BTK Degrader BGB-16673 Shows Durable Efficacy in Relapsed or Refractory (R/R) Indolent NHL

Bruton tyrosine kinase (BTK) inhibitors have significantly advanced the treatment of B-cell malignancies but are limited by disease progression linked to BTK mutations, according to Constantine S. Tam, MD, MBBS, and colleagues. BGB-16673, a bivalent small molecule, addresses this challenge by inducing BTK degradation through ubiquitination and proteasomal destruction. In preclinical models, it has shown efficacy against both wild-type and mutant BTK forms resistant to existing inhibitors. The CaDAnCe-101 trial (NCT05006716), a phase 1/2 first-in-human study, evaluates the safety, tolerability, and efficacy of BGB-16673 in patients with relapsed/refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL).

Dr. Tam’s team examined 20 patients with FL (n=8) or MZL (n=12) who received BGB-16673 across three dose levels (100 mg, 200 mg, and 350 mg) in 28-day cycles. Patients had a median age of 68 years for FL and 76 years for MZL, with extensive prior treatments (median 4.5 for FL, 3.0 for MZL). The median follow-up durations were 11.1 months for FL and 3.2 months for MZL. No dose-limiting toxicities (DLTs) occurred, and the maximum tolerated dose (MTD) was not reached.

Treatment-emergent adverse events (TEAEs) were reported in 80% of patients, though grade ≥3 TEAEs were relatively infrequent (25%). Common TEAEs included upper respiratory tract infections, fatigue, and contusions, primarily of low grade. Serious adverse events were rare and manageable, with no deaths attributed to TEAEs. Importantly, no TEAEs led to dose reductions, although one patient discontinued treatment due to disease-related pleural effusion.

According to the study authors, the overall response rate was encouraging, with 50% of evaluable FL patients and 67% of MZL patients achieving partial responses or better. Complete responses were observed in one FL patient (time to CR: 3.3 months) and two MZL patients (time to CR: 3.6 and 13.7 months). Responses were durable, with six of eight ongoing at the data cutoff. Importantly, BGB-16673 demonstrated activity in patients previously treated with covalent or noncovalent BTK inhibitors.

This study highlights the potential of BGB-16673 as a novel therapeutic option for heavily pretreated FL and MZL patients, including those with prior BTK inhibitor exposure.

“Emerging data from this ongoing, first-in-human study demonstrate that the novel BTK degrader BGB-16673 has a tolerable safety profile and shows clinically meaningful, durable responses in heavily pretreated patients with FL and MZL, including those with prior BTK inhibitor treatment,” the research team concluded.

Tam CS, Frustaci AM, Bijou F, et al. Preliminary Efficacy and Safety of the Bruton Tyrosine Kinase Degrader BGB-16673 in Patients with Relapsed or Refractory (R/R) Indolent NHL: Results from the Phase 1 CaDAnCe-101 Study. Abstract 1649. Presented at ASH Annual Meeting. San Diego, CA.