, 49-81). A total of 61.1% of patients were male, and 47.2% vs 47.2% had an ECOG performance score of 0 or 1. Furthermore, the median hemoglobin level was 102 g/L (range, 60-146) at baseline, the median neutrophil count was 2.6 x 10⁹/L (range, 0.2-7.4), and the median platelet count was 153.5 x 10⁹/L (range, 14.0-455.0).

The most common mutation statuses included MYD88 (88.6%), CXCR4 (54.3%), and TP53 mutations (51.6%). There was a median of 3 (range, 1-11) prior lines of therapy, with the most common prior therapy including cBTK inhibition (100%), anti-CD20 antibodies (100%), chemotherapy (94.4%), and proteasome inhibition (30.6%). A total of 83.3% of patients discontinued prior BTK inhibition due to disease progression.

The primary end point of the study was the safety and tolerability of BGB-16673, as well as the maximum tolerated dose and recommended dose for expansion. Secondary end points included pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 88.9% of patients, 69.4% of which were related to treatment. Grade 3 or higher TEAEs occurred in 61.1% of patients, of which 38.9% were related to treatment. Additionally, serious TEAEs occurred in 33.3% of patients, with 11.1% related to treatment.

Overall, 2 TEAEs led to treatment discontinuation, and 1 resulted in death, which was not related to treatment. The most common TEAEs included neutropenia (39%) and contusion (31%), followed by diarrhea (25%) and thrombocytopenia (20%). The most common grade 3 or higher TEAEs included neutropenia (31%), anemia (17%), and thrombocytopenia (6%).

Of note, no cases of atrial fibrillation, major hemorrhage, febrile neutropenia, or pancreatitis were observed in the study. Additional safety data revealed that platelet counts significantly improved after treatment with BGB-16673, with median platelet counts increasing from baseline at 39.5 x 10⁹/L to 126.0 x 10⁹/L at week 9, as well as neutrophil counts from 0.9 x 10⁹/L to 1.1 x 10⁹/L over the same period. Hemoglobin counts also increased from 98.0 g/L at baseline to 114.0 g/L by week 9.

Disclosures: Frustaci cited affiliations with AbbVie, AstraZeneca, Janssen, and BeOne Medicines Ltd.

Reference

Frustaci AM, Seymour JF, Cheah CY, et al. Updated efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed/refractory Waldenström macroglobulinemia: ongoing phase 1 CaDAnCe-101 study results. Presented at: European Hematology Association 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract S231.