Introduction: BTK inhibitors (BTKis) are approved for chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Disease that progresses on BTKis often has BTK mutations that lead to treatment (tx) resistance; novel BTK-targeting agents that overcome BTKi resistance are needed. BGB-16673 is a heterobifunctional small molecule that binds to BTK and E3 ligase, resulting in BTK degradation via ubiquitination. In preclinical models, BGB-16673 degraded wild-type (WT) BTK and known covalent and noncovalent BTKi-resistant mutant proteins, leading to tumor suppression.

Methods: Pts with R/R CLL, WM, MCL, MZL, non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or Richter transformation (RT) were eligible for this open-label, first-in-human, phase 1 trial (BGB-16673-101; NCT05006716). Pts must have received ≥2 prior therapies (≥1 for RT) and have an ECOG performance status of 0-2 and adequate end-organ function. In the US and Australia, pts must have received a covalent BTKi (cBTKi) if approved for their disease. BGB-16673 was dosed daily by mouth in 28-day cycles. Escalation using a Bayesian optimal interval design with 6 dose levels (50-600 mg once daily) is planned. Primary objectives are to assess safety/tolerability and establish the maximum tolerated dose (MTD) and recommended phase 2 dose. Key secondary objectives are to assess pharmacokinetics, pharmacodynamics (PD), and preliminary antitumor activity. Safety was assessed according to CTCAE v5.0 (all pts) and iwCLL hematologic toxicity criteria (pts with CLL). Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks. Response was assessed per Lugano criteria for all except CLL (iwCLL 2018 criteria) and WM (iwWM-6 criteria).

Results: As of May 26, 2023, 26 pts (10 CLL, 4 MCL, 2 MZL, 4 WM, 4 FL, 1 DLBCL, 1 RT) were enrolled at 5 dose levels (50 mg, 4; 100 mg, 9; 200 mg, 9; 350 mg, 3; 500 mg, 1). Median age was 70.5 y (range, 25-83). Median number of prior therapies was 3.5 (range, 2-9), including cBTKis (n=21; 10 CLL, 4 WM, 4 MCL, 1 MZL, 1 RT, 1 DLBCL), BCL2 inhibitors (n=12; 9 CLL, 2 WM, 1 RT), and noncovalent BTKis (ncBTKis; n=4; 2 CLL, 1 WM, 1 FL). In CLL, del17p/ TP53 mutation (n=8) and unmutated IGHV (n=7) were frequent.

Median follow-up was 3.5 mo (range, 0.2-13.9). MTD was not reached. Treatment-emergent AEs (TEAEs) were reported by 88.5% of pts (grade [gr] ≥3, 46.2%; serious, 38.5%). The most common TEAEs were contusion (30.8%; no gr ≥3), pyrexia (23.1%; no gr ≥3), neutropenia/neutrophil count decreased (23.1%; gr ≥3, 15.4%), and lipase increased (23.1%; gr ≥3, 3.8%; all transient and asymptomatic). No hypertension or atrial fibrillation was observed. One pt died from sepsis with possible disease progression. No discontinuations due to AEs occurred. Two pts had dose reductions due to TEAEs (gr 3 hematuria with urinary tract infection and recurrent urothelial carcinoma and gr 2 arthralgia). One DLT occurred in 1 pt at 200 mg (gr 3 maculopapular rash on day 27; after 5-day dose hold, assigned dose was recommenced with persistent gr 1 rash).

BGB-16673 exposure increased in a dose-dependent manner. At steady state with doses ≥50 mg daily, BGB-16673 exposure exceeded the calculated half maximal degradation concentration for WT and cysteine 481-mutated BTK for the dosing interval. Preliminary PD data showed deep, sustained reductions in BTK protein levels in peripheral blood and tumor tissue, even at the lowest dose. Most CLL pts experienced lymphocytosis during the first 3 cycles of tx. Twenty of 26 pts (77%) remain on therapy (discontinuation: 4 progressive disease, 2 withdrawal). Of 18 response-evaluable pts, 12 (67%) responded (5/6 CLL, 1/3 MCL, 2/2 MZL, 3/4 WM, 1/2 FL, 0/1 DLBCL; 1 CR in MCL, all others had PR; Figure), including pts who received a cBTKi (n=10) and an ncBTKi (n=2). Responses started at the lowest dose level. All responders remain in response, the longest responder remaining on tx for 60 weeks.

Conclusions: Preliminary data from this ongoing, first-in-human study of the novel BTK degrader BGB-16673 demonstrate a tolerable safety profile and clinical responses in heavily pretreated pts with B-cell malignancies, including those with BTKi-resistant disease. Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.

Seymour:F. Hoffmann-La Roche Ltd: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Consultancy; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genor Bio: Membership on an entity's Board of Directors or advisory committees. Cheah:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenecca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; AbbVie: Research Funding; Menarini: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Daizai: Consultancy, Honoraria. Thompson:Curio Science: Honoraria; Massachusetts Medical Society: Honoraria; VJHemOnc: Honoraria; Loxo Oncology at Lilly: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Dava Oncology: Other: Travel ; Intellisphere LLC: Honoraria; Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH): Honoraria; MJH Life Sciences: Honoraria; Genmab: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Nurix Therapeutics: Research Funding; Beigene: Research Funding. Lasica:Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; JanssenJanssen: Other: Education. Wang:Studio ER Congressi: Honoraria; WebMD: Honoraria; Celgene: Other: Travel, Research Funding; Juno Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Scripps: Honoraria; Practice Point Communications (PPC): Honoraria; OncLive: Honoraria; Physicians Education Resources (PER): Honoraria, Other: Travel; Oncology Specialty Group: Honoraria; Moffit Cancer Center: Honoraria; NIH: Honoraria; Nurix: Honoraria; MJH Life Sciences: Honoraria; MD Education: Honoraria; Meeting Minds Experts: Honoraria; Medscape: Honoraria; IDEOlogy Health: Honoraria; i3Health: Honoraria; Eli Lilly and Company: Consultancy, Research Funding; Merck: Consultancy, Honoraria; Miltenyi Biomedicine: Consultancy; Milken Institute: Consultancy; Leukemia & Lymphoma Society: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel, Research Funding; InnoCare: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; Deciphera: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; BioInvent: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Be Biopharma: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, Research Funding; Amphista Therapeutics Limited: Consultancy; ADC Therapeutics America: Consultancy; Acerta Pharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Oncternal: Consultancy, Research Funding; Parexel: Consultancy; Genmab: Honoraria, Research Funding; Eastern Virginia Medical School: Honoraria; Dava Oncology: Honoraria, Other: Travel; CAHON: Honoraria; VelosBio: Consultancy, Research Funding; Bantam Pharmaceutical: Honoraria; Pepromene Bio: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Research Funding; Molecular Templates: Research Funding; Vincerx: Research Funding; Anticancer Association: Honoraria; BGICS: Honoraria; Clinical Care Options: Honoraria; Epizyme: Consultancy, Honoraria; Hebei Cancer Prevention Federation: Honoraria; Imedex: Honoraria; TS Oncology: Honoraria; Mumbai Hematology Group: Honoraria; OMI: Honoraria; Pharmacyclics: Honoraria; Physicians Education Resources: Honoraria; Practice Point Communications: Honoraria; CSTone: Consultancy. Kumar:BMS: Current equity holder in publicly-traded company; Merck: Divested equity in a private or publicly-traded company in the past 24 months. Trotman:BeiGene: Research Funding; BMS: Research Funding; Roche: Research Funding; Cellectar: Research Funding; Janssen: Research Funding. Ding:DTRM: Research Funding; AbbVie: Research Funding; AstraZeneca: Research Funding; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Honoraria; MEI pharama: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. By:BeiGene: Current Employment. Tariq:BeiGene: Current Employment; BeiGene: Current equity holder in publicly-traded company. Chen:BeiGene: Current Employment; BeiGene: Current equity holder in publicly-traded company. Fabre:BeiGene: Current Employment, Current equity holder in publicly-traded company; BMS: Ended employment in the past 24 months. Paik:BeiGene: Current Employment; BeiGene: Current equity holder in publicly-traded company. Agarwal:BeiGene: Current equity holder in publicly-traded company; BeiGene: Current Employment. Tam:Roche: Honoraria; Novartis: Honoraria; LOXO: Honoraria; Beigene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding.

Figure 1
Figure 1
View largeDownload slide
This content is only available as a PDF.
2023
Sign in via your Institution