BGB-16673 Shows Early Activity, Tolerability in Heavily Pretreated Waldenström Macroglobulinemia

John F. Seymour, MBBS, FRACP, PhD

BGB-16673 had was generally well tolerated and elicited responses in patients with relapsed or refractory Waldenström macroglobulinemia, according to data from the phase 1 CaDAnCe-101 study (BGB-16673-101; NCT05006716) presented during the 12th International Workshop on Waldenström’s Macroglobulinemia.¹

At a median follow-up of 4.3 months (range, 0.3-21.3), the BTK degrader elicited an objective response rate (ORR) of 91% in efficacy-evaluable patients (n = 21). Among responders, 14% experienced a very good partial response, 67% had a partial response, and 10%, had a minor response. Five percent of patients had stable disease and 5% discontinued treatment before the first assessment. The major response rate achieved with BGB-16673 was 81% and the disease control rate was 95%. The time to first response was 1.0 month (range, 0.9-3.7).

Notably, responses were observed when the agent was given at the lowest dose of 100 mg (n = 4/4) and in those who had prior exposure to a covalent BTK inhibitor (n = 19/21) or a noncovalent BTK inhibitor (n = 3/3). Responses with the agent were also achieved irrespective of mutations in BTK (with, n = 5/5; without, n = 6/8; unknown, n = 8/8), MYD88 (with, n = 18/20; without, n = 1/1), and CXCR4 (with, n = 8/8; without, n = 11/13).

“With promising clinical activity of BGB-16672 in the treatment of relapsed/refractory Waldenström macroglobulinemia, enrollment for the CaDAnCe-101 study is ongoing,” John F. Seymour, MBBS, FRACP, PhD, of Peter MacCallum Cancer Centre, Royal Melbourne Hospital, and University of Melbourne, in Melbourne, Australia, and colleagues, noted in the presentation.

The open-label, dose-escalation and -expansion study enrolled adult patients with relapsed or refractory B-cell malignancies.² Those with Waldenström macroglobulinemia needed to have histological confirmation per International Workshops on Waldenström Macroglobulinemia–7 criteria, an ECOG performance status ranging from 0 to 2, and acceptable organ function.¹ Those in the United States and European Union only were also required to have previously received at least 2 therapies, including an anti-CD20 monoclonal antibody and a covalent BTK inhibitor.

For part 1a, the dose-escalation phase of the research, the trial utilized a Bayesian optimal interval design in which BGB-16673 was given at the following 6 dose levels: 50 mg, 100 mg, 200 mg, 350 mg, 500 mg, and 600 mg once daily as part of 28-day cycles in selected patients with relapsed/refractory B-cell malignancies. Patients could have had marginal zone lymphoma (MZL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia, diffuse large B-cell lymphoma (DLBCL), and those with Richter transformation.

Part 1b represents the safety expansion phase of the trial in patients with MZL, MCL, CLL/SLL, and Waldenström macroglobulinemia (n ≤ 120); and part 1c will evaluate additional safety expansion in those with MZL, Waldenström macroglobulinemia, Richter transformation, DLBCL, and FL (n ≤ 40). Parts 1a, 1b, and 1c are all seeking to determine the recommended phase 2 dose (RP2D) of the agent.

The primary objective for part 1 was to evaluate safety and tolerability of BGB-16673 and identify the maximum tolerated dose and the RP2D. Secondary objectives include pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.

As of May 24, 2024, a total of 22 patients with relapsed/refractory Waldenström macroglobulinemia were enrolled and received the agent at 100 mg (n = 4), 200 mg (n = 10), and 350 mg (n = 8). Seventy-seven percent of patients were still receiving treatment at data cutoff; the 5 patients who discontinued did so because of progressive disease (n = 2), withdrawal (n = 2), or investigator decision (n = 1).

The median patient age was 73 years (range, 56-81) and 55% were male. Regarding ECOG performance status, 50% had a status of 0 and 46% had a status of 1. Moreover, 91%, 38%, and 38% of patients had mutations present in MYD88, CXCR4, and BTK, respectively. The median hemoglobin level was 10.1 g/dL (range, 6.0-13.5) and the median neutrophil count was 2.8 10⁹/L (range, 0.2-7.4). Patients had received a median of 3.5 lines of therapy (range, 2-11), which could have included a covalent BTK inhibition (100%), chemotherapy (91%), a proteasome inhibitor (32%), a BCL-2 inhibitor (18%), covalent BTK plus BCL-2 inhibitors (18%), and noncovalent BTK inhibitors (14%). Most patients (82%) discontinued a prior BTK inhibitor because of disease progression.

“Responses continue to evolve; the median follow-up is 4.3 months,” and “updated data will be presented at future congresses,” the authors wrote in the presentation.

Regarding safety, no dose-limiting toxicities occurred. Any-grade treatment-emergent adverse effects (TEAEs) were reported in 96% of patients; they were related to treatment in 68% of patients, and grade 3 or higher in 46% of patients. Treatment-related grade 3 or higher AEs were reported in 27% of patients. Serious AEs occurred in 23% of patients and none were related to BGB-16673. One patient experienced an event that proved fatal; this patient was receiving the agent at 200 mg and experienced septic shock.

The most common TEAEs experienced with BGB-16673 were decreased neutrophil count or neutropenia (all grade, 32%; grade ≥3, 23%), contusion (23%; 0%), diarrhea (23%; 0%), anemia (18%; 9%), pyrexia (18%; 5%), increased amylase (18%; 0%), petechiae (18%; 0%), dizziness (18%; 0%), rash (18%; 0%), decreased platelet count or thrombocytopenia (14%; 9%), increased lipase (14%; 5%), fall (14%; 0%), and upper respiratory infection (14%; 0%). “No atrial fibrillation or hypertension have been reported so far,” the authors wrote.

TEAEs required dose interruptions for 18% of patients; no patients needed dose reduction. Moreover, no patients experienced toxicities that led to treatment discontinuation.

All patients experienced a numerical reduction from baseline in immunoglobulin, the study authors concluded.

Disclosures: Dr Seymour disclosed serving in an advisory role for AbbVie, AstraZeneca, BeiGene, BMS, Genor Bio, Gilead, Janssen, and Roche. Research funding was received from AbbVie, BMS, Janssen, and Roche. Dr Seymour serves on the speakers bureau for AbbVie, BMS, and Roche, and in a consultancy role for TG Therapeutics.

References

• Seymour JF, Cheah CY, Parrondo RD, et al. Preliminary efficacy and safety of the Bruton Tyrosine Kinase degrader BGB-16673 in patients with relapsed or refractory Waldenström macroglobulinemia: results from the phase 1 CaDAnCe-101 study. Presented at: 12th International Workshop on Waldenström’s Macroglobulinemia; October 17-19, 2024; Prague, Czech Republic. Accessed October 25, 2024. https://www.beigenemedical.com/CongressDocuments/Seymour_BGB-16673-CDAC-101_IWWM_Presentation_2024.pdf
• A dose-escalation and expansion study of BGB-16673 in participants with B-cell malignancies. ClinicalTrials.gov. Updated October 26, 2024. Accessed October 28, 2024. https://clinicaltrials.gov/study/NCT05006716