Preliminary efficacy and safety of the Bruton tyrosine kinase (BTK) degrader BGB16673 in patients with relapsed or refractory (R/R) indolent NHL: results from thephase 1 BGB-16673-101 studyAuthors: Chan Cheah,1 John F. Seymour,2 Masa Lasica,3 Herbert Eradat,4 Anna Maria Frustaci,5John N. Allan,6 Victor T.G. Lin,7 Judith Trotman,8 Ranjana Advani,9 Xiangmei Chen,10 Kunthel By,11Shannon Fabre,11 Jason C. Paik,11 Amit Agarwal,11 Constantine Tam12Affiliations: 1Sir Charles Gairdner Hospital and Pathwest Laboratory Medicine, Nedlands, WA,Australia; Medical School, University of Western Australia, Crawley, WA, Australia; Linear ClinicalResearch, Nedlands, WA, Australia; 2Peter MacCallum Cancer Centre, Royal Melbourne Hospital,and University of Melbourne, Melbourne, VIC, Australia; 3St. Vincent’s Hospital, Melbourne, Australia
4David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA; 5Ospedale

Niguarda, Milano, Italy; 6Weill Cornell Medicine, New York, NY, USA; 7Mary Bird Perkins Cancer
Center, Baton Rouge, LA; 8Concord Repatriation General Hospital, University of Sydney, Concord,NSW, Australia; 9Stanford Cancer Institute, Stanford, CA; 10BeiGene (Shanghai) Co, Ltd, Shanghai,China; 11BeiGene USA, Inc, San Mateo, CA, USA; 12Alfred Hospital and Monash University,Melbourne, VIC, Australia

Background: BTK inhibitors have significantly advanced the treatment of B-cellmalignancies; however, treatment resistance often emerges and is sometimes associatedwith emergence of BTK mutations. BGB-16673 is a heterobifunctional small molecule thatinduces BTK degradation via ubiquitination and was designed to avoid IMiD activity. In
preclinical models, BGB-16673 degraded wild-type BTK and known covalent andnoncovalent BTK inhibitor-resistant mutant proteins, leading to tumor regression. BGB-16673
is being assessed across B-cell malignancies, including follicular lymphoma (FL), marginalzone lymphoma (MZL), and Waldenstrom macroglobulinemia (WM).
Aims: Describe updated results from patients with FL, MZL, and WM enrolled in the phase 1
portion of the open-label, first-in-human trial, BGB-16673-101 (NCT05006716).
Methods: Eligible patients must have R/R NHL (≥2 prior therapies), an ECOG performancestatus of 0-2, and adequate end-organ function. In the US and EU, patients with WM andMZL must have previously received a CD20 antibody; US patients with WM must havepreviously received a covalent BTK inhibitor (cBTKi). BGB-16673 was dosed once daily orally
in 28-day cycles. Dose escalation using a Bayesian optimal interval design with 6 dose levels
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(50-600 mg once daily) was planned. Primary objectives were to assess safety/tolerability
and establish the maximum tolerated dose (MTD) and recommended phase 2 dose. Safety
was assessed per CTCAE v5.0. Dose-limiting toxicities (DLTs) were assessed in the first 4weeks (cycle 1). Response was assessed per 2014 Lugano Classification or IWWM
consensus criteria, with first assessment after 4 weeks (WM) or 12 weeks (FL and MZL) oftreatment.
Results: As of 09 November 2023, 24 patients with FL (n=7), MZL (n=4), and WM (n=13)
were enrolled (median age, 72 years [range, 56-79]). Twenty-three patients have beentreated (100 mg [n=5]; 200 mg, [n=11]; 350 mg, [n=7]) and 1 patient with WM had not yet
started treatment. For treated patients, the median number of prior therapies was 4 (FL andWM) and 2 (MZL), including cBTKis (14/23), BCL2 inhibitors (5/23), and noncovalent BTKis(ncBTKis; 3/23). The median follow-up times were 6.6, 5.9, and 1.9 months for FL, MZL, andWM, respectively. TEAEs occurring in >10% of patients were contusion (22%), fatigue (22%),amylase increased (17%), headache (13%), lipase increased (13%), neutropenia (13%), andupper respiratory tract infection (13%). Neutropenia was the only grade ≥3 event in >1 patient(n=2). No events of hypertension or atrial fibrillation occurred. One patient with WM (350 mg)
had a TEAE that led to treatment discontinuation (bronchopulmonary aspergillosis;
subsequent investigation showed presence prior to treatment). One patient with WM (200mg) experienced a TEAE that led to death (septic shock, in the context of diseaseprogression, not related to treatment). No patients had a TEAE that led to dose reduction. NoDLTs occurred. Seventeen of 23 patients remain on therapy (discontinuations: 4 progressivedisease, 1 AE, 1 patient withdrawal). For 14 response-evaluable patients, the ORR was 50%(2/4) for FL, 100% (2/2) for MZL, and 75% (6/8) for WM, which included patients who
received a cBTKi (n=7; 6 WM, 1 MZL) and an ncBTKi (n=2).
Summary/Conclusion: Preliminary data from this ongoing, first-in-human study of the novel
BTK degrader BGB-16673 demonstrate a tolerable safety profile and antitumor activity inheavily pretreated patients with NHL, including those with BTK inhibitor-resistant disease.

Figure. Treatment duration and response assessment in patients with FL/MZL/WM

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