Preliminary efficacy and safety of the Bruton tyrosine kinase (BTK) degrader BGB16673 in patients with relapsed or refractory (R/R) CLL/SLL: Results from the phase 1BGB-16673-101 study
Authors: Ricardo Parrondo,1 Meghan C. Thompson,2 Anna Maria Frustaci,3 John N. Allan,4Paolo Ghia,5 Igori Vinogradov,6 Constantine Tam,7 Judith Trotman,8 Michael Choi,9 Xiangmei
Chen,10 Kunthel By,11 Shannon Fabre,11 Jason C. Paik,11 Amit Agarwal,11 John F.
Seymour12,13Affiliations: 1Mayo Clinic - Jacksonville, Jacksonville, FL, USA; 2Memorial Sloan Kettering Cancer
Center, New York, NY, USA; 3Ospedale Niguarda, Milano, Italy; 4Weill Cornell Medicine, New York,NY, USA; 5Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy; 6The
Institute of Oncology, ARENSIA EXPLORATORY Medicine, Düsseldorf, Germany; 7Alfred Hospitaland Monash University, Melbourne, VIC, Australia; 8Concord Repatriation General Hospital, Universityof Sydney, Concord, NSW, Australia; 9Moores Cancer Center, University of California San Diego, LaJolla, CA, USA; 10BeiGene (Shanghai) Co, Ltd, Shanghai, China; 11BeiGene USA, Inc, San Mateo,CA, USA; 12Peter MacCallum Cancer Centre, Royal Melbourne Hospital; 13University of Melbourne,Melbourne, VIC, Australia

Background: BTK inhibitors are approved for CLL, but intolerability and treatment resistancecan limit their use. There is a clinical need for novel CLL treatments following progression
after treatment with current standard of care therapies, including BTK inhibitors. BGB-16673
is a heterobifunctional small molecule that induces BTK degradation via ubiquitination andwas designed to avoid IMiD activity. In preclinical models, BGB-16673 degraded wild-type
BTK and known covalent and noncovalent BTK inhibitor-resistant mutant proteins, leading totumor regression. BGB-16673 is currently being evaluated in phase 1 studies.
Aims: Describe updated results from patients with CLL/SLL enrolled in the phase 1 portion of
the open-label, first-in-human, BGB-16673-101 (NCT05006716) study.
Methods: Eligible patients must have R/R CLL/SLL (≥2 prior therapies), an ECOG
performance status of 0-2, and adequate end-organ function. In the US, EU, and Australia,
patients must have previously received a covalent BTK inhibitor (cBTKi). BGB-16673 wasdosed once daily orally in 28-day cycles. Dose escalation using a Bayesian optimal interval
design with 6 dose levels (50-600 mg once daily) was planned. Primary objectives were toassess safety/tolerability and establish the maximum tolerated dose (MTD) andEHA 2024

recommended phase 2 dose. Safety was assessed per CTCAE v5.0 and iwCLL hematologic
toxicity criteria. Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks (cycle 1).
Response was assessed per iwCLL 2018 criteria (or Cheson et al, 2014 for SLL), with firstassessment after 12 weeks of treatment.
Results: As of 09 November 2023, 42 patients with CLL were enrolled (median age, 70years [range, 50-91]) and 39 were treated (50 mg [n=1]; 100 mg [n=5]; 200 mg, [n=15]; 350
mg, [n=14]; 500 mg, [n=4]). For treated patients, the median number of prior therapies was 4(range, 2-8), including cBTKis (n=37; 95%), BCL2 inhibitors (n=34; 87%), and noncovalent
BTK inhibitors (ncBTKis; n=10; 26%). Of tested patients, 54% (20/37) had del(17p) and/or
TP53 mutation, 87% (27/31) had unmutated IGHV, and 43% (12/28) had ≥3 karyotypicabnormalities. The median follow-up time was 3.3 months (range, 0.1-16.7). One DLT
occurred in 1 patient at 200 mg (gr 3 maculopapular rash on day 27; after 5-day dose hold,assigned dose was reinitiated with persistent gr 1 rash). MTD was not reached. The mostcommon TEAEs were contusion (31%; no gr ≥3), fatigue (31%; no gr ≥3), diarrhea (26%; nogr ≥3), and neutropenia (23%; gr ≥3, 18%). One patient (500 mg) had a TEAE of gr 3
hypertension. No atrial fibrillation was observed. Two patients had TEAEs that led to death(septic shock and pneumonia); neither was considered related to treatment. Two additional
patients had TEAEs that led to treatment discontinuation (subdural hemorrhage and thyroidcancer). One patient had a dose reduction due to gr 2 arthralgia. Thirty-five of 39 patients(90%) remain on therapy (4 discontinuations: progressive disease [n=1], AEs [n=3]). For 24response-evaluable patients, the ORR was 67%, with all but 1 response ongoing. Responses
were seen at the lowest dose, in patients previously treated with a cBTKi (n=16) and an
ncBTKi (n=2), and in patients with and without BTK mutation (Figure).
Summary/Conclusion: Emerging 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 CLL/SLL, including those with BTK inhibitor-resistantmutations.

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Figure. Treatment duration and response assessment in patients with CLL/SLL

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