BGB-16673 Is Safe, Elicits Nearly 85% ORR in Relapsed/Refractory CLL/SLL

BGB-16673 in CLL/SLL | Image
Credit: © Om.Nom.Nom -
stock.adobe.com

BGB-16673 was found to be safe, well tolerated, and demonstrated encouraging antitumor activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), with responses observed regardless of baseline mutations and high-risk features, according to findings from the phase 1/2 CaDAnCe-101 trial (NCT05006716) that were presented during the 2025 European Hematology Association Congress.1

Results showed that, at a median follow-up in 66 safety-evaluable patients of 15.6 months (range, 0.3-30.6+), treatment-emergent adverse events (TEAEs) occurred in most (95.5%), were treatment-related in 74.2% of patients and grade 3 or higher in 60.8%; treatment-related TEAEs that were grade 3 or higher occurred in 30.3% of patients. Serious adverse events were reported in 45.5% of patients, 12.1% of which were related to treatment. Four patients had TEAEs that led to death, but none were related to therapy. Nine patients discontinued BGB-16673, 2 of which were due to treatment-related TEAEs.

Of the 66 patients, the overall response rate (ORR) was 84.8%, which included a 4.5% complete response (CR)/CR with incomplete marrow recovery (CRi) rate, a 66.7% partial response (PR) rate, and a PR with lymphocytosis (PR-L) rate of 13.6%. A total of 7.6% of patients had stable disease (SD), 3.0% of patients had progressive disease (PD), and 4.5% had discontinued prior to their first assessment. At 1 year, the progression-free survival rate was 77.4% (95% CI, 63.1%-86.8%).

“The novel BTK degrader BGB-16673 was safe and well tolerated in this heavily pretreated population of patients with relapsed/refractory CLL and small lymphocytic lymphoma,” lead study author Lydia Scarfò, MD, a physician scientist at the B-cell Neoplasia Unit, and an assistant professor of at the Università Vita-Salute San Raffaele in Milano, Italy, said in an oral presentation of the data. “BGB-16673 shows significant antitumor activity regardless of disease features; patients carrying BTK mutations and those previously exposed to a covalent BTK inhibitor, noncovalent BTK inhibitor, and BCL2 inhibitor responded.”

Disease progression is common in patients with CLL/SLL who are undergoing treatment with BTK inhibitors, which can be caused by BTK resistance mutations, Scarfò explained. BGB-16673 is an oral protein degrader designed to block BTK signaling by tagging BTK for degradation through the cell proteasome pathway and thereby creating tumor regression.

First-in-human results from CaDAnCe-101 showed that BGB-16673 was associated with BTK protein level reductions in the peripheral blood and tumor tissue.2 At the EHA meeting, investigators reported on updated safety and efficacy results in patients with relapsed/refractory CLL/SLL.

In the open-label, dose-escalation/-expansion phase 1/2 study, up to 72 patients with select relapsed/refractory B-cell malignancies were first enrolled onto part 1a, which was the dose-escalation phase, and treated with BGB-16673 orally at doses of 50 mg, 100 mg, 200 mg, 350 mg, 500 mg, and 600 mg once daily in 28-day cycles. This portion included those with marginal zone lymphoma (MZL), follicular lymphoma, mantle cell lymphoma (MCL), CLL/SLL, Waldenström macroglobulinemia (WM), diffuse large B-cell lymphoma, and Richter’s transformation.

Part 1b is the safety expansion phase, comprising up to 120 patients with MZL, MCL, CLL/SLL, and WM. Data from both phase 1a and 1b were presented at the meeting.

To be eligible for enrollment for the CLL/SLL cohort, patients’ disease has to meet International Workshop CLL 2018 criteria for treatment, receive at least 2 prior therapies, including a covalent BTK inhibitor if approved for their disease, have an ECOG performance status between 0 and 2, and have adequate end-organ function.

The primary end point for part 1 of the trial, which also includes part 1c as an additional safety expansion for other disease cohorts, is safety and tolerability, maximum-tolerated dose, and recommended dose for expansion (RDFE). Secondary end points are pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.

Sixty-six patients were included in the analysis as of the data cutoff date, March 3, 2025. Regarding baseline characteristics, the median age was 70 years (range, 47-91), 68.2% of patients were male, and more than half had an ECOG performance status of 0 (57.6%). Risk characteristics at study entry were identified as Binet stage C (46.8%), unmutated IGHV (77.6%), 17p deletion (del[17p]) and/or TP53 (65.2%), and complex karyotype (≥3 abnormalities; 50.0%). Mutations present included BTK (38.1%), PLCG2 (15.9%), and a combination of both (7.9%).

The median number of prior therapies was 4 (range, 2-10), and previous treatments included chemotherapy (71.2%), a covalent BTK inhibitor (93.9%), a noncovalent BTK inhibitor (21.2%), a BCL2 inhibitor (81.8%), a covalent BTK inhibitor plus a BCL2 inhibitor (double exposure; 63.6%), and a covalent BTK inhibitor plus a noncovalent BTK inhibitor and a BCL2 inhibitor (triple exposure; 18.2%). A total of 88.7% of patients discontinued their prior BTK inhibitor due to disease progression.

“As you can see, this cohort is … for patients with unfavorable biological biomarkers,” Scarfòsaid. “This is a heavily pretreated patient population.”

Additional safety data showed that the most common TEAEs were fatigue (37%), contusion (30%), diarrhea (27%), neutropenia (5%; grade ≥3, 24%), and anemia (21%). Atrial fibrillation occurred in 2 patients; 1 was grade 1 due to infection, and 1 was grade 2 in the context of disease progression. Two patients experienced major hemorrhage, one was a grade 1 subarachnoid hemorrhage, and one was a grade 3 subdural hemorrhage. No new hemorrhage events have occurred since the last update, and there were no cases of pancreatitis, Scarfò said.

BGB-16673 was also associated with rapid and significant cytopenia improvement in responders in terms of median platelet counts (baseline, 67.0 x 109/L; week 9, day 1, 141.0 x 109/L, neutrophil counts (1.1 x 109/L; 2.1 x 109/L), and hemoglobin levels (99.0 g/L; 108.0 g/L).

Further efficacy data showed that 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 3.4 months (range, 2.0-19.4), and the median duration of exposure was 12.9 months (range, 0.2-29.6).

Scarfò zeroed in on the efficacy observed at the 200-mg dose level (n = 16), as this was the dose approved for the trial’s expansion phase. Here, the ORR was 93.8%, including a 6.3% CR/CRi rate, a 75.0% PR rate, and a 12.5% PR-L rate. One patient had disease progression. The median time to first response was 2.9 months (range, 2.6-8.3), the median time to best response was 3.4 months (range, 2.6-13.8), and the median duration of exposure was 16.2 months (range, 2.9-24.6).

The ORRs at the 50-mg (n = 1), 100-mg (n = 22), 350-mg (n = 15), and 500-mg (n = 12) dose levels were 100%, 81.8%, 73.3%, and 91.7%.

Responses were also recorded in high-risk subgroups. In patients with double exposure, the ORR was 90.5%; in those with triple exposure, the ORR was 75.0%. For those with del(17p) and/or TP53 mutation, complex karyotype, BTK mutations, and PLCG2 mutations, the ORRs were 81.4%, 72.7%, 75.0%, and 90.0%, respectively.

BGB-16673 is being evaluated in ongoing phase 2 and 3 trials in patients with relapsed/refractory CLL, Scarfò concluded.

Disclosures: Scarfò cited consulting or advisory roles with AbbVie, AstraZeneca, BeOne Medicines Ltd, Johnson & Johnson, Lilly, and Merck; and travel, accommodations, and expenses with AstraZeneca, BeOne Medicines Lts., and Johnson & Johnson.

References

1. 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.
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