Dr Scarfò on Early Safety Data With BGB-16673 in R/R CLL/SLL

“The safety profile appears [to be] tolerable and manageable according to what we know about previous [BTK-targeted] agents.”

Lydia Scarfò, MD, an assistant professor of internal medicine and a consultant hematologist for the Strategic Research Program on CLL at the Università Vita-Salute San Raffaele, outlined early safety observations from the ongoing phase 1 CADANCE-101 trial (NCT05006716) evaluating the BTK degrader BGB-16673 in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The first-in-human dose-escalation and expansion study was designed to characterize the safety, tolerability, and preliminary activity of BGB-16673, particularly in heavily pretreated patients, including those previously exposed to covalent BTK inhibitors.

Scarfò noted that no unexpected toxicities have been identified to date compared with the established safety spectrum of BTK-targeting agents. The most common grade 3 or higher adverse effect (AE) among all patients who received BGB-16673 (n = 66) was neutropenia, which was generally manageable with granulocyte colony-stimulating factor support. Cardiac AEs included 2 cases of atrial fibrillation: 1 in a patient with a prior history of the arrhythmia and another in the setting of disease progression with concurrent infection. Additionally, 2 major hemorrhagic effects were reported, representing clinically relevant bleeding episodes that required standard supportive intervention.

Scarfò emphasized that the overall tolerability of BGB-16673 appeared to be consistent with that of covalent BTK inhibitors such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), with the observed AEs aligning with expected patterns for BTK-directed therapy. Importantly, the frequency and severity of these AEs suggested that treatment can be delivered with appropriate monitoring and supportive measures, even in a high-risk, heavily pretreated patient population.

BGB-16673 functions through targeted degradation of BTK, offering a mechanistically distinct approach that may address resistance mutations limiting the efficacy of covalent inhibitors. Within CADANCE-101, multiple dose levels were evaluated to establish the recommended phase 2 dose; early signals of antitumor activity were also assessed. Although efficacy data were not the focus of Scarfò’s remarks, she underscored the importance of these initial safety findings in guiding the drug’s continued development.

Scarfò concluded that the preliminary safety results from CADANCE-101 support ongoing investigation of BGB-16673 in relapsed/refractory CLL/SLL. Continued accrual and follow-up will be necessary to refine the understanding of its hematologic, cardiac, and bleeding risk profiles, as well as to determine whether the drug’s targeted degradation mechanism translates into meaningful clinical benefit for patients with limited treatment options.