BGB-16673 Is Safe, Highly Active Regardless of Baseline Mutations or High-Risk Features in R/R CLL/SLL

The novel BTK degrader BGB-16673 was well tolerated and had significant antitumor activity regardless of BTK mutation status and prior exposure to BTK or BCL-2 inhibitors among heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to updated findings from the phase 1/2 CaDAnCe-101 trial (NCT05006716).¹

Results presented during the 2025 ASH Annual Meeting and Exposition showed that BGB-16673 elicited high overall response rates (ORRs) across all 5 dose levels. In the overall patient population (n = 68), the ORR rate was 85.3%; the rates of complete response (CR)/CR with incomplete marrow recovery (CRi) rate, partial response (PR), and PR lymphocytosis were 2.9%, 72.1%, and 10.3% Stable disease (SD) was achieved by 7.4% of patients, 2.9% experienced disease progression (PD), and 4.4% of patients had discontinued treatment prior to their first assessment.

Investigators noted that BGB-16673 was particularly effective at the 200-mg dose level, with an ORR of 94.4%. This comprised CR/CRi, PR, PR-L, and PD rates of 5.6%, 66.7%, 22.2%, and 5.6%. No patients achieved stable disease or discontinued treatment prior to their first assessment. Based on these data, the 200-mg dose was selected for further investigation in part 2.

Regarding safety, at a median follow-up of 19.8 months (range, 0.3-34.0+), 95.6% of patients experienced any treatment-emergent adverse effects (TEAEs), 76.5% of which were treatment-related. Grade 3 or higher AEs were reported in 61.8% of patients, 33.8% of which were treatment related.Serious TEAEs occurred in 48.5% of patients, 13.2% of which were treatment related. TEAEs led to death or treatment discontinuation in 7.4% and 17.6% of patients, respectively. No patients experienced treatment-related AEs (TRAEs) leading to death, and 3 patients (4.4%) experienced TRAEs leading to discontinuation.

“We also observed sustained disease control, [as evidenced by] an 18-month progression-free survival [PFS] rate of 65.9% with a median follow-up of 19.8 months, and over half of patients remain on treatment [at the time of this analysis],” Inhye Ahn, MD, the associate director of the CLL Center and a member of the faculty of medicine at Dana-Farber Cancer Institute in Boston, Massachusetts, stated in her oral presentation of the data. “We also observed promising single-agent activity with BGB-16673 in patients with Richter transformation.

What efficacy and safety data have already been reported with BGB-16673?

BGB-16673 is an oral protein degrader that leverages the cell proteasome pathway to tag BTK for degradation, thereby blocking BTK signaling and leading to tumor regression.

The initial readout of data from CaDAnCe-101 in 2023 showed that BGB-16673 was associated with BTK protein level reductions in the peripheral blood and tumor tissue.² Safety and efficacy data from the study were subsequently presented at the 2025 EHA Congress.³

At a median follow-up of 15.6 months (range, 0.3-30.6+), patients with relapsed/refractory CLL/SLL (n = 66), who received the 200-mg dose of BGB-16673 achieved an ORR of 93.8%, including 1 CR, 12 PRs, and 2 PRs with lymphocytosis. The 12-month PFS rate was 77.4%. (95% CI, 63.1%-86.8%). In terms of safety, 95.5% of patients experienced any-grade TEAEs, 74.2% of which were treatment-related and 60.6% of which were grade 3 or greater.

How was CaDAnCe-101 designed?

CaDAnCe-101 is an open-label, dose-escalation/-expansion phase 1/2 study enrolling patients with select relapsed/refractory B-cell malignancies. Part 1 of the study comprises 6 parts, including a dose-escalation portion (phase 1a), a safety-expansion cohort (phase 1b), and an additional safety expansion cohort in Japan only (phase 1e).

To be eligible for enrollment for the CLL/SLL cohort, patients must meet the International Workshop CLL 2018 criteria for treatment; have previously received 2 or more therapies, including a covalent BTK inhibitor if approved; have an ECOG performance status (PS) of 0 to 2 (0 to 1 in the European Union); and display adequate organ function.

Phase 1a will include no more than 72 patients with marginal zone lymphoma (MZL), follicular lymphoma (FL), mantle cell lymphoma (MCL), CLL/SLL, Waldenström macroglobulinemia (WM), diffuse large B-cell lymphoma, and Richter transformation (RT). These patients receive oral BGB-16673 at escalating doses of 50 mg, 100 mg, 200 mg, 350 mg, 500 mg, and 600 mg once daily in 28-day cycles. Phase 1b includes up to 120 patients with MZL, MCL, CLL/SLL, and WM. In phase 1c, between 6 to 9 patients with MZL, FL, MCL, CLL/SLL, and WM will be enrolled.

The primary end points in part 1 are safety and tolerability, as well as identification of the maximum tolerated dose and recommended dose for expansion (RDFE). Secondary end points include pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.

What should be known about the baseline characteristics of patients in CaDAnCe-101?

As of the data cutoff date of August 22, 2025, 68 patients were enrolled onto part 1. The median age was 70 years (range, 47-91), and most patients were male (69.1%) and had an ECOG PS of 0 (55.9%).

CLL/SLL risk characteristics present at study entry included Binet stage C disease (45.3%; n = 29/64 patients with known status), unmutated IGHV (77.6%; n = 38/49), 17p deletions del(17p) and/or TP53 mutations (67.6%; n = 46/68), and a complex karyotype (50.0%; n = 22/44). BTK mutations, PLCG2 mutations, and both BTK and PLCG2 mutations were present in 39.4%, 15.2%, and 7.6% of patients with known mutation status (n = 66), respectively.

The median number of prior lines of therapy was 4 (range, 2-10), and prior regimens included chemotherapy (72.1%), covalent BTK inhibitors (94.1%), noncovalent BTK inhibitors (20.6%), BCL-2 inhibitors (82.4%), both a covalent BTK and BCL-2 inhibitor (64.7%; double-exposed) and a covalent BTK, noncovalent BTK and BCL-2 inhibitor (17.6%; triple-exposed). Notably, 89.1% of patients previously discontinued treatment with a BTK inhibitor due to PD.

What additional efficacy data were reported during this year’s ASH Annual Meeting?

In the total population, the median time to first response was 2.8 months (range, 2.0-19.4), the median time to best response was 4.2 months (range, 2.0-19.4), and the median duration of exposure was 13.6 months (range, 0.2-30.3). Corresponding durations in the 200 mg cohort were 2.9 months (range, 2.6-6.3), 3.0 months (range, 2.6-13.8), and 14.4 (range, 2.9-30.3).

Responses were also evaluated according to prior treatment status and baseline genetic characteristics. In patients who were double-exposed, the ORR was 93.2%; the ORR was 75.0% in those with triple exposure. Respective ORRs for patients with exposure to 6 or more prior lines, a del(17p) and/or TP53 mutation, complex karyotype, BTK mutations, and PLCG2 mutations were 81.3%, 80.4%, 72.7%, 76.9%, and 90.0%.

“In an exploratory analysis of genetic subgroups, we also observed comparable PFS rates regardless of baseline BTK mutation [status],” Ahne noted in the presentation.

What else did the study reveal about the safety and pharmacokinetic profile of BGB-16673?

No new toxicities were identified in this analysis, Ahn noted. The most common TEAEs with BGB-16673 were fatigue (36.8%) and contusion (30.9%). Seventeen patients (25.0%) experienced grade 3 or higher neutropenia, and 16 (23.5%) had grade 2 or higher neutropenia at baseline. One patient experienced neutropenic fever. Three patients had atrial fibrillation (grade 1, n = 1; grade 2, n = 2); all events were transient in the context of infection and PD, and deemed unrelated to treatment. Treatment-related major hemorrhage occurred in 2 patients.

Among responders, BGB-16673 was also associated with rapid and significant cytopenia improvements, including increases in median platelet counts (baseline, 67.5 x 10⁹/L; week 9, day 1, 136.0 x 10⁹/L, neutrophil counts (1.1 x 10⁹/L; 2.1 x 10⁹/L), and hemoglobin levels (99.0 g/L; 111.0 g/L).

Taken together, Ahn and colleagues feel that these findings support the continued development of BGB-16673 in relapsed/refractory B-cell malignancies, particularly CLL/SLL. “[BGB-16673] is being evaluated in ongoing phase 2 and phase 3 studies in relapsed/refractory CLL, and the current study is also ongoing at over 100 sites across the world,” Ahn concluded.

Disclosures: Ahn reported serving as a consultant for AstraZeneca, BeiOne Medicines Ltd, and Eli Lilly; she also received research funding from Eli Lilly.

References

1. Ahn I, Parrondo R, Thompson M, et al. Updated efficacy and safety results of the bruton tyrosine kinase (BTK) degrader BGB-16673 in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) from the ongoing phase 1 CaDAnCe-101 study. Blood. 2025;146(suppl 1):85. doi:10.1182/blood-2025-85
2. First results from a phase 1, first-in-human study of the Bruton’s tyrosine kinase (BTK) degrader BGB-16673 in patients (pts) with relapsed or refractory (R/R) B-cell malignancies (BGB-16673-101). Blood. 2023;142(suppl 1):4401. doi:10.1182/blood-2023-180109
3. Scarfò L, Parrondo RD, Thompson MC, et al. Updated efficacy and safety of the Bruton tyrosine kinase (BTK) degrader BGB-16673 in patients (pts) with relapsed or refractory (R/R) CLL/SLL: results from the ongoing phase (ph) 1 CADANCE-101 study. Presented at: European Hematology Association 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract S158.